用Affymetrix芯片筛选前列腺癌进展相关基因及功能初探
|
摘要
目的:近年来,我国男性前列腺癌发病率呈明显上升趋势,在欧美国家,前列腺癌已连续15年居男性恶性肿瘤发病率首位,其发病率超过肺癌,死亡率在男性恶性肿瘤中居第二位。前列腺癌是一个起源于多病灶和随机进展模式的异质性疾病。到目前为止对晚期和转移性尤其是激素非依赖型、放疗和化疗抵抗型前列腺癌依然没有治愈的疗法。研究前列腺癌进展相关的基因可能揭示其机制或找出分新的治疗靶标。本研究拟应用基因芯片、RT-PCR、Realtime-PCR、免疫组化等技术筛选出前列腺癌分子标志物候选基因、雄激素反应性基因及电离辐射诱导基因从而为探索前列腺癌的进展、雄激素非依赖的产生及辐射抗性相关的分子机制提供线索和依据,为临床诊断与治疗提供新的途径和可能。
结果:
1、应用Affymetrix公司的人类全基因组U133A芯片筛选出LNCaP与C4-2细胞系间差异表达的基因/转录本1053个;仅在LNCaP或C4-2中独立表达的基因/转录本分别是739和835个。根据差异倍数、染色体定位及研究进展确定104个候选基因/转录本进行RT-PCR验证获得76个基因/转录本与芯片结果一致的候选基因/转录本。
2、为了筛选出前列腺癌分子标志物候选基因,用RT-PCR检测上述76个候选差异基因/转录本在BPH1、LNCaP、C4-2、C4-2B、PC—3、DUl45、MCF-7、HEPG2、Hela、PC12、293T 11种细胞系中的表达谱。其中与前列腺癌进展程度呈正相关特异性较好的基因/转录本26个,与前列腺癌进展程度呈负相关特异性较好的基因/转录本17个。
3、为了筛选出雄激素调控基因,分别用1nM R1881和20μM Casodex处理LNCaP和C4-2,用RT-PCR检测76个候选基因/转录本在LNCaP、C4-2中处理前后的表达。其中在LNCaP细胞中R1881应答基因49个,Casodex应答基因42个。在C4-2细胞中R1881应答基因16个,Casodex应答基因15个。
4、为了探索适合电离辐射诱导基因筛选的遗传背景相同的辐射敏感性和辐射抗性细胞模型,分别用MTT、平板克隆形成、软琼脂克隆形成、周期变化检测了LNCaP和C4-2细胞系对5 Gy辐射的反应,结果证明了LNCaP的辐射敏感性和C4-2的辐射抗性。用Real-time PCR检测LNCaP和C4-2间p53、p21、Chek1、Chek2、Bcl-2、ATR、MRE11间表达的差异,结果:C4-2与LNCaP相比,p53、Chekl、Bcl-2、ATR、MRE11皆下调表达,同时检测了5、10Gy辐射后24小时LNCaP和C4-2上述7基因的表达差异,结果:LNCaP细胞5Gy辐射后24小时,p21上调表达,Chek1、Chek2、Bcl-2、MRE11下调表达,10Gy辐射后24小时,p21上调表达、Chek1、Chek2下调表达。C4-2细胞5Gy辐射后24小时,p53、p21、Chek1、Bcl-2、ATR、MRE11上调表达,10Gy辐射后24小时p21、Chek1、Bcl-2、ATR、MRE11上调表达。以上基因的差异表达是LNCaP辐射敏感性和C4-2辐射抗性的分子基础。
5、为了筛选出电离辐射诱导基因分别用0、2.5、5、10Gy ~(60)Coγ射线辐射处理LNCaP和C4-2细胞,用RT-PCR检测76个候选基因/转录本在上述处理后6、12、24、48、72小时的表达,其中在LNCaP细胞中辐射应答31个基因/转录本。
6、根据上述前列腺癌分子标志物、雄激素反应性基因及电离辐射诱导基因3方面的筛选结果综合考虑再次筛选出25个候选基因/转录本,用Real-timeRT-PCR再次验证它们在LNCaP与C4-2细胞间的差异表达。25个基因Real-time RT-PCR验证结果与芯片结果、RT-PCR验证结果一致。
7、为了验证上述筛出的前列腺癌分子标志物的可靠和实用性,用组织切片和组织芯片做免疫组化对AGR2和RPS4Y1临床表达进行了检测,其中AGR2胞浆阳性,其表达与恶性程度呈正相关,这与表达谱结果一致,RPS4Y1胞浆阳性,表达与恶性程度呈负相关,这与表达谱结果相符。该结果说明上述筛出的前列腺癌分子标志物候选基因有可能成为真正的前列腺癌分子标志物应用到临床。
8、为了探索上述筛出的雄激素调控基因及电离辐射诱导基因在前列腺癌雄激素非依赖和辐射抗性产生中扮演的角色,首先建立了ELF5-2b和ACADL的前列腺癌细胞系高表达稳定克隆并且得到了ELF5-2b和ACADL高表达的Real-time RT-PCR结果。接着,为了研究ELF5-2b和ACADL高表达对前列腺癌细胞生长、克隆形成能力、恶性进展、雄激素非依赖性、辐射抗性的影响,用MTT、平板克隆形成、软琼脂克隆形成、Casodex和辐射处理后MTT对此开展研究,结果:ELF5-2b的高表达促进了LNCaP和C4-2细胞的生长、克隆形成能力及恶性程度进展,提高了LNCaP细胞雄激素的非依赖性/Casodex耐受能力及抗辐射能力。ACADL的高表达促进了C4-2细胞的生长、克隆形成能力及恶性程度进展,提高了C4-2细胞雄激素的非依赖性/Casodex耐受能力及抗辐射能力。为了探讨ELF5-2b和ACADL高表达诱导或促进前列腺癌细胞雄激素非依赖性/Casodex耐受能力及辐射抗性进展的分子基础,用Real-timeRT-PCR分别检测了ELF5-2b和ACADL高表达对AR、PSA、p53、p21、Chek1、hek2、Bcl-2、ATR、MRE11表达的影响,结果发现ELF5-2b在LNCaP中高表达分别促进了PSA、p53、、ATR、MRE11的表达却抑制了Chek2的表达。ELF5-2b在C4-2中高表达分另0促进了AR、PSA、p21、Chek2、Bcl-2、ATR、MRE11的表达。ACADL在C4-2中高表达分别促进了p21、Bcl-2、ATR、MRE11的表达却抑制了PSA、Chek1的表达。ELF5-2b和ACADL高表达对这些分子表达的影响与ELF5-2b和ACADL高表达促进了前列腺癌细胞雄激素非依赖性/Casodex耐受能力及辐射抗性的进展是相吻合的。从而证实了上述筛出的雄激素调控基因及电离辐射诱导基因的可靠性,提示前列腺癌雄激素非依赖和辐射抗性产生可能与雄激素调控基因及电离辐射诱导基因密切相关。
结论:
1、LNCaP与C4-2间存在差异表达基因/转录本1023个:其中在C4-2中高表达的690个,低表达的333个,经RT-PCR验证的76个,经过Real time RT-PCR验证的25个。
2、筛选出分子标志物候选基因43个,受雄激素调控候选基因62个,受辐射诱导的候选基因31。
3、前列腺癌细胞系C4-2具有辐射抗性,LNCaP和C4-2具有相同的遗传背景,不但能够用作研究前列腺癌雄激素依赖和非依赖进展的细胞模型,还可以用作研究前列腺癌辐射敏感和抗性进展的细胞模型。
4、AGR2和RPS4Y1的表达与前列腺癌的进展程度分别呈正相关和负相关。
5、ELF5-2b的高表达能够促进前列腺癌细胞的生长、存活及恶性进展,诱导前列腺癌细胞雄激素非依赖性和辐射抗性的发生和进展而且具有前期阶段性。
6、ACADL的高表达能够促进前列腺癌细胞的生长、存活及恶性进展,诱导前列腺癌细胞雄激素非依赖性和辐射抗性的进展而且具有后期阶段性。
Objective:The incidence of prostate cancer has been increasing in recent years in Chinese males,In the western countries,the incidence of prostate cancer has been remained in the first position over lung cancer for continuous 15 yeas in male malignant carcinomas,and prostate cancer has become the second leading cause of death in male malignant carcinomas.Prostate cancer is a kind of alloplastic disease derived from multiple nidus and developing in random mode.Effective therapeutic methods remain to be found for the advanced prostate cancer with metastasis, especially the androgen-independent and chemical and radio therapy resistant prostate cancer.Our investigation was designed to find novel molecular biomarkers, androgen-responsive genes and radiation induced genes using Cdna microarray, RT-PCR,Real time PCR and immunohistochemistry methods to provide clues and foundation for exploring the molocular mechanism mediating prostate cancer development to androgen-independence and radiation resistence and provide novel insight for clinical diagnosis and therapy.
Methods and Results:
1.1053 genes/transcripts were screened out to be differently expressed in LNCaP and C4-2 using U133A microarray chip from Affymetrix company.739 and 835 genes/transcripts were screened out to be expressed solely in LNCaP and C4-2 respectively.104 genes/transcripts were selected and 76 genes/transcripts differential expression were confirmed to be consistent with microarray results using RT-PCR.
2.To screen out the molecular biomarker of PCa,RT-PCR was performed to examine the expression pattern of the 76 genes described above in BPH1、LNCaP、C4-2、C4-2B、PC-3、DU145、MCF-7、HEPG2、Hela、PC12、293T cell lines.26 genes expression were screened out to be positively associated with prostate cancer development and prostate tissue specific.17 genes expression were found out to be negatively associated with prostate cancer progression and possess prostate tissue specific characteristic.
3.To screen out androgen responsive genes,1nM R1881 and 20μM Casodex were used to treat LNCaP and C4-2.RT-PCR were performed to examine the androgen responsive characteristics in the 76 genes described above.As the result,49 R1881 responsive genes were screened out and 42 genes were found to be responsive to Casodex in LNCaP;In C4-2 cell,16 genes were found to be responsive to R1881 and 15 responsive to Casodex.
4.To investigate whether LNCaP and C4-2 are suitable to be radiation sensitive/resistant model cell lines for screening the radiation induced genes,MTT, soft agar colony formation and cell cycle assays were performed to detect the 5 Gy radiation response in LNCaP and C4-2 respectively.As the result,LNCaP and C4-2 were found to be radiation sensitive and resistant cell lines respectively. Real-time PCR were performed to examine the differential expression of p53、p21、Chek1、Chek2、Bcl-2、ATR、MRE11 in LNCaP and C4-2.As the result, expression of p53、Chek1、Bcl-2、ATR、MRE11 genes were found to be up-regulated in LNCaP cells compared with C4-2 cells.Then the radiation responses were examined in the 7 genes described above using 5 or 10 Gy radiation in LNCaP and C4-2.As the result,in LNCaP cell line,p21 expression was up-regulated in 24hs post-5Gy-radiation and the expression of Chek1,Chek2, Bcl-2,MRE11 were found to be down-regulated in the same condition.In 24hs post-10Gy-radiation p21 expression was up-regulated and the expression of Chek1,Chek2 were found to be down-regulated in the same condition.In C4-2 cell line,p53、p21、Chek1、Bcl-2、ATR、MRE11 expression were enhanced in 24hs post-5Gy radiation.The expression of p21、Chek1、Bcl-2、ATR、MRE11 were found to be increased in 24hs post-10Gy radiation.The genes expression differentiation provide the molecular foundation for the radiation sensitive LNCaP and radiation resistant C4-2.
5.To screen out the radiation induced genes,LNCaP and C4-2 cells were treated with 0,2.5,5,10Gy Co60 radiation and RT-PCR were performed to examine the expression of the 76 candidate genes described above 6,12,24,72 hours post radiation.As the result,31genes/transcript were found to be responsive to the radiation.
6.Base on the results of the screening ofbiomarker,androgen response and radiation response described above,25 genes/transcript were selected and real-time PCR were performed to confirm the differential expression pattern of these genes in LNCaP and C4-2.The results were demonstrated to be consistent with the microarray and RT-PCR assays.
7.To confirm the reliability and practicality of the results from PCa molecular marker screening,immunohistochemistry were performed using the antibodies against AGR2 and RPS4Y1 respectively.The results revealed that AGR2 expression was positive in cytoplasma and in positive relation to the malignant level,which is consistent with the expression pattern analysis.Moreover,RPS4Y1 expression was also found to in cytoplasma and negatively associated with the malignant level,consistent with the expression pattern analysis.These results revealed that the molecular screened may be applied to the clinic as molecular marker for PCa.
8.To evaluate the role of the androgen and radiation responsive genes in the androgen independent and radiation resistant development of prostate cancer,the prostate cancer cell lines stably overexpressing ELF5-2 and ACADL respectively were constructed.The MTT,plate colony formation assay,soft agar colony formation assay and Casodex or radiation treatment were performed to investigate the effect of ELF5-2 and ACADL overexpression on the growth ability, anchorage-independent growth ability and androgen-dependence,radiation resistence and malignant progress in prostate cancer.The results demonstrated that ELF5-2 overexpression promoted the growth ability,colony formation and malignant progress in LNCaP and C4-2 and augmented the androgen-independence,Casodex and radiation resistence in LNCaP.Moreover, ACADL expression increased the growth ability,colony formation and malignant progress in C4-2,and promoted the androgen-independence,Casodex and radiation resistence in C4-2.In order to investigate the molecular mechanism mediating ELF5-2 and ACADL function,real-time PCR were performed to examine the expression changes of AR,PSA,p53,p21,Chek1,Chek2,Bcl-2, ATR,MRE11 mediated by ELF5-2 and ACADL overexpression.The results revealed that ELF5-2 expression up-regulated the expression of PSA、p53、、ATR、MRE11 and inhibited the expression of Chek1 in LNCaP.ELF5-2 overexpression in C4-2 increased the expression of AR、PSA、p21、Chek2、Bcl-2、ATR、MRE11. Moreover,ACADL expression in C4-2 promoted the expression of p21、Bcl-2、ATR、MRE11 and inhibited the expression of PSA、Chekl.These molecular results are consistent with the function of ELF5-2 and ACADL in promoting androgen-independence,Casodex and radiation resistence.These results also show the reliability of the screening assay,indicating that the androgen-independent and radiation resistant progress of PCa may be significantly associated with androgen and radiation responsive genes.
Conclusions:
1.1023 genes/transcripts were screened out to be differentially expressed between LNCaP and C4-2.690 genes/transcripts expression are up-regulated and 333 are down-regulated in C4-2.76 genes/transcripts expression differentiation were confirmed using RT-PCR,and 25 were confirmed using Real-time PCR.
2.43 candidate molecular markers,62 androgen induced and 31 radiation induced genes/transcripts were screened out.
3.C4-2 possesses radiation resistant property compared with parent LNCaP cell line. LNCaP and C4-2 prostate cancer progress model can be used not only for investigation of androgen-independent progress,but also for research of radiation resistence in prostate cancer.
4.AGR2 and RPS4Y1 were demonstrated to be positively and negatively associated with prostate cancer progress respectively.
5.ELF5-2b overexpression promotes cell growth,survival and malignant progress, moreover induces androgen independence and radiation resistence in early stage of prostate cancer development.
6.ACADL overexpression enhances cell growth,survival and malignant progress, moreover induces androgen independence and radiation resistence in late stage of prostate cancer development.
结果:
1、应用Affymetrix公司的人类全基因组U133A芯片筛选出LNCaP与C4-2细胞系间差异表达的基因/转录本1053个;仅在LNCaP或C4-2中独立表达的基因/转录本分别是739和835个。根据差异倍数、染色体定位及研究进展确定104个候选基因/转录本进行RT-PCR验证获得76个基因/转录本与芯片结果一致的候选基因/转录本。
2、为了筛选出前列腺癌分子标志物候选基因,用RT-PCR检测上述76个候选差异基因/转录本在BPH1、LNCaP、C4-2、C4-2B、PC—3、DUl45、MCF-7、HEPG2、Hela、PC12、293T 11种细胞系中的表达谱。其中与前列腺癌进展程度呈正相关特异性较好的基因/转录本26个,与前列腺癌进展程度呈负相关特异性较好的基因/转录本17个。
3、为了筛选出雄激素调控基因,分别用1nM R1881和20μM Casodex处理LNCaP和C4-2,用RT-PCR检测76个候选基因/转录本在LNCaP、C4-2中处理前后的表达。其中在LNCaP细胞中R1881应答基因49个,Casodex应答基因42个。在C4-2细胞中R1881应答基因16个,Casodex应答基因15个。
4、为了探索适合电离辐射诱导基因筛选的遗传背景相同的辐射敏感性和辐射抗性细胞模型,分别用MTT、平板克隆形成、软琼脂克隆形成、周期变化检测了LNCaP和C4-2细胞系对5 Gy辐射的反应,结果证明了LNCaP的辐射敏感性和C4-2的辐射抗性。用Real-time PCR检测LNCaP和C4-2间p53、p21、Chek1、Chek2、Bcl-2、ATR、MRE11间表达的差异,结果:C4-2与LNCaP相比,p53、Chekl、Bcl-2、ATR、MRE11皆下调表达,同时检测了5、10Gy辐射后24小时LNCaP和C4-2上述7基因的表达差异,结果:LNCaP细胞5Gy辐射后24小时,p21上调表达,Chek1、Chek2、Bcl-2、MRE11下调表达,10Gy辐射后24小时,p21上调表达、Chek1、Chek2下调表达。C4-2细胞5Gy辐射后24小时,p53、p21、Chek1、Bcl-2、ATR、MRE11上调表达,10Gy辐射后24小时p21、Chek1、Bcl-2、ATR、MRE11上调表达。以上基因的差异表达是LNCaP辐射敏感性和C4-2辐射抗性的分子基础。
5、为了筛选出电离辐射诱导基因分别用0、2.5、5、10Gy ~(60)Coγ射线辐射处理LNCaP和C4-2细胞,用RT-PCR检测76个候选基因/转录本在上述处理后6、12、24、48、72小时的表达,其中在LNCaP细胞中辐射应答31个基因/转录本。
6、根据上述前列腺癌分子标志物、雄激素反应性基因及电离辐射诱导基因3方面的筛选结果综合考虑再次筛选出25个候选基因/转录本,用Real-timeRT-PCR再次验证它们在LNCaP与C4-2细胞间的差异表达。25个基因Real-time RT-PCR验证结果与芯片结果、RT-PCR验证结果一致。
7、为了验证上述筛出的前列腺癌分子标志物的可靠和实用性,用组织切片和组织芯片做免疫组化对AGR2和RPS4Y1临床表达进行了检测,其中AGR2胞浆阳性,其表达与恶性程度呈正相关,这与表达谱结果一致,RPS4Y1胞浆阳性,表达与恶性程度呈负相关,这与表达谱结果相符。该结果说明上述筛出的前列腺癌分子标志物候选基因有可能成为真正的前列腺癌分子标志物应用到临床。
8、为了探索上述筛出的雄激素调控基因及电离辐射诱导基因在前列腺癌雄激素非依赖和辐射抗性产生中扮演的角色,首先建立了ELF5-2b和ACADL的前列腺癌细胞系高表达稳定克隆并且得到了ELF5-2b和ACADL高表达的Real-time RT-PCR结果。接着,为了研究ELF5-2b和ACADL高表达对前列腺癌细胞生长、克隆形成能力、恶性进展、雄激素非依赖性、辐射抗性的影响,用MTT、平板克隆形成、软琼脂克隆形成、Casodex和辐射处理后MTT对此开展研究,结果:ELF5-2b的高表达促进了LNCaP和C4-2细胞的生长、克隆形成能力及恶性程度进展,提高了LNCaP细胞雄激素的非依赖性/Casodex耐受能力及抗辐射能力。ACADL的高表达促进了C4-2细胞的生长、克隆形成能力及恶性程度进展,提高了C4-2细胞雄激素的非依赖性/Casodex耐受能力及抗辐射能力。为了探讨ELF5-2b和ACADL高表达诱导或促进前列腺癌细胞雄激素非依赖性/Casodex耐受能力及辐射抗性进展的分子基础,用Real-timeRT-PCR分别检测了ELF5-2b和ACADL高表达对AR、PSA、p53、p21、Chek1、hek2、Bcl-2、ATR、MRE11表达的影响,结果发现ELF5-2b在LNCaP中高表达分别促进了PSA、p53、、ATR、MRE11的表达却抑制了Chek2的表达。ELF5-2b在C4-2中高表达分另0促进了AR、PSA、p21、Chek2、Bcl-2、ATR、MRE11的表达。ACADL在C4-2中高表达分别促进了p21、Bcl-2、ATR、MRE11的表达却抑制了PSA、Chek1的表达。ELF5-2b和ACADL高表达对这些分子表达的影响与ELF5-2b和ACADL高表达促进了前列腺癌细胞雄激素非依赖性/Casodex耐受能力及辐射抗性的进展是相吻合的。从而证实了上述筛出的雄激素调控基因及电离辐射诱导基因的可靠性,提示前列腺癌雄激素非依赖和辐射抗性产生可能与雄激素调控基因及电离辐射诱导基因密切相关。
结论:
1、LNCaP与C4-2间存在差异表达基因/转录本1023个:其中在C4-2中高表达的690个,低表达的333个,经RT-PCR验证的76个,经过Real time RT-PCR验证的25个。
2、筛选出分子标志物候选基因43个,受雄激素调控候选基因62个,受辐射诱导的候选基因31。
3、前列腺癌细胞系C4-2具有辐射抗性,LNCaP和C4-2具有相同的遗传背景,不但能够用作研究前列腺癌雄激素依赖和非依赖进展的细胞模型,还可以用作研究前列腺癌辐射敏感和抗性进展的细胞模型。
4、AGR2和RPS4Y1的表达与前列腺癌的进展程度分别呈正相关和负相关。
5、ELF5-2b的高表达能够促进前列腺癌细胞的生长、存活及恶性进展,诱导前列腺癌细胞雄激素非依赖性和辐射抗性的发生和进展而且具有前期阶段性。
6、ACADL的高表达能够促进前列腺癌细胞的生长、存活及恶性进展,诱导前列腺癌细胞雄激素非依赖性和辐射抗性的进展而且具有后期阶段性。
Objective:The incidence of prostate cancer has been increasing in recent years in Chinese males,In the western countries,the incidence of prostate cancer has been remained in the first position over lung cancer for continuous 15 yeas in male malignant carcinomas,and prostate cancer has become the second leading cause of death in male malignant carcinomas.Prostate cancer is a kind of alloplastic disease derived from multiple nidus and developing in random mode.Effective therapeutic methods remain to be found for the advanced prostate cancer with metastasis, especially the androgen-independent and chemical and radio therapy resistant prostate cancer.Our investigation was designed to find novel molecular biomarkers, androgen-responsive genes and radiation induced genes using Cdna microarray, RT-PCR,Real time PCR and immunohistochemistry methods to provide clues and foundation for exploring the molocular mechanism mediating prostate cancer development to androgen-independence and radiation resistence and provide novel insight for clinical diagnosis and therapy.
Methods and Results:
1.1053 genes/transcripts were screened out to be differently expressed in LNCaP and C4-2 using U133A microarray chip from Affymetrix company.739 and 835 genes/transcripts were screened out to be expressed solely in LNCaP and C4-2 respectively.104 genes/transcripts were selected and 76 genes/transcripts differential expression were confirmed to be consistent with microarray results using RT-PCR.
2.To screen out the molecular biomarker of PCa,RT-PCR was performed to examine the expression pattern of the 76 genes described above in BPH1、LNCaP、C4-2、C4-2B、PC-3、DU145、MCF-7、HEPG2、Hela、PC12、293T cell lines.26 genes expression were screened out to be positively associated with prostate cancer development and prostate tissue specific.17 genes expression were found out to be negatively associated with prostate cancer progression and possess prostate tissue specific characteristic.
3.To screen out androgen responsive genes,1nM R1881 and 20μM Casodex were used to treat LNCaP and C4-2.RT-PCR were performed to examine the androgen responsive characteristics in the 76 genes described above.As the result,49 R1881 responsive genes were screened out and 42 genes were found to be responsive to Casodex in LNCaP;In C4-2 cell,16 genes were found to be responsive to R1881 and 15 responsive to Casodex.
4.To investigate whether LNCaP and C4-2 are suitable to be radiation sensitive/resistant model cell lines for screening the radiation induced genes,MTT, soft agar colony formation and cell cycle assays were performed to detect the 5 Gy radiation response in LNCaP and C4-2 respectively.As the result,LNCaP and C4-2 were found to be radiation sensitive and resistant cell lines respectively. Real-time PCR were performed to examine the differential expression of p53、p21、Chek1、Chek2、Bcl-2、ATR、MRE11 in LNCaP and C4-2.As the result, expression of p53、Chek1、Bcl-2、ATR、MRE11 genes were found to be up-regulated in LNCaP cells compared with C4-2 cells.Then the radiation responses were examined in the 7 genes described above using 5 or 10 Gy radiation in LNCaP and C4-2.As the result,in LNCaP cell line,p21 expression was up-regulated in 24hs post-5Gy-radiation and the expression of Chek1,Chek2, Bcl-2,MRE11 were found to be down-regulated in the same condition.In 24hs post-10Gy-radiation p21 expression was up-regulated and the expression of Chek1,Chek2 were found to be down-regulated in the same condition.In C4-2 cell line,p53、p21、Chek1、Bcl-2、ATR、MRE11 expression were enhanced in 24hs post-5Gy radiation.The expression of p21、Chek1、Bcl-2、ATR、MRE11 were found to be increased in 24hs post-10Gy radiation.The genes expression differentiation provide the molecular foundation for the radiation sensitive LNCaP and radiation resistant C4-2.
5.To screen out the radiation induced genes,LNCaP and C4-2 cells were treated with 0,2.5,5,10Gy Co60 radiation and RT-PCR were performed to examine the expression of the 76 candidate genes described above 6,12,24,72 hours post radiation.As the result,31genes/transcript were found to be responsive to the radiation.
6.Base on the results of the screening ofbiomarker,androgen response and radiation response described above,25 genes/transcript were selected and real-time PCR were performed to confirm the differential expression pattern of these genes in LNCaP and C4-2.The results were demonstrated to be consistent with the microarray and RT-PCR assays.
7.To confirm the reliability and practicality of the results from PCa molecular marker screening,immunohistochemistry were performed using the antibodies against AGR2 and RPS4Y1 respectively.The results revealed that AGR2 expression was positive in cytoplasma and in positive relation to the malignant level,which is consistent with the expression pattern analysis.Moreover,RPS4Y1 expression was also found to in cytoplasma and negatively associated with the malignant level,consistent with the expression pattern analysis.These results revealed that the molecular screened may be applied to the clinic as molecular marker for PCa.
8.To evaluate the role of the androgen and radiation responsive genes in the androgen independent and radiation resistant development of prostate cancer,the prostate cancer cell lines stably overexpressing ELF5-2 and ACADL respectively were constructed.The MTT,plate colony formation assay,soft agar colony formation assay and Casodex or radiation treatment were performed to investigate the effect of ELF5-2 and ACADL overexpression on the growth ability, anchorage-independent growth ability and androgen-dependence,radiation resistence and malignant progress in prostate cancer.The results demonstrated that ELF5-2 overexpression promoted the growth ability,colony formation and malignant progress in LNCaP and C4-2 and augmented the androgen-independence,Casodex and radiation resistence in LNCaP.Moreover, ACADL expression increased the growth ability,colony formation and malignant progress in C4-2,and promoted the androgen-independence,Casodex and radiation resistence in C4-2.In order to investigate the molecular mechanism mediating ELF5-2 and ACADL function,real-time PCR were performed to examine the expression changes of AR,PSA,p53,p21,Chek1,Chek2,Bcl-2, ATR,MRE11 mediated by ELF5-2 and ACADL overexpression.The results revealed that ELF5-2 expression up-regulated the expression of PSA、p53、、ATR、MRE11 and inhibited the expression of Chek1 in LNCaP.ELF5-2 overexpression in C4-2 increased the expression of AR、PSA、p21、Chek2、Bcl-2、ATR、MRE11. Moreover,ACADL expression in C4-2 promoted the expression of p21、Bcl-2、ATR、MRE11 and inhibited the expression of PSA、Chekl.These molecular results are consistent with the function of ELF5-2 and ACADL in promoting androgen-independence,Casodex and radiation resistence.These results also show the reliability of the screening assay,indicating that the androgen-independent and radiation resistant progress of PCa may be significantly associated with androgen and radiation responsive genes.
Conclusions:
1.1023 genes/transcripts were screened out to be differentially expressed between LNCaP and C4-2.690 genes/transcripts expression are up-regulated and 333 are down-regulated in C4-2.76 genes/transcripts expression differentiation were confirmed using RT-PCR,and 25 were confirmed using Real-time PCR.
2.43 candidate molecular markers,62 androgen induced and 31 radiation induced genes/transcripts were screened out.
3.C4-2 possesses radiation resistant property compared with parent LNCaP cell line. LNCaP and C4-2 prostate cancer progress model can be used not only for investigation of androgen-independent progress,but also for research of radiation resistence in prostate cancer.
4.AGR2 and RPS4Y1 were demonstrated to be positively and negatively associated with prostate cancer progress respectively.
5.ELF5-2b overexpression promotes cell growth,survival and malignant progress, moreover induces androgen independence and radiation resistence in early stage of prostate cancer development.
6.ACADL overexpression enhances cell growth,survival and malignant progress, moreover induces androgen independence and radiation resistence in late stage of prostate cancer development.
引文
1、叶定伟 朱耀.中国前列腺癌的发病趋势.中国临床肿瘤学教育专辑,2007,616-620
2、Ahmedin Jemal,DVM,Rebecca Siegel,Elizabeth Ward,et al.Cancer Statistics,2007.CA Cancer J Clin,2007,7(57):43-66
3、前列腺癌 风向标时尚论坛-我的风向标,我的流行指南,我的生活新主张!.htm(网页).
4、陕西论坛 西部网.Bbs Cnwest Com.htm(网页).
5、中国人口信息网 老人比例╲2007年中国主要人口数据.htm(网页).
6、Ho,S.M.Estrogens and anti-estrogens:key mediators of prostate carcinogenesis and new therapeutic candidates.J.Cell Biochem,2004,91:491-503.
7、Walsh,P.C.High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate.Cancer patients treated with radical prostatectomy.J.Urol.,2005,173:1967-1968.
8、Suzuki,H,Ueda,T,Ichikawa,T,et al.Androgen receptor involvement in the progression of prostate cancer.Endocr.Relat Cancer,2003,10:209-216.
9、Torring,N,gnaes-Hansen,F,Sorensen,B.S,et al.ErbBl and prostate cancer:ErbB1 activity is essential for androgen-induced proliferation and protection from the apoptotic effects of LY294002.Prostate,2003,56:142-149.
10、Nanni,S,Narducci,M,Della,P.L,et al.Signaling through estrogen receptors modulates telomerase activity in human prostatecancer.J.Clin.Invest,2002,110:219-227.
11、Brian J.Feldman and David Feldman.THE DEVELOPMENT OF AND ROGEN-INDEPENDENT PROSTATE CANCER.Nature REVIEWS CANCER,2001,1:35-45.
12、Feldman,B.J.and Feldman,D.The development of androgen-independent prostate cancer.Nat.Rev.Cancer,2001,1:34-45.
13、Taplin,M.E.and Balk,S.P.Androgen receptor:a key molecule in the progression of prostate cancer to hormone independence.J.Cell Biochem,2004,91:483-490.
14、Culig,Z.,Steiner,H.,Bartsch,G.,and Hobisch,A.Interleukin-6 regulation of prostate cancer cell growth.J.Cell Biochem.,2005,95:497-505.
15、Taplin,M.E.and Balk,S.P.Androgen receptor:a key molecule in the progression of prostate cancer to hormone independence.J.Cell Biochem.,2004,91:483-490.
16、Culig,Z.,Comuzzi,B.,Steiner,H.,Bartsch,G.,and Hobisch,A.Expression and function of androgen receptor coactivators in prostate cancer.J.Steroid Biochem.Mol.Biol.,2004,92:265-271.
17、Culig,Z.,Steiner,H.,Bartsch,G.,and Hobisch,A.Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours.Endocr.Relat Cancer,2005,12:229-244.
18、Jarrard,D.F.,Kinoshita,H.,Shi,Y.,Sandefur,C.,Hoff,D.,Meisner,L.F.,Chang,C.,Herman,J.G.,Isaacs,W.B.,and Nassif,N.Methylation of the androgen receptor promoter CpG island is associated with loss of androgen receptor expression in prostate cancer cells.Cancer Res.,1998,58:5310-5314.
19、Mimeault,M.,Pommery,N.,and Henichart,J.P.New advances on prostate carcinogenesis and therapies:involvement of EGF-EGFR transduction system.Growth Factors,2003,21:1-14.
20、Hermans,K.G.,van,A.,Veltman,J.A.,van,W.W.,van Kessel,A.G.,and Trapman,J.Loss of a small region around the PTEN locus is a major chromosome 10 alteration in prostate cancer xenografts and cell lines.Genes Chromosomes.Cancer,2004,39:171-184.
21、Bostwick,D.G., Qian,J., and Maihle,N.J. Amphiregulin expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 93 cases. Prostate, 2004, 58:164-168.
22、 Hernes,E., Fossa,S.D., Berner,A., Otnes,B., and Nesland,J.M. Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence. Br.J.Cancer, 2004, 90:449-454.
23、 Chen,G., Shukeir,N., Potti,A., Sircar,K., Aprikian,A., Goltzman,D., and Rabbani,S.A. Upregulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer, 2004, 101:1345-1356.
24、 Zhu,H., Mazor,M., Kawano,Y., Walker,M.M., Leung,H.Y., Armstrong,K., Waxman,J., and Kypta,R.M. Analysis of Wnt gene expression in prostate cancer: mutual inhibition by WNT11 and the androgen
receptor. Cancer Res., 2004, 64:7918-7926.
25、 Olsen,C.L., Hsu,P.P., Glienke,J., Rubanyi,G.M., and Brooks,A.R. Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors. BMC.Cancer, 2004, 4:43.
26、 Karhadkar,S.S., Bova,G.S., Abdallah,N., Dhara,S., Gardner,D., Maitra,A., Isaacs,J.T., Berman,D.M., and Beachy,P.A. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 2004, 431:707-712.
27、 Ashida,S., Nakagawa,H., Katagiri,T., Furihata,M., Iiizumi,M., Anazawa,Y., Tsunoda,T., Takata,R., Kasahara,K., Miki,T., Fujioka,T., Shuin,T., and Nakamura,Y. Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs. Cancer Res., 2004, 64:5963-5972.
28、 Zellweger,T., Ninck,C., Bloch,M., Mirlacher,M., Koivisto,P.A., Helin,H.J., Mihatsch,M.J., Gasser,T.C., and Bubendorf,L. Expression patterns of potential therapeutic targets in prostate cancer. Int.J.Cancer, 2005, 113:619-628.
29、 Yardy,G.W. and Brewster,S.F. Wnt signalling and prostate cancer. Prostate Cancer ProstaticDis., 2005, 8:119-126.
30、 Walsh,P.C. High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate. Cancer patients treated with radical prostatectomy. J.Urol., 2005, 173:1967-1968.
31、 Chung,L.W., Baseman,A., Assikis,V., and Zhau,H.E. Molecular insights into prostate cancer progression: the missing link of tumor microenvironment. J.Urol., 2005,173:10-20.
32、 Bartlett,J.M., Brawley,D., Grigor,K., Munro,A.F., Dunne,B., and Edwards,J. Type I receptor tyrosine kinases are associated with hormone escape in prostate cancer. J.Pathol., 2005, 205:522-529.
33、 Mimeault,M., Moore,E., Moniaux,N., Henichart,J.P., Depreux,P., Lin,F.F., and Batra,S. Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Int J Cancer 2006, 118(4): 1022-1031
34、 Sanchez,P., Hernandez,A.M., Stecca,B., Kahler,A.J., DeGueme,A.M., Barrett,A., Beyna,M., Datta,M.W., Datta,S., and Altaba,A. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GL11 signaling. Proc.Natl.Acad.Sci.U.SA, 2004, 101:12561-12566.
35、 Stecca,B., Mas,C, and Altaba,A.R. Interference with HH-GLI signaling inhibits prostate cancer. Trends Mol.Med., 2005 ,11:199-203.
36、 Kambhampati,S., Ray,G., Sengupta,K., Reddy,V.P., Banerjee,S.K., and Van Veldhuizen,P.J. Growth factors involved in prostate carcinogenesis. Front Biosci., 2005,10:1355-1367.
37、 Mimeault,M. New advances on structural and biological functions of ceramide in apoptotic/necrotic cell death and cancer. FEBS Lett., 2002, 530:9-16.
33、 Wang,H., Charles,A.G., Frankel,A.J., and Cabot,M.C. Increasing intracellular ceramide: an approach that enhances the cytotoxic response in prostate cancer cells. Urology, 2003,61:1047-1052.
39、 Lee,E.C. and Tenniswood,M. Programmed cell death and survival pathways in prostate cancer cells. Arch.Androl, 2004, 50:27-32.
40、 Samsel,L., Zaidel,G., Drumgoole,H.M., Jelovac,D., Drachenberg,C, Rhee,J.G., Brodie,A.M., Bielawska,A., and Smyth,M.J. The ceramide analog, B13, induces apoptosis in prostate cancer cell lines and inhibits tumor growth in prostate cancer xenografts. Prostate, 2004, 58:382-393.
41、 Gleave,M.E., Miayake,H., Goldie,J., Nelson,C, and Tolcher,A. Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Urology, 1999,54:36-46.
42、 Gleave,M. and Miyake,H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J.Urol. 2005, 23:8-46.
43、 Garzotto,M., Hudson,R.G., Peters,L., Hsieh,Y.C., Barrera,E., Mori,M., Beer,T.M., and Klein,T. Predictive modeling for the presence of prostate carcinoma using clinical, laboratory, and ultrasound parameters in patients with prostate specific antigen levels < or = 10 ng/mL. Cancer, 2003,98:417-1422.
44、 Grammaticos,P. Diagnostic and prognostic value of serum prostate specific antigen in prostate carcinoma. Hell.J.Nucl.Med., 2004 , 7:6-148.
45、 Pelzer,A., Bektic,J., Berger,A.P., Pallwein,L., Halpern,E.J., Horninger,W., Bartsch,G., and Frauscher,F. Prostate cancer detection in men with prostate specific antigen 4 to 10 ng/ml using a combined approach of contrast enhanced color Doppler targeted and systematic biopsy. J.Urol., 2005,173:1926-1929.
46、 Wu,G.J., Wu,M.W., Wang,S.W., Liu,Z., Qu,P., Peng,Q., Yang,H., Varma,V.A., Sun,Q.C, Petros,J.A., im,S.D., and Amin,M.B. Isolation and characterization of the major form of human MUC18 cDNA gene and correlation of MUC18 over-expression in prostate cancer cell lines and tissues with malignant progression. Gene, 2001, 79:17-31.
47、 Nakamura,T., Scorilas,A., Stephan,C, Yousef,G.M., Kristiansen,G., Jung,K., and Diamandis,E.P.) Quantitative analysis of macrophage inhibitory cytokine-1 (MIC-1) gene expression in human prostatic tissues. Br.J.Cancer, 2003,8:101-1104.
48、 Bauskin,A.R., Brown,D.A., Junankar,S., Rasiah,K.K., Eggleton,S., Hunter,M., Liu,T., Smith,D., uffner,T., Pankhurst,G.J., Johnen,H., Russell,P.J., Barret,W., Stricker,P.D., Grygiel,J.J., Kench,J.G., Henshall,S.M., Sutherland,R.L., and Breit,S.N. The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. Cancer Res., 2005,65:330-2336.
49、 Downing,S.R., Russell,P.J., and Jackson,P. Alterations of p53 are common in early stage prostate cancer. Can.J.Urol., 2003,10:924-1933.
50、 Matsueda,S., Yao,A., Ishihara,Y., Ogata,R., Noguchi,M., Itoh,K., and Harada,M. A prostate stem cell antigen-derived peptide immunogenic in HLA-A24- prostate cancer patients. Prostate, 2004,60:05-213.
51、 Zhigang,Z. and Wenlv,S. Prostate stem cell antigen (PSCA) expression in human prostate cancer tissues and its potential role in prostate carcinogenesis and progression of prostate cancer. World J.Surg.Oncol., 2004,2:3.
52、 Allard,W.J., Matera, J., Miller,M.C., Repollet,M., Connelly,M.C., Rao,C., Tibbe,A.G., Uhr,J.W., and Terstappen,L.W. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin.Cancer Res., 2004,10:897-6904.
53、 O'Hara,S.M., Moreno,J.G., Zweitzig,D.R., Gross,S., Gomella,L.G., and Terstappen,L.W. Multigene reverse transcription-PCR profiling of circulating tumor cells in hormone-refractory prostate ancer. Clin.Chem., 2004, 50:826-835.
54、 Chen,B.T., Loberg,R.D., Neeley,C.K., O'Hara,S.M., Gross,S., Doyle,G., Dunn,R.L., Kalikin,L.M., and Pienta,K.J. Preliminary study of immunomagnetic quantification of circulating tumor cells in patients with advanced disease. Urology, 2005 ,65:616-621.
55、 Henshall,S.M., Afar, J D.E., Hiller,J., Horvath,L.G., Quinn,D.I., Rasiah,K.K., Gish,K., Willhite,D.,Kench,J.G., Gardiner-Garden,M., Stricker,P.D., Scher,H.L, Grygiel,J.J., Agus,D.B., Mack,D.H., and Sutherland,R.L. Survival analysis of genome-wide gene expression profiles of prostate cancers identifies new prognostic targets of disease relapse. Cancer Res., 2003, 63:4196-4203.
56、 Kieffer,N., Schmitz,M., Plancon,S., Margue,C., Huselstein,F., Grignard,G., Dippel,W., Nathan,M., Giacchi,S., and Scheiden,R. ILK as a potential marker gene to ascertain specific adenocarcinoma cell mRNA isolation from frozen prostate biopsy tissue sections. Int.J.Oncol., 2005,26:1549-1558.
57、 Bandyopadhyay,S., Pai,S.K., Hirota,S., Hosobe,S., Tsukada,T., Miura,K., Takano,Y., Saito,K., Commes,T., Piquemal,D., Watabe,M., Gross,S., Wang,Y., Huggenvik,J., and Watabe,K. PTEN upregulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res., 2004, 64:7655- 7660.
58、 Yang,G., Timme,T.L., Frolov,A., Wheeler,T.M., and Thompson,T.C. () Combined c-Myc and caveolin-1 expression in human prostate carcinoma predicts prostate carcinoma progression. Cancer, 2005,1 03:1186-1194.
59、 Landers,K.A., Burger,M.J., Tebay,M.A., Purdie,D.M., Scells,B., Samaratunga,H., Lavin,M.F., and Gardiner,R.A. Use of multiple biomarkers for a molecular diagnosis of prostate cancer. Int. J.Cancer, 2005, 114:950-956.
60、 Ayala,G.E.,Dai,H., lttmann,M., Li,R., Powell,M., Frolov,A., Wheeler,J.M., Thompson,T.C.,Rowley,D. Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res., 2004,64:6082-6090.
61、 Freedland,S.J., Sutter,M.E., Dorey,F., and Aronson,W.J. Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen. Urology, 2003,61:365-369.
62、 Krygiel,J.M., Smith,D.S., Homan,S.M., Sumner,W., Nease,R.F., Jr., Brownson,R.C, and Catalona,W.J. Intrmediate termbiochemical progression rates after radical prostatectomy and radiotherapy in patients with screen detected prostate cancer. J.Urol., 2005, 174: 126-130.
63、 Doust,J., Miller,E., Duchesne,G., Kitchener,M., and Weller,D. A systematic review of brachytherapy. Is it an effective and safe treatment for localised prostate cancer? Aust.Fam.Physician, 2004, 33:525-529.
64、 Potters,L., Morgenstern,C, Calugaru,E., Fearn,P., Jassal,A., Presser.J., and Mullen,E. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J.Urol., 2005,173:1562-1566.
65、 Buyyounouski,M.K., Hanlon,A.L., Horwitz,E.M., Uzzo,R.G., and Pollack,A. Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation. Int.J.Radiat.Oncol.Biol.Phys., 2005,61:1291-1298.
66、 Peyromaure,M., Delongchamps,N.B., Debre,B., and Zerbib,M. Intermittent androgen deprivation for biologic recurrence after radical prostatectomy: long-term experience. Urology, 2005,65:724-729.
67、 Hobisch,A., Hoffmann,J., Lambrinidis,L., Eder,I.E., Bartsch,G., Klocker,H., and Culig,Z. Antagonist/agonist balance of the nonsteroidal antiandrogen bicalutamide (Casodex) in a new prostate cancer model. Urol.Int., 2000,65:73-79.
68、 Festuccia,C., Gravina,G.L., Angelucci,A., Millimaggi,D., Muzi,P., Vicentini,C, and Bologna,M. Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro. Int.J.Cancer, 2005,115:630-640.
69、 Oettgen,P., Finger,E., Sun,Z., Akbarali,Y., Thamrongsak,U., Boltax, J., Grall,F., Dube,A., Weiss,A., Brown,L., Quinn,G., Kas,K., Endress,G., Kunsch,C., and Libermann,T.A. PDEF, a novel prostate epithelium-specific ets transcription factor, interacts with the androgen receptor and activates prostatespecific antigen gene expression. J.Biol.Chem., 2000, 275:1216-1225.
70、 Hoffmann,J and Sommer,A. Steroidhormone receptors as targets for the therapy of breast and prostate cancer-recent advances, mechanisms of resistance, and new approaches. J.Steroid Biochem.Mol.Biol., 2005,93:191 -200.
71、 Nanni,S., Narducci,M., Della,P.L., Moretti,F., Grasselli,A., De,C.P., Sacchi,A., Pontecorvi,A., and Farsetti,A. Signaling through estrogen receptors modulates telomerase activity in human prostate cancer. J.Clin.Invest, 2002, 110:219-227.
72、 Wang,Y.Z. and Wong,Y.C. Sex hormone-induced prostatic carcinogenesis in the noble rat: the role of insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in the development of prostate cancer. Prostate, 1998, 35:165-177.
73、 Wong,Y.C., Wang,Y.Z., and Tam,N.N. The prostate gland and prostate carcinogenesis. Ital.J.Anat.Embryol., 1998,103:237-252.
74、 Shenouda,N.S., Zhou,C., Browning J.D., Ansell,P.J., Sakla,M.S., Lubahn,D.B., and Macdonald,R.S. Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro. Nutr.Cancer, 2004, 49:200-208.
75、 Neubauer,B.L., McNulty,A.M., Chedid,M., Chen,K., Goode,R.L., Johnson,M.A., Jones,C.D., Krishnan,V., Lynch,R., Osborne,H.E., and Graff,J.R. The selective estrogen receptor modulator trioxifene (LY133314) inhibits metastasis and extends survival in the PAIII rat prostatic carcinoma model. Cancer Res., 2003,63:6056-6062.
76、 El Etreby,M.F., Liang,Y., and Lewis,R.W.Induction of apoptosis by mifepristone and tamoxifen in human LNCaP prostate cancer cells in culture. Prostate, 2000, 43:31-42.
77、 Kim,I.Y., Seong,d.H., Kim,B.C., Lee,D.K., Remaley,A.T., Leach,F., Morton,R.A., and Kim,S.J. Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway. Cancer Res., 2002, 62:3649-3653.
78、 Wang,J, Eltoum,I.E., and Lamartiniere,C.A. Genistein alters growth factor signaling in transgenic prostate model (TRAMP). Mol.Cell Endocrinol., 2004, 219:171-180.
79、 Coward,P., Lee,D., Hull,M.V., and Lehmann,J.M. 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. Proc.Natl.Acad.Sci.U.S.A, 2001, 98:8880-8884.
80、 Kawashima,H., Tanaka,T., Cheng,J.S., Sugita,S., Ezaki,K., Kurisu,T., and Nakatani,T. Effect of anti-estrogens on the androgen receptor activity and cell proliferation in prostate cancer cells. Urol.Res., 2004,32:406-410.
81、 Coffey,R.N., Watson,R.W., and Fitzpatrick,J.M Signaling for the caspases: their role in prostate cell apoptosis. J.Urol., 2001,165:5-14.
82、 Califice,S., Waltregny,D., Castronovo,V., and van den,B.F. Prostate carcinoma cell lines and poptosis: a review. Rev.Med.Liege, 2004, 59:704-710.
83、 Deutsch,E., Kaliski,A., Maggiorella,L., and Bourhis,J. New strategies to interfere with radiation response: "biomodulation" of radiation therapy. Cancer Radiother., 2005, 9:139-146.
84、 Burch,P.A., Croghan,G.A., Gastineau,D.A., Jones,L.A., Kaur,J.S., Kylstra,J.W., Richardson,R.L., Valone,F.H., and Vuk-Pavlovic,S. Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a Phase 2 trial. Prostate, 2004, 60:197-204.
85、 Hsieh,C.L., Gardner,T.A., Miao,L., Balian,G., and Chung,L.W. Cotargeting tumor and stroma in a novel chimeric tumor model involving the growth of both human prostate cancer and bone stromalcells. Cancer Gene Ther., 2004,11: 148-155.
86、 Lopez,C.A., Kimchi,E.T., Mauceri,H.J., Park,J.O., Mehta,N., Murphy,K.T., Beckett,M.A., Hellman,S.,Posner,M.C, Kufe,D.W., and Weichselbaum,R.R. Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity. Mol.Cancer Ther., 2004,3:1167-1175.
87、 Chen,Z., Koeneman,K.S., and Corey,D.R. Consequences of telomerase inhibition and combination treatments for the proliferation of cancer cells. Cancer Res., 2003, 63:5917-5925.
88、 Bernard,D., Pourtier-Manzanedo,A., Gil,J., and Beach,D.H. Myc confers androgen-independent prostate cancer cell growth. J.Clin.Invest, 2003, 112:1724-1731.
89、 Xu LL, Shanmugan N, Segawa T, Sesterhenn IA, McLeod DG,Moul JW, Srivastava S. A novel androgen-regulated gene, PMEPA1,located on chromosome 20q13 exhibits high level expression in prostate. Genomics 2000,66:257-63.
90、 Xu LL, Su YP, Labiche R, Segawa T, Shanmugam N, McLeod DG,Moul JW, Srivastava S. Quantitative expression profile of androgenregulated genes in prostate cancer cells and identification of prostatespecific genes. Int J Cancer 2001,92:322-8.
91、 Waghray A, Schober M, Feroze F, Yao F, Virgin J, Chen YQ. Identification of differentially expressed genes by serial analysis of gene expression in human prostate cancer. Cancer Res 2001,61:4283-6.
92、 Untergasser G, Koch HB, Menssen A, Hermeking H. Characterization of epithelial senescence by serial analysis of gene expression: identification of genes potentially involved in prostate cancer. Cancer Res 2002,62:6255-62.
93、 DePrimo SE, Diehn M, Nelson HB, Reiter RE, Matese H, Fero M,Ribshirani R, Brown PO, Brooks JD. Transcriptional programs activated by exposure of human prostate cancer cells to androgen. Genome Biol 2002,3:1-12.
94、 Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP,Rubin MA, Chinnaiyan AM. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002,419:624-9.
95、 Luo J, Duggan DJ, Chen Y, Sauvageot J, Ewing CM, Bittner ML,Trent JM, Isaacs WB. Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling. Cancer Res 2001 ;61:4683-8.
96、 Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J,Hood L, Lin B. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci 2002,99:11890-5.
97、 LaTulippe E, Satagopan J, Smith A, Scher H, Scardino P, Reuter V,Gerald WL. Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res 2002,62:4499-506.
98、 Holzbeieirlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, Ryan C, Smith S, Scher H, Scardino P, Reuter V, Gerald WL. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 2004,164:217-27.
99、 Halvorsen OJ, Oyan AM, Bo TH, Olsen S, Rostad K, Kaukass SA, Bakke AM, Marzolf B, Dimitrov K, Stordrange L, Lin B, Jonassen I, Hood L, Akslen LA, Kalland KH. Gene expression profiles in prostate cancer: association with subgroups and tumor differentiation. Int J Oncol 2005,26:329-36.
100、 Bouchal J, Baumforth KR, Svachova M, Murray PG, von Angerer E, Kolar Z. Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol 2005,57:83-92.
101、 Chang GTG, Steenbeek M, Schippers E, Blok LJ, van Weerden WM, van Alewijk DCJG, Eussen BHJ, van Steenbrugge GJ, Brinkmann AO. A novel gene on human chromosome 2p24 is differentially expressed between androgen-dependent and androgen-independent prostate cancer cells. Eur J Cancer 2001,37:2129-34.
102、 Bussemakers MJG, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HFM, Schalken JA, Debruyne FMJ, Ru N, Isaacs WB. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res 1999,59:5975-9.
103、 Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, Livezey JR, Connell T, Sesterhenn IA, Yoshino K, Buzard GS, Mostofi FK, McLeod DG, Moul JW, Srivstava S. PCGEM1, a prostate- specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci 2000,97:12216-21.
104、 Benedit P, Paciucci R, Thomson TM, Valeri M, Nadal M, Caceres C, de Torres I, Estivill X, Lozano JJ, Morote J, Reventos J. PTOV1, a novel protein overexpressed in prostate cancer containing a new class of protein homology. Oncogene 2001,20:1455-64.
105、 Chakrabarti R, Robles LD, Gibson J, Muroski M. Profiling of differential expression of messenger RNA in normal, benign, and metastatic prostate cell lines. Cancer Genet Cytogenet 2002,139:115-25.
106、 Ishiguro H, Uemura H, Fujinami K, Ikeda N, Ohta S, Kubota Y. 55Kda nuclear matrix protein (nmt55) mRNA is expressed in human prostate cancer tissue and is associated with the androgen receptor. Int J Cancer 2003,105:26-32.
107、 Lockhart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, Mittmann M, Wang C, Kobayashi M, Horton H, Brown EL Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol. 1996,14:1675-1680
108、 Wodicka L, Dong H, Mittmann M, Ho MH, Lockhart DJ Genome-wide expression monitoring in Saccharomyces cerevisiae. Nat Biotechnol 1997, 15:1359-1367
109、 Vaarala Markku H, Porvari K, Kyllonen A, Vihko P Differentially expressed genes in two LNCaP prostate cancer cell lines reflecting changes during prostate cancer progression. Lab Invest 2000,80:1259-1268
110、 Amler LC, Agus DB, LeDuc C, Sapinoso ML, Fox WD, Kern S, Lee D, WangV, Leysens M, Higgins B, Martin J, Gerald W, Dracopoli N, Cordon-Cardo C, Scher HI, Hampton GM Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1. Cancer Res 2000,60:6134-6141
111、 Mousses S, Wagner U, Chen Y, Kim JW, Bubendorf L, Bittner M, Pretlow T, Elkahloun Abdel G, Trepel Jane B, Kallioniemi Olli P Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene 2001,20:6718-6723
112、 Elek J, Park KH, Narayanan R Microarray-based expression profiling in prostate tumors. In Vivo.2000, 14:173-182
113、 Howell SB DNA microarrays for analysis of gene expression in prostate cancer. Mol Urol 1999,3:295-299
114、 Welsh JB, Sapinoso LM, Su AI, Kern SG, Wang-Rodriguez J, Moskaluk CA, Frierson HF, Hampton GM Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 2001,61:5974-5978
115、 Chaib H, Cockrell EK, Rubin MA, Macoska JA Profiling and verification of gene expression patterns in normal and malignant human prostate tissues by cDNA microarray analysis. Neoplasia 2001, 3:43-52
116、 Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J, Hood L, Lin BY The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci USA 2002, 99:11890-11895
117、 Karan D, Kelly DL, Rizzino A, Lin MF, Batra SK Expression profile of differentially regulated genes during progression of androgen-independent growth in human prostate cancer cells. Carcinogenesis 2002,23:967-975
118、 DePrimo SE, Diehn M, Nelson JB, Reiter RE, Matese J, Fero M, Tibshirani R, Brown PO, Brooks JD Transcriptional programs activated by exposure of human prostate cancer cells to androgen. Genome Biol, 2002,3:RESEARCH0032
119、 Segawa T, Nau ME, Xu LL, Chilukuri RN, Makarem M, Zhang W, Petrovics G, Sesterhenn 1A, McLeod DG, Moul JW, Vahey M, Srivastava S Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene, 2002,21:8749-8758
120、 张晓毅 洪宝发．前列腺癌的放射治疗进展．国际泌尿系统杂志,2006,26(2)：173—176
121、 Tucker SL, Turesson I, Thames HD. Evidence for individual differences in the radiosensitivity of human skin. European Journal of Cancer 1992,28A: 1783-1791.
122、 Bentzen SM, Overgaard J. Patient-to-patient variability in the expression of radiation-induced normal tissue injury. Seminars in Radiation Oncology 1994,4:68 - 80.
123、 Turesson I, Nyman J, Holmberg E, Oden A. Prognostic, factors for acute and late skin reactions in radiotherapy patients. Internationa] Journal of Radiation Oncology, Biology, hysics 1996,36:1065-1075.
124、 Andreassen CN, Alsner J, Overgaard J. Does variability in normal tissue reactions after radiotherapy have a genetic basis - where and how to look for it? Radiotherapy and Oncology 2002,64:131-140.
125、 Oppitz U, Schulte S, Stopper H, Baier K, Muller M, Wulf J, Schakowski R, Flentje M. In vitro radiosensitivity measured in lymphocytes and fibroblasts by colony formation and comet assay: comparison with clinical acute reactions to radiotherapy in breast cancer patients. International Journal of Radiation Biology 2002,78:611-616.
126、 Rosen EM, Fan SJ, Rockwell S, Goldberg ID. The molecular and cellular basis of radiosensitivity: Implications for understanding how normal tissues and tumors respond to therapeutic radiation. Cancer Investigation 1999, 17:56-72.
127、 Amundson SA, Bittner M, Chen YD, Trent J, Meltzer P, Fornace AJ. Fluorescent cDNA microarray hybridization reveals complexity and heterogeneity of cellular genotoxic stress responses. Oncogene 11999,8:3666-3672.
128、 Amundson SA, Do KT, Shahab S, Bittner M, Meltzer P, Trent J, Fornace AJ. Identification of potential mRNA biomarkers in peripheral blood lymphocytes for humanexposure to ionizing radiation. Radiation Research 2000,154:342-346.
129、 Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proceedings of the National Academy of Sciences of theUSA 2001,98:5116-5121.
130、 Heinloth AN, Shackelford RE, Innes CL, Bennett L, Li LP, Amin RP, Sieber SO, Flores KG, Bushel PR, Paules RS. Identification of distinct and common gene expression changes after oxidative stress and gamma and ultraviolet radiation. Molecular Carcinogenesis 2003,37:65-82.
131、 Jen KY, Cheung VG. Transcriptional response of lymphoblastoid cells to ionizing radiation. Genome Research 2003.13:2092-2100.
132、 Rieger KE, Chu G. Portrait of transcriptional responses to ultraviolet and ionizing radiation in human cells. Nucleic Acids Research 2004,32:4786-4803.
133、 Amundson SA, Grace MB, McLeland CB, Epperly MW, Yeager A, Zhan QM, Greenberger JS, Fornace AJ. Human in vivo radiation-induced biomarkers: Gene expression changes in radiotherapy patients. Cancer Research .2004,64:6368 -6371.
134、 Sakamoto-Hojo ET, Mello SS, Pereira E, Fachin AL, Cardoso RS, Junta CM, Sandrin-Garcia P, Donadi EA, Passos GA. Gene expression profiles in human cells submitted to genotoxic stress. Mutation Research2003, 544:403-413.
135、 Akerman GS, Rosenzweig BA, Domon OE, Tsai CA, Bishop ME, McGarrity LJ, MacGregor JT, Sistare FD, Chen JJ, Morris SM. Alterations in gene expression profiles and the DNAdamage response in ionizing radiation-exposed TK6 cells. Environmental and Molecular Mutagenesis 2005,45:188-205.
136、 Gatti RA. The inherited basis of human radiosensitivity.Acta Oncologica 2001,40:702-711.
137、 Popanda O, Ebbeler R, Twardella D, Helmbold I, Gotzes F, Schmezer P, Thielmann HW, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Bartsch H, Chang-Claude J. Radiation-induced DNA damage and repair in lymphocytes from breast cancer patients and their correlation with acute skin reactions to radiotherapy. International Journal of Radiation Oncology Biology Physics 2003,55:1216-1225.
138、 Horoszewicz JS, Leong SS, Kawinski E, et al. LNCaP model of human prostatic carcinoma. Cancer Res 1983,43:1809-18.
139、 Thalmann, G. N., Anezinis, P. E., Chang, S. M., et al. Androgen-independentcancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res 1994,54:2577-2581.
140、 Wu HC, Hsieh JT, Gleave ME, Brown NM, Pathak S, Chung LWK. Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int J Cancer 1994,57:406-492.
141、 Thalmann, G. N., Sikes, R.A., Wu, T.T, Degeorges, A., et al. LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. The Prostate 2000, 44:91-103.
142、 Josson S, Xu Y, Fang F, Dhar SK, St. Clair DK, St. Clair WH. RelB regulates manganese superoxide dismutase gene and resistance to ionizing radiation of prostate cancer cells. Oncogene 2005,25:1554-9.
143、 Scott SL, Gumerlock PH, Beckett L, Li Y, Goldberg Z. Survival and cell cycle kinetics of human prostate cancer cell lines after single- and multifraction exposures to ionizing radiation. Int J Radiat Oncol Biol Phys 2004,59:219-27.
144、 J.S. Horoszewicz, S.S. Leong, T.M. Chu, Z.L. Wajsman, M. Friedman, L. Papsidero, et al., The lncap cell line—a new model for studies on human prostatic carcinoma, Prog. Clin. Biol. Res. 1980,37:115-132.
145、 R.E. Sobel, M.D. Sadar, Cell lines used in prostate cancer research: a compendium of old and new lines—part 1, J. Urol. 2005, 173:342-359.
146、 R.E. Sobel, M.D. Sadar, Cell lines used in prostate cancer research: a compendium of old and new lines—part 2, J. Urol. 2005, 173:360-372.
147、 G.N. Thalmann, P.E. Anezinis, S.M. Chang, H.E. Zhau, E.E. Kim, V.L. Hopwood, et al., Androgen-independent cancer progression and bone metastasis in the lncap model of human prostate cancer, Cancer Res. 1994,54:2577-2581.
148、 G.N. Thalmann, R.A. Sikes, T.T. Wu, A. Degeorges, S.M. Chang, M. Ozen, et al., Lncap progression model of human prostate cancer: androgen-independence and osseous metastasis, Prostate ,2000, 144(102):91-103.
149、 L. Trojan, A. Schaaf, A. Steidler, M. Haak, G. Thalmann, T. Knoll, et al., Identification of metastasis-associated genes in prostate cancer by genetic profiling of human prostate cancer cell lines, Anticancer Res. 2005, 25: 183-191.
150、 M. Bisoffi, I. Klima, E. Gresko, P.N. Durfee, W.C. Hines, J.K. Griffith, et al., Expression profiles of androgen independent bone metastatic prostate cancer cells indicate up-regulation ofthe putative serine-threonine kinase gs3955, J. Urol. 2004,172:1145-1150.
151、 Asa J Oudes, Jared C Roach, Laura S Walashek et al.Application of affymetrix array and massively parallel signature sequencing for identification of genes involved in prostate cancer progression . BMC Cancer 2005, 5:86
152、 Cla'udia M. Coutinho-Camilloa, Sibeli Salaorni et al. Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen Cancer Genetics and Cytogenetics. 2006,166:130-138
153、 See-Tong Pang, Wen-Hui Weng, Amilcar Flores-Morales et al.Cytogenetic and Expression ProfilesAssociated WithTransformationtoAndrogen-Resistant ProstateCancer The Prostate 2006,66:157-172.
154、 Blank, V.; Andrews, N. C. The Maf transcription factors: regulators of differentiation. Trends Biochem. Sci. [J] 1997, 22(11):437-41
155、 Qiu, Y.; Krishnan, V.; Zeng, Z.; et al. Isolation, characterization, and chromosomal localization of mouse and human COUP-TF I and II genes. Genomics [J]. 1995, 29(1): 240-6.
156、 Levesque E, Turgeon D, Carrier JS, et al. Isolation and characterization of the UGT2B28 cDNA encoding a novel human steroid conjugating UDP-glucuronosyltransferase. Biochemistry [J] .2001,40 (13): 3869-3881.
157、 S. Funghini, M.A. Donati, E. Pasquini, et al. Structural Organization of the Human Carbamyl Phosphate Synthetase I Gene (CPS1) and Identification of Two Novel Genetic Lesions [J].2003,22(4):340-1.
158、 Isaacs JT (1999) The biology of hormone refractory prostate cancer. Why does it develop? Urol Clin North Am 26:263-273.
159、 Newling DW, Dennis L, Vermeylen K Orchiectomy versus goesrelin and flutamide in the treatment of newly diagnosed metastatic prostate cancer. Cancer ,1993,72:3793-3798.
160、 Mark Garzotto, Adriana Haimovitz-Friedman, Wen-Chieh Liao et al.Reversal of Radiation Resistance in LNCaP Cells by Targeting Apoptosis through Ceramide Synthase CANCER RESEARCH. 1999,59:5194-5201.
161、 Shuhei Matsuoka, Bryan A. Ballif, Agata Smogorzewska et al. ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage Science 2007,316:1160-1166.
162、 Heisler, L.E., Evangelou, A., Lew, A.M., Trachtenberg, J., Elsholtz, H..P. &Brown, T..J.() Mol. Cell. Endocrinol. 1997,126:59-73.
163、 Hongyan Wang, Huichen Wang, Simon N. Powel et al. ATR Affecting Cell Radiosensitivity Is Dependent on Homologous Recombination Repair but Independent of Nonhomologous End Joining CANCER RESEARCH 2004,64:7139-7143.
164、 Mohammed S. Inayat. Damodaran Chendi, Mohammed Mohiuddin et al. Didox (A Novel Ribonucleotide Reductase Inhibitor) Overcomes bcl-2 Mediated Radiation Resistance in Prostate Cancer Cell Line PC-3 Cancer Biology & Therapy 2002,l(5):539-545.
165、 Zheng Wang,1 Ying Hao,l and Anson W. Lowe The Adenocarcinoma-Associated Antigen, AGR2, Promotes Tumor Growth, Cell Migration, and Cellular Transformation Cancer Res 2008,68(2): 492-497.
166、 Glen Kristiansen, Christian Pilarsky, Christoph Wissmann et al. Expression profiling of microdissected matched prostate cancer samples reveals CD166/MEMD and CD24 as new prognostic markers for patient survival J Pathol 2005, 205:359-376.
167、 David B. Miklos, Haesook T. Kim, Katherine H. Miller et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission BLOOD.2005,105:2973-2978.
168、 Peter Oettgen , Koen Kas , Antoinise Dube et al. Characterization of ESE-2, a Novel ESE-1 -related Ets Transcription Factor That Is Restricted to Glandular Epithelium and Differentiated Keratinocytes 1999,274(41):29439-29452,
169、 Javier A. Menendez and Ruth Lupu Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis nat ure reviews cancer 2007,7:763-777.
170、 Weiping Le a, Azfar S. Abbas a, Howard Sprecher et al. Long-chain acyl-CoA dehydrogenase is a key enzyme in themitochondrial L-oxidation of unsaturated fatty acids Biochimica et BiophysicaActa2000,1485:121-128.
1.Lubahn DB,Joseph DR,Sar M,Tan J,et al.The human androgen receptor:complementary deoxyribonucleic acid cloning,sequence analysis and gene expression in prostate[J].Mol Endocrinol, 1988,2(12): 1265-75
2. Cunha GR, Donjacour AA, Cooke PS, et al. The endocrinology and developmental biology of the prostate [J]. Endocr Rev, 1987, 8(3):338-62
3. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy [J]. Nat Med, 2004, 10:33 - 39
4. Shibata H, Spencer TE, Onate SA, et al. Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action [J]. Recent Prog Horm Res, 1997,52:141-64; discussion 164-5.
5. Xu L, Glass CK, Rosenfeld MG. Coactivator and corepressor complexes in nuclear receptor function [J]. Curr Opin Genet Dev, 1999, 9(2): 140-7
6. McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology [J]. Endocr Rev, 1999, 20 (3): 321-344
7 . http: //www3. interscience. wiley.com/ cgi-bin/ fulltext/113511967/HTMLSTART)
8. Chen H, Lin RJ, Schiltz RL, et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300 [J]. Cell, 1997, 90(3):569-80
9. Stallcup MR, Kim JH, Teyssier C, et al. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators [J]. J Steroid Biochem Mol Biol, 2003, 85(2-5):139-45
10. Gregory CW, He B, Johnson RT, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy [J]. Cancer Res, 2001, 61:4315-4319
11. Zhou HJ, Yan J, Luo W, et al. SRC-3 is required for prostate cancer cell proliferation and survival [J]. Cancer Res, 2005, 65:7976-7983
12. Halkidou K, Gnanapragasam VJ, Mehta PB, et al. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development [J]. Oncogene, 2003, 22(16):2466-77
13. Nishimura K, Ting HJ, Harada Y, et al. Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator [J]. Cancer Res, 2003,63: 4888-4894
14. Cunningham CC, Stossel TP, Kwiatkowski DJ. Enhanced motility in NIH 3T3 fibroblasts that overexpress gelsolin [A]. Science, 1991, 251(4998): 1233-1236
15. Taneja SS, Ha S, Swenson NK, et al. ART-27, an androgen receptor coactivator regulated in prostate development and cancer [J]. J Biol Chem, 2004,279(14):13944-13952
16. Hsiao PW, Lin DL, Nakao R, et al. The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator [J]. J Biol Chem, 1999, 274(29):20229-34
17. Li P, Yu X, Ge K, et al. Heterogeneous expression and functions of androgen receptor co-factors in primary prostate cancer [J]. Am J Pathol, 2002,161 (4): 1467-1474
18. Fujimoto N, Yeh S, Kang HY, et al. Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate [J]. J Biol Chem, 1999, 274(12):8316-8321
19. Miyoshi Y, Ishiguro H, Uemura H, et al. Expression of AR associated protein 55 (ARA55) and androgen receptor in prostate cancer [J]. Prostate, 2003,56(4):280-6.
20. Miyamoto H, Rahman MM, Chang C. Molecular basis for the antiandrogen withdrawal syndrome [J]. J Cell Biochem, 2004, 91(1):3-12
[1]A.Jemal,T Murray,E Ward,et al.Cancer statistics,CA Cancer J.Clin[J],2005,55(1):10-30
[2]C.Huggins,C.V.Hodges,Studies on prostate cancer:Ⅰ.The effect of castration,of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate,Cancer Res[J].1972,2:232-240
[3]C.Huggins,R.E.Stevens,C.V.Hodges.Studies on prostate cancer:Ii.The effects of castration on advanced carcinoma of the prostate gland,Arch.Surg.[J].1941,43:209
[4]G.N.Thalmann,P.E.Anezinis,S.M.Chang,et al.androgen-independent cancer progression and bone metastasis in the lncap model of human prostate cancer,Cancer Res[J].1994,54:2577-2581
[5]Blank,V.;Andrews,N.C.The Maf transcription factors:regulators of differentiation.Trends Biochem.Sci.[J]1997,22(11):437-41
[6]Qiu,Y.;Krishnan,V.;Zeng,Z.;et al.Isolation,characterization,and chromosomal localization of mouse and human COUP-TF Ⅰ and Ⅱ genes.Genomics[J].1995,29(1):240-6
[7]R.J.Jin,C.Kwak,S.G.Lee,et al.The application of an anti-angiogenic gene (thrornbospondin-1)in the treatment of human prostate cancer xenografts,Cancer Gene Ther[J]2000,7(12):1537-42
[8]M.Colombel,S.Filleur,R Fournier,et al.Androgens repress the expression of the angiogenesis inhibitor thrombospondin-1 in normal and neoplastic prostate,Cancer Res[J].2005,65:300-308
[9]Levesque E,Turgeon D,Carrier JS,et al.Isolation and characterization of the UGT2B28cDNA encoding a novel human steroid conjugating UDP-glucuronosyltransferase.Biochemistry [J].2001,40(13):3869-3881
[10]S.Funghini,M.A.Donati,E.Pasquini,et al.Structural Organization of the Human Carbamyl Phosphate Synthetase Ⅰ Gene(CPS1)and Identification of Two Novel Genetic Lesions [J].2003,22(4):340-1
2、Ahmedin Jemal,DVM,Rebecca Siegel,Elizabeth Ward,et al.Cancer Statistics,2007.CA Cancer J Clin,2007,7(57):43-66
3、前列腺癌 风向标时尚论坛-我的风向标,我的流行指南,我的生活新主张!.htm(网页).
4、陕西论坛 西部网.Bbs Cnwest Com.htm(网页).
5、中国人口信息网 老人比例╲2007年中国主要人口数据.htm(网页).
6、Ho,S.M.Estrogens and anti-estrogens:key mediators of prostate carcinogenesis and new therapeutic candidates.J.Cell Biochem,2004,91:491-503.
7、Walsh,P.C.High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate.Cancer patients treated with radical prostatectomy.J.Urol.,2005,173:1967-1968.
8、Suzuki,H,Ueda,T,Ichikawa,T,et al.Androgen receptor involvement in the progression of prostate cancer.Endocr.Relat Cancer,2003,10:209-216.
9、Torring,N,gnaes-Hansen,F,Sorensen,B.S,et al.ErbBl and prostate cancer:ErbB1 activity is essential for androgen-induced proliferation and protection from the apoptotic effects of LY294002.Prostate,2003,56:142-149.
10、Nanni,S,Narducci,M,Della,P.L,et al.Signaling through estrogen receptors modulates telomerase activity in human prostatecancer.J.Clin.Invest,2002,110:219-227.
11、Brian J.Feldman and David Feldman.THE DEVELOPMENT OF AND ROGEN-INDEPENDENT PROSTATE CANCER.Nature REVIEWS CANCER,2001,1:35-45.
12、Feldman,B.J.and Feldman,D.The development of androgen-independent prostate cancer.Nat.Rev.Cancer,2001,1:34-45.
13、Taplin,M.E.and Balk,S.P.Androgen receptor:a key molecule in the progression of prostate cancer to hormone independence.J.Cell Biochem,2004,91:483-490.
14、Culig,Z.,Steiner,H.,Bartsch,G.,and Hobisch,A.Interleukin-6 regulation of prostate cancer cell growth.J.Cell Biochem.,2005,95:497-505.
15、Taplin,M.E.and Balk,S.P.Androgen receptor:a key molecule in the progression of prostate cancer to hormone independence.J.Cell Biochem.,2004,91:483-490.
16、Culig,Z.,Comuzzi,B.,Steiner,H.,Bartsch,G.,and Hobisch,A.Expression and function of androgen receptor coactivators in prostate cancer.J.Steroid Biochem.Mol.Biol.,2004,92:265-271.
17、Culig,Z.,Steiner,H.,Bartsch,G.,and Hobisch,A.Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours.Endocr.Relat Cancer,2005,12:229-244.
18、Jarrard,D.F.,Kinoshita,H.,Shi,Y.,Sandefur,C.,Hoff,D.,Meisner,L.F.,Chang,C.,Herman,J.G.,Isaacs,W.B.,and Nassif,N.Methylation of the androgen receptor promoter CpG island is associated with loss of androgen receptor expression in prostate cancer cells.Cancer Res.,1998,58:5310-5314.
19、Mimeault,M.,Pommery,N.,and Henichart,J.P.New advances on prostate carcinogenesis and therapies:involvement of EGF-EGFR transduction system.Growth Factors,2003,21:1-14.
20、Hermans,K.G.,van,A.,Veltman,J.A.,van,W.W.,van Kessel,A.G.,and Trapman,J.Loss of a small region around the PTEN locus is a major chromosome 10 alteration in prostate cancer xenografts and cell lines.Genes Chromosomes.Cancer,2004,39:171-184.
21、Bostwick,D.G., Qian,J., and Maihle,N.J. Amphiregulin expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 93 cases. Prostate, 2004, 58:164-168.
22、 Hernes,E., Fossa,S.D., Berner,A., Otnes,B., and Nesland,J.M. Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence. Br.J.Cancer, 2004, 90:449-454.
23、 Chen,G., Shukeir,N., Potti,A., Sircar,K., Aprikian,A., Goltzman,D., and Rabbani,S.A. Upregulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer, 2004, 101:1345-1356.
24、 Zhu,H., Mazor,M., Kawano,Y., Walker,M.M., Leung,H.Y., Armstrong,K., Waxman,J., and Kypta,R.M. Analysis of Wnt gene expression in prostate cancer: mutual inhibition by WNT11 and the androgen
receptor. Cancer Res., 2004, 64:7918-7926.
25、 Olsen,C.L., Hsu,P.P., Glienke,J., Rubanyi,G.M., and Brooks,A.R. Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors. BMC.Cancer, 2004, 4:43.
26、 Karhadkar,S.S., Bova,G.S., Abdallah,N., Dhara,S., Gardner,D., Maitra,A., Isaacs,J.T., Berman,D.M., and Beachy,P.A. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 2004, 431:707-712.
27、 Ashida,S., Nakagawa,H., Katagiri,T., Furihata,M., Iiizumi,M., Anazawa,Y., Tsunoda,T., Takata,R., Kasahara,K., Miki,T., Fujioka,T., Shuin,T., and Nakamura,Y. Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs. Cancer Res., 2004, 64:5963-5972.
28、 Zellweger,T., Ninck,C., Bloch,M., Mirlacher,M., Koivisto,P.A., Helin,H.J., Mihatsch,M.J., Gasser,T.C., and Bubendorf,L. Expression patterns of potential therapeutic targets in prostate cancer. Int.J.Cancer, 2005, 113:619-628.
29、 Yardy,G.W. and Brewster,S.F. Wnt signalling and prostate cancer. Prostate Cancer ProstaticDis., 2005, 8:119-126.
30、 Walsh,P.C. High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate. Cancer patients treated with radical prostatectomy. J.Urol., 2005, 173:1967-1968.
31、 Chung,L.W., Baseman,A., Assikis,V., and Zhau,H.E. Molecular insights into prostate cancer progression: the missing link of tumor microenvironment. J.Urol., 2005,173:10-20.
32、 Bartlett,J.M., Brawley,D., Grigor,K., Munro,A.F., Dunne,B., and Edwards,J. Type I receptor tyrosine kinases are associated with hormone escape in prostate cancer. J.Pathol., 2005, 205:522-529.
33、 Mimeault,M., Moore,E., Moniaux,N., Henichart,J.P., Depreux,P., Lin,F.F., and Batra,S. Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Int J Cancer 2006, 118(4): 1022-1031
34、 Sanchez,P., Hernandez,A.M., Stecca,B., Kahler,A.J., DeGueme,A.M., Barrett,A., Beyna,M., Datta,M.W., Datta,S., and Altaba,A. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GL11 signaling. Proc.Natl.Acad.Sci.U.SA, 2004, 101:12561-12566.
35、 Stecca,B., Mas,C, and Altaba,A.R. Interference with HH-GLI signaling inhibits prostate cancer. Trends Mol.Med., 2005 ,11:199-203.
36、 Kambhampati,S., Ray,G., Sengupta,K., Reddy,V.P., Banerjee,S.K., and Van Veldhuizen,P.J. Growth factors involved in prostate carcinogenesis. Front Biosci., 2005,10:1355-1367.
37、 Mimeault,M. New advances on structural and biological functions of ceramide in apoptotic/necrotic cell death and cancer. FEBS Lett., 2002, 530:9-16.
33、 Wang,H., Charles,A.G., Frankel,A.J., and Cabot,M.C. Increasing intracellular ceramide: an approach that enhances the cytotoxic response in prostate cancer cells. Urology, 2003,61:1047-1052.
39、 Lee,E.C. and Tenniswood,M. Programmed cell death and survival pathways in prostate cancer cells. Arch.Androl, 2004, 50:27-32.
40、 Samsel,L., Zaidel,G., Drumgoole,H.M., Jelovac,D., Drachenberg,C, Rhee,J.G., Brodie,A.M., Bielawska,A., and Smyth,M.J. The ceramide analog, B13, induces apoptosis in prostate cancer cell lines and inhibits tumor growth in prostate cancer xenografts. Prostate, 2004, 58:382-393.
41、 Gleave,M.E., Miayake,H., Goldie,J., Nelson,C, and Tolcher,A. Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Urology, 1999,54:36-46.
42、 Gleave,M. and Miyake,H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J.Urol. 2005, 23:8-46.
43、 Garzotto,M., Hudson,R.G., Peters,L., Hsieh,Y.C., Barrera,E., Mori,M., Beer,T.M., and Klein,T. Predictive modeling for the presence of prostate carcinoma using clinical, laboratory, and ultrasound parameters in patients with prostate specific antigen levels < or = 10 ng/mL. Cancer, 2003,98:417-1422.
44、 Grammaticos,P. Diagnostic and prognostic value of serum prostate specific antigen in prostate carcinoma. Hell.J.Nucl.Med., 2004 , 7:6-148.
45、 Pelzer,A., Bektic,J., Berger,A.P., Pallwein,L., Halpern,E.J., Horninger,W., Bartsch,G., and Frauscher,F. Prostate cancer detection in men with prostate specific antigen 4 to 10 ng/ml using a combined approach of contrast enhanced color Doppler targeted and systematic biopsy. J.Urol., 2005,173:1926-1929.
46、 Wu,G.J., Wu,M.W., Wang,S.W., Liu,Z., Qu,P., Peng,Q., Yang,H., Varma,V.A., Sun,Q.C, Petros,J.A., im,S.D., and Amin,M.B. Isolation and characterization of the major form of human MUC18 cDNA gene and correlation of MUC18 over-expression in prostate cancer cell lines and tissues with malignant progression. Gene, 2001, 79:17-31.
47、 Nakamura,T., Scorilas,A., Stephan,C, Yousef,G.M., Kristiansen,G., Jung,K., and Diamandis,E.P.) Quantitative analysis of macrophage inhibitory cytokine-1 (MIC-1) gene expression in human prostatic tissues. Br.J.Cancer, 2003,8:101-1104.
48、 Bauskin,A.R., Brown,D.A., Junankar,S., Rasiah,K.K., Eggleton,S., Hunter,M., Liu,T., Smith,D., uffner,T., Pankhurst,G.J., Johnen,H., Russell,P.J., Barret,W., Stricker,P.D., Grygiel,J.J., Kench,J.G., Henshall,S.M., Sutherland,R.L., and Breit,S.N. The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. Cancer Res., 2005,65:330-2336.
49、 Downing,S.R., Russell,P.J., and Jackson,P. Alterations of p53 are common in early stage prostate cancer. Can.J.Urol., 2003,10:924-1933.
50、 Matsueda,S., Yao,A., Ishihara,Y., Ogata,R., Noguchi,M., Itoh,K., and Harada,M. A prostate stem cell antigen-derived peptide immunogenic in HLA-A24- prostate cancer patients. Prostate, 2004,60:05-213.
51、 Zhigang,Z. and Wenlv,S. Prostate stem cell antigen (PSCA) expression in human prostate cancer tissues and its potential role in prostate carcinogenesis and progression of prostate cancer. World J.Surg.Oncol., 2004,2:3.
52、 Allard,W.J., Matera, J., Miller,M.C., Repollet,M., Connelly,M.C., Rao,C., Tibbe,A.G., Uhr,J.W., and Terstappen,L.W. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin.Cancer Res., 2004,10:897-6904.
53、 O'Hara,S.M., Moreno,J.G., Zweitzig,D.R., Gross,S., Gomella,L.G., and Terstappen,L.W. Multigene reverse transcription-PCR profiling of circulating tumor cells in hormone-refractory prostate ancer. Clin.Chem., 2004, 50:826-835.
54、 Chen,B.T., Loberg,R.D., Neeley,C.K., O'Hara,S.M., Gross,S., Doyle,G., Dunn,R.L., Kalikin,L.M., and Pienta,K.J. Preliminary study of immunomagnetic quantification of circulating tumor cells in patients with advanced disease. Urology, 2005 ,65:616-621.
55、 Henshall,S.M., Afar, J D.E., Hiller,J., Horvath,L.G., Quinn,D.I., Rasiah,K.K., Gish,K., Willhite,D.,Kench,J.G., Gardiner-Garden,M., Stricker,P.D., Scher,H.L, Grygiel,J.J., Agus,D.B., Mack,D.H., and Sutherland,R.L. Survival analysis of genome-wide gene expression profiles of prostate cancers identifies new prognostic targets of disease relapse. Cancer Res., 2003, 63:4196-4203.
56、 Kieffer,N., Schmitz,M., Plancon,S., Margue,C., Huselstein,F., Grignard,G., Dippel,W., Nathan,M., Giacchi,S., and Scheiden,R. ILK as a potential marker gene to ascertain specific adenocarcinoma cell mRNA isolation from frozen prostate biopsy tissue sections. Int.J.Oncol., 2005,26:1549-1558.
57、 Bandyopadhyay,S., Pai,S.K., Hirota,S., Hosobe,S., Tsukada,T., Miura,K., Takano,Y., Saito,K., Commes,T., Piquemal,D., Watabe,M., Gross,S., Wang,Y., Huggenvik,J., and Watabe,K. PTEN upregulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res., 2004, 64:7655- 7660.
58、 Yang,G., Timme,T.L., Frolov,A., Wheeler,T.M., and Thompson,T.C. () Combined c-Myc and caveolin-1 expression in human prostate carcinoma predicts prostate carcinoma progression. Cancer, 2005,1 03:1186-1194.
59、 Landers,K.A., Burger,M.J., Tebay,M.A., Purdie,D.M., Scells,B., Samaratunga,H., Lavin,M.F., and Gardiner,R.A. Use of multiple biomarkers for a molecular diagnosis of prostate cancer. Int. J.Cancer, 2005, 114:950-956.
60、 Ayala,G.E.,Dai,H., lttmann,M., Li,R., Powell,M., Frolov,A., Wheeler,J.M., Thompson,T.C.,Rowley,D. Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res., 2004,64:6082-6090.
61、 Freedland,S.J., Sutter,M.E., Dorey,F., and Aronson,W.J. Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen. Urology, 2003,61:365-369.
62、 Krygiel,J.M., Smith,D.S., Homan,S.M., Sumner,W., Nease,R.F., Jr., Brownson,R.C, and Catalona,W.J. Intrmediate termbiochemical progression rates after radical prostatectomy and radiotherapy in patients with screen detected prostate cancer. J.Urol., 2005, 174: 126-130.
63、 Doust,J., Miller,E., Duchesne,G., Kitchener,M., and Weller,D. A systematic review of brachytherapy. Is it an effective and safe treatment for localised prostate cancer? Aust.Fam.Physician, 2004, 33:525-529.
64、 Potters,L., Morgenstern,C, Calugaru,E., Fearn,P., Jassal,A., Presser.J., and Mullen,E. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J.Urol., 2005,173:1562-1566.
65、 Buyyounouski,M.K., Hanlon,A.L., Horwitz,E.M., Uzzo,R.G., and Pollack,A. Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation. Int.J.Radiat.Oncol.Biol.Phys., 2005,61:1291-1298.
66、 Peyromaure,M., Delongchamps,N.B., Debre,B., and Zerbib,M. Intermittent androgen deprivation for biologic recurrence after radical prostatectomy: long-term experience. Urology, 2005,65:724-729.
67、 Hobisch,A., Hoffmann,J., Lambrinidis,L., Eder,I.E., Bartsch,G., Klocker,H., and Culig,Z. Antagonist/agonist balance of the nonsteroidal antiandrogen bicalutamide (Casodex) in a new prostate cancer model. Urol.Int., 2000,65:73-79.
68、 Festuccia,C., Gravina,G.L., Angelucci,A., Millimaggi,D., Muzi,P., Vicentini,C, and Bologna,M. Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro. Int.J.Cancer, 2005,115:630-640.
69、 Oettgen,P., Finger,E., Sun,Z., Akbarali,Y., Thamrongsak,U., Boltax, J., Grall,F., Dube,A., Weiss,A., Brown,L., Quinn,G., Kas,K., Endress,G., Kunsch,C., and Libermann,T.A. PDEF, a novel prostate epithelium-specific ets transcription factor, interacts with the androgen receptor and activates prostatespecific antigen gene expression. J.Biol.Chem., 2000, 275:1216-1225.
70、 Hoffmann,J and Sommer,A. Steroidhormone receptors as targets for the therapy of breast and prostate cancer-recent advances, mechanisms of resistance, and new approaches. J.Steroid Biochem.Mol.Biol., 2005,93:191 -200.
71、 Nanni,S., Narducci,M., Della,P.L., Moretti,F., Grasselli,A., De,C.P., Sacchi,A., Pontecorvi,A., and Farsetti,A. Signaling through estrogen receptors modulates telomerase activity in human prostate cancer. J.Clin.Invest, 2002, 110:219-227.
72、 Wang,Y.Z. and Wong,Y.C. Sex hormone-induced prostatic carcinogenesis in the noble rat: the role of insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in the development of prostate cancer. Prostate, 1998, 35:165-177.
73、 Wong,Y.C., Wang,Y.Z., and Tam,N.N. The prostate gland and prostate carcinogenesis. Ital.J.Anat.Embryol., 1998,103:237-252.
74、 Shenouda,N.S., Zhou,C., Browning J.D., Ansell,P.J., Sakla,M.S., Lubahn,D.B., and Macdonald,R.S. Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro. Nutr.Cancer, 2004, 49:200-208.
75、 Neubauer,B.L., McNulty,A.M., Chedid,M., Chen,K., Goode,R.L., Johnson,M.A., Jones,C.D., Krishnan,V., Lynch,R., Osborne,H.E., and Graff,J.R. The selective estrogen receptor modulator trioxifene (LY133314) inhibits metastasis and extends survival in the PAIII rat prostatic carcinoma model. Cancer Res., 2003,63:6056-6062.
76、 El Etreby,M.F., Liang,Y., and Lewis,R.W.Induction of apoptosis by mifepristone and tamoxifen in human LNCaP prostate cancer cells in culture. Prostate, 2000, 43:31-42.
77、 Kim,I.Y., Seong,d.H., Kim,B.C., Lee,D.K., Remaley,A.T., Leach,F., Morton,R.A., and Kim,S.J. Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway. Cancer Res., 2002, 62:3649-3653.
78、 Wang,J, Eltoum,I.E., and Lamartiniere,C.A. Genistein alters growth factor signaling in transgenic prostate model (TRAMP). Mol.Cell Endocrinol., 2004, 219:171-180.
79、 Coward,P., Lee,D., Hull,M.V., and Lehmann,J.M. 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. Proc.Natl.Acad.Sci.U.S.A, 2001, 98:8880-8884.
80、 Kawashima,H., Tanaka,T., Cheng,J.S., Sugita,S., Ezaki,K., Kurisu,T., and Nakatani,T. Effect of anti-estrogens on the androgen receptor activity and cell proliferation in prostate cancer cells. Urol.Res., 2004,32:406-410.
81、 Coffey,R.N., Watson,R.W., and Fitzpatrick,J.M Signaling for the caspases: their role in prostate cell apoptosis. J.Urol., 2001,165:5-14.
82、 Califice,S., Waltregny,D., Castronovo,V., and van den,B.F. Prostate carcinoma cell lines and poptosis: a review. Rev.Med.Liege, 2004, 59:704-710.
83、 Deutsch,E., Kaliski,A., Maggiorella,L., and Bourhis,J. New strategies to interfere with radiation response: "biomodulation" of radiation therapy. Cancer Radiother., 2005, 9:139-146.
84、 Burch,P.A., Croghan,G.A., Gastineau,D.A., Jones,L.A., Kaur,J.S., Kylstra,J.W., Richardson,R.L., Valone,F.H., and Vuk-Pavlovic,S. Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a Phase 2 trial. Prostate, 2004, 60:197-204.
85、 Hsieh,C.L., Gardner,T.A., Miao,L., Balian,G., and Chung,L.W. Cotargeting tumor and stroma in a novel chimeric tumor model involving the growth of both human prostate cancer and bone stromalcells. Cancer Gene Ther., 2004,11: 148-155.
86、 Lopez,C.A., Kimchi,E.T., Mauceri,H.J., Park,J.O., Mehta,N., Murphy,K.T., Beckett,M.A., Hellman,S.,Posner,M.C, Kufe,D.W., and Weichselbaum,R.R. Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity. Mol.Cancer Ther., 2004,3:1167-1175.
87、 Chen,Z., Koeneman,K.S., and Corey,D.R. Consequences of telomerase inhibition and combination treatments for the proliferation of cancer cells. Cancer Res., 2003, 63:5917-5925.
88、 Bernard,D., Pourtier-Manzanedo,A., Gil,J., and Beach,D.H. Myc confers androgen-independent prostate cancer cell growth. J.Clin.Invest, 2003, 112:1724-1731.
89、 Xu LL, Shanmugan N, Segawa T, Sesterhenn IA, McLeod DG,Moul JW, Srivastava S. A novel androgen-regulated gene, PMEPA1,located on chromosome 20q13 exhibits high level expression in prostate. Genomics 2000,66:257-63.
90、 Xu LL, Su YP, Labiche R, Segawa T, Shanmugam N, McLeod DG,Moul JW, Srivastava S. Quantitative expression profile of androgenregulated genes in prostate cancer cells and identification of prostatespecific genes. Int J Cancer 2001,92:322-8.
91、 Waghray A, Schober M, Feroze F, Yao F, Virgin J, Chen YQ. Identification of differentially expressed genes by serial analysis of gene expression in human prostate cancer. Cancer Res 2001,61:4283-6.
92、 Untergasser G, Koch HB, Menssen A, Hermeking H. Characterization of epithelial senescence by serial analysis of gene expression: identification of genes potentially involved in prostate cancer. Cancer Res 2002,62:6255-62.
93、 DePrimo SE, Diehn M, Nelson HB, Reiter RE, Matese H, Fero M,Ribshirani R, Brown PO, Brooks JD. Transcriptional programs activated by exposure of human prostate cancer cells to androgen. Genome Biol 2002,3:1-12.
94、 Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP,Rubin MA, Chinnaiyan AM. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002,419:624-9.
95、 Luo J, Duggan DJ, Chen Y, Sauvageot J, Ewing CM, Bittner ML,Trent JM, Isaacs WB. Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling. Cancer Res 2001 ;61:4683-8.
96、 Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J,Hood L, Lin B. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci 2002,99:11890-5.
97、 LaTulippe E, Satagopan J, Smith A, Scher H, Scardino P, Reuter V,Gerald WL. Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res 2002,62:4499-506.
98、 Holzbeieirlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, Ryan C, Smith S, Scher H, Scardino P, Reuter V, Gerald WL. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 2004,164:217-27.
99、 Halvorsen OJ, Oyan AM, Bo TH, Olsen S, Rostad K, Kaukass SA, Bakke AM, Marzolf B, Dimitrov K, Stordrange L, Lin B, Jonassen I, Hood L, Akslen LA, Kalland KH. Gene expression profiles in prostate cancer: association with subgroups and tumor differentiation. Int J Oncol 2005,26:329-36.
100、 Bouchal J, Baumforth KR, Svachova M, Murray PG, von Angerer E, Kolar Z. Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol 2005,57:83-92.
101、 Chang GTG, Steenbeek M, Schippers E, Blok LJ, van Weerden WM, van Alewijk DCJG, Eussen BHJ, van Steenbrugge GJ, Brinkmann AO. A novel gene on human chromosome 2p24 is differentially expressed between androgen-dependent and androgen-independent prostate cancer cells. Eur J Cancer 2001,37:2129-34.
102、 Bussemakers MJG, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HFM, Schalken JA, Debruyne FMJ, Ru N, Isaacs WB. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res 1999,59:5975-9.
103、 Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, Livezey JR, Connell T, Sesterhenn IA, Yoshino K, Buzard GS, Mostofi FK, McLeod DG, Moul JW, Srivstava S. PCGEM1, a prostate- specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci 2000,97:12216-21.
104、 Benedit P, Paciucci R, Thomson TM, Valeri M, Nadal M, Caceres C, de Torres I, Estivill X, Lozano JJ, Morote J, Reventos J. PTOV1, a novel protein overexpressed in prostate cancer containing a new class of protein homology. Oncogene 2001,20:1455-64.
105、 Chakrabarti R, Robles LD, Gibson J, Muroski M. Profiling of differential expression of messenger RNA in normal, benign, and metastatic prostate cell lines. Cancer Genet Cytogenet 2002,139:115-25.
106、 Ishiguro H, Uemura H, Fujinami K, Ikeda N, Ohta S, Kubota Y. 55Kda nuclear matrix protein (nmt55) mRNA is expressed in human prostate cancer tissue and is associated with the androgen receptor. Int J Cancer 2003,105:26-32.
107、 Lockhart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, Mittmann M, Wang C, Kobayashi M, Horton H, Brown EL Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol. 1996,14:1675-1680
108、 Wodicka L, Dong H, Mittmann M, Ho MH, Lockhart DJ Genome-wide expression monitoring in Saccharomyces cerevisiae. Nat Biotechnol 1997, 15:1359-1367
109、 Vaarala Markku H, Porvari K, Kyllonen A, Vihko P Differentially expressed genes in two LNCaP prostate cancer cell lines reflecting changes during prostate cancer progression. Lab Invest 2000,80:1259-1268
110、 Amler LC, Agus DB, LeDuc C, Sapinoso ML, Fox WD, Kern S, Lee D, WangV, Leysens M, Higgins B, Martin J, Gerald W, Dracopoli N, Cordon-Cardo C, Scher HI, Hampton GM Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1. Cancer Res 2000,60:6134-6141
111、 Mousses S, Wagner U, Chen Y, Kim JW, Bubendorf L, Bittner M, Pretlow T, Elkahloun Abdel G, Trepel Jane B, Kallioniemi Olli P Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene 2001,20:6718-6723
112、 Elek J, Park KH, Narayanan R Microarray-based expression profiling in prostate tumors. In Vivo.2000, 14:173-182
113、 Howell SB DNA microarrays for analysis of gene expression in prostate cancer. Mol Urol 1999,3:295-299
114、 Welsh JB, Sapinoso LM, Su AI, Kern SG, Wang-Rodriguez J, Moskaluk CA, Frierson HF, Hampton GM Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 2001,61:5974-5978
115、 Chaib H, Cockrell EK, Rubin MA, Macoska JA Profiling and verification of gene expression patterns in normal and malignant human prostate tissues by cDNA microarray analysis. Neoplasia 2001, 3:43-52
116、 Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J, Hood L, Lin BY The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci USA 2002, 99:11890-11895
117、 Karan D, Kelly DL, Rizzino A, Lin MF, Batra SK Expression profile of differentially regulated genes during progression of androgen-independent growth in human prostate cancer cells. Carcinogenesis 2002,23:967-975
118、 DePrimo SE, Diehn M, Nelson JB, Reiter RE, Matese J, Fero M, Tibshirani R, Brown PO, Brooks JD Transcriptional programs activated by exposure of human prostate cancer cells to androgen. Genome Biol, 2002,3:RESEARCH0032
119、 Segawa T, Nau ME, Xu LL, Chilukuri RN, Makarem M, Zhang W, Petrovics G, Sesterhenn 1A, McLeod DG, Moul JW, Vahey M, Srivastava S Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene, 2002,21:8749-8758
120、 张晓毅 洪宝发．前列腺癌的放射治疗进展．国际泌尿系统杂志,2006,26(2)：173—176
121、 Tucker SL, Turesson I, Thames HD. Evidence for individual differences in the radiosensitivity of human skin. European Journal of Cancer 1992,28A: 1783-1791.
122、 Bentzen SM, Overgaard J. Patient-to-patient variability in the expression of radiation-induced normal tissue injury. Seminars in Radiation Oncology 1994,4:68 - 80.
123、 Turesson I, Nyman J, Holmberg E, Oden A. Prognostic, factors for acute and late skin reactions in radiotherapy patients. Internationa] Journal of Radiation Oncology, Biology, hysics 1996,36:1065-1075.
124、 Andreassen CN, Alsner J, Overgaard J. Does variability in normal tissue reactions after radiotherapy have a genetic basis - where and how to look for it? Radiotherapy and Oncology 2002,64:131-140.
125、 Oppitz U, Schulte S, Stopper H, Baier K, Muller M, Wulf J, Schakowski R, Flentje M. In vitro radiosensitivity measured in lymphocytes and fibroblasts by colony formation and comet assay: comparison with clinical acute reactions to radiotherapy in breast cancer patients. International Journal of Radiation Biology 2002,78:611-616.
126、 Rosen EM, Fan SJ, Rockwell S, Goldberg ID. The molecular and cellular basis of radiosensitivity: Implications for understanding how normal tissues and tumors respond to therapeutic radiation. Cancer Investigation 1999, 17:56-72.
127、 Amundson SA, Bittner M, Chen YD, Trent J, Meltzer P, Fornace AJ. Fluorescent cDNA microarray hybridization reveals complexity and heterogeneity of cellular genotoxic stress responses. Oncogene 11999,8:3666-3672.
128、 Amundson SA, Do KT, Shahab S, Bittner M, Meltzer P, Trent J, Fornace AJ. Identification of potential mRNA biomarkers in peripheral blood lymphocytes for humanexposure to ionizing radiation. Radiation Research 2000,154:342-346.
129、 Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proceedings of the National Academy of Sciences of theUSA 2001,98:5116-5121.
130、 Heinloth AN, Shackelford RE, Innes CL, Bennett L, Li LP, Amin RP, Sieber SO, Flores KG, Bushel PR, Paules RS. Identification of distinct and common gene expression changes after oxidative stress and gamma and ultraviolet radiation. Molecular Carcinogenesis 2003,37:65-82.
131、 Jen KY, Cheung VG. Transcriptional response of lymphoblastoid cells to ionizing radiation. Genome Research 2003.13:2092-2100.
132、 Rieger KE, Chu G. Portrait of transcriptional responses to ultraviolet and ionizing radiation in human cells. Nucleic Acids Research 2004,32:4786-4803.
133、 Amundson SA, Grace MB, McLeland CB, Epperly MW, Yeager A, Zhan QM, Greenberger JS, Fornace AJ. Human in vivo radiation-induced biomarkers: Gene expression changes in radiotherapy patients. Cancer Research .2004,64:6368 -6371.
134、 Sakamoto-Hojo ET, Mello SS, Pereira E, Fachin AL, Cardoso RS, Junta CM, Sandrin-Garcia P, Donadi EA, Passos GA. Gene expression profiles in human cells submitted to genotoxic stress. Mutation Research2003, 544:403-413.
135、 Akerman GS, Rosenzweig BA, Domon OE, Tsai CA, Bishop ME, McGarrity LJ, MacGregor JT, Sistare FD, Chen JJ, Morris SM. Alterations in gene expression profiles and the DNAdamage response in ionizing radiation-exposed TK6 cells. Environmental and Molecular Mutagenesis 2005,45:188-205.
136、 Gatti RA. The inherited basis of human radiosensitivity.Acta Oncologica 2001,40:702-711.
137、 Popanda O, Ebbeler R, Twardella D, Helmbold I, Gotzes F, Schmezer P, Thielmann HW, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Bartsch H, Chang-Claude J. Radiation-induced DNA damage and repair in lymphocytes from breast cancer patients and their correlation with acute skin reactions to radiotherapy. International Journal of Radiation Oncology Biology Physics 2003,55:1216-1225.
138、 Horoszewicz JS, Leong SS, Kawinski E, et al. LNCaP model of human prostatic carcinoma. Cancer Res 1983,43:1809-18.
139、 Thalmann, G. N., Anezinis, P. E., Chang, S. M., et al. Androgen-independentcancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res 1994,54:2577-2581.
140、 Wu HC, Hsieh JT, Gleave ME, Brown NM, Pathak S, Chung LWK. Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int J Cancer 1994,57:406-492.
141、 Thalmann, G. N., Sikes, R.A., Wu, T.T, Degeorges, A., et al. LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. The Prostate 2000, 44:91-103.
142、 Josson S, Xu Y, Fang F, Dhar SK, St. Clair DK, St. Clair WH. RelB regulates manganese superoxide dismutase gene and resistance to ionizing radiation of prostate cancer cells. Oncogene 2005,25:1554-9.
143、 Scott SL, Gumerlock PH, Beckett L, Li Y, Goldberg Z. Survival and cell cycle kinetics of human prostate cancer cell lines after single- and multifraction exposures to ionizing radiation. Int J Radiat Oncol Biol Phys 2004,59:219-27.
144、 J.S. Horoszewicz, S.S. Leong, T.M. Chu, Z.L. Wajsman, M. Friedman, L. Papsidero, et al., The lncap cell line—a new model for studies on human prostatic carcinoma, Prog. Clin. Biol. Res. 1980,37:115-132.
145、 R.E. Sobel, M.D. Sadar, Cell lines used in prostate cancer research: a compendium of old and new lines—part 1, J. Urol. 2005, 173:342-359.
146、 R.E. Sobel, M.D. Sadar, Cell lines used in prostate cancer research: a compendium of old and new lines—part 2, J. Urol. 2005, 173:360-372.
147、 G.N. Thalmann, P.E. Anezinis, S.M. Chang, H.E. Zhau, E.E. Kim, V.L. Hopwood, et al., Androgen-independent cancer progression and bone metastasis in the lncap model of human prostate cancer, Cancer Res. 1994,54:2577-2581.
148、 G.N. Thalmann, R.A. Sikes, T.T. Wu, A. Degeorges, S.M. Chang, M. Ozen, et al., Lncap progression model of human prostate cancer: androgen-independence and osseous metastasis, Prostate ,2000, 144(102):91-103.
149、 L. Trojan, A. Schaaf, A. Steidler, M. Haak, G. Thalmann, T. Knoll, et al., Identification of metastasis-associated genes in prostate cancer by genetic profiling of human prostate cancer cell lines, Anticancer Res. 2005, 25: 183-191.
150、 M. Bisoffi, I. Klima, E. Gresko, P.N. Durfee, W.C. Hines, J.K. Griffith, et al., Expression profiles of androgen independent bone metastatic prostate cancer cells indicate up-regulation ofthe putative serine-threonine kinase gs3955, J. Urol. 2004,172:1145-1150.
151、 Asa J Oudes, Jared C Roach, Laura S Walashek et al.Application of affymetrix array and massively parallel signature sequencing for identification of genes involved in prostate cancer progression . BMC Cancer 2005, 5:86
152、 Cla'udia M. Coutinho-Camilloa, Sibeli Salaorni et al. Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen Cancer Genetics and Cytogenetics. 2006,166:130-138
153、 See-Tong Pang, Wen-Hui Weng, Amilcar Flores-Morales et al.Cytogenetic and Expression ProfilesAssociated WithTransformationtoAndrogen-Resistant ProstateCancer The Prostate 2006,66:157-172.
154、 Blank, V.; Andrews, N. C. The Maf transcription factors: regulators of differentiation. Trends Biochem. Sci. [J] 1997, 22(11):437-41
155、 Qiu, Y.; Krishnan, V.; Zeng, Z.; et al. Isolation, characterization, and chromosomal localization of mouse and human COUP-TF I and II genes. Genomics [J]. 1995, 29(1): 240-6.
156、 Levesque E, Turgeon D, Carrier JS, et al. Isolation and characterization of the UGT2B28 cDNA encoding a novel human steroid conjugating UDP-glucuronosyltransferase. Biochemistry [J] .2001,40 (13): 3869-3881.
157、 S. Funghini, M.A. Donati, E. Pasquini, et al. Structural Organization of the Human Carbamyl Phosphate Synthetase I Gene (CPS1) and Identification of Two Novel Genetic Lesions [J].2003,22(4):340-1.
158、 Isaacs JT (1999) The biology of hormone refractory prostate cancer. Why does it develop? Urol Clin North Am 26:263-273.
159、 Newling DW, Dennis L, Vermeylen K Orchiectomy versus goesrelin and flutamide in the treatment of newly diagnosed metastatic prostate cancer. Cancer ,1993,72:3793-3798.
160、 Mark Garzotto, Adriana Haimovitz-Friedman, Wen-Chieh Liao et al.Reversal of Radiation Resistance in LNCaP Cells by Targeting Apoptosis through Ceramide Synthase CANCER RESEARCH. 1999,59:5194-5201.
161、 Shuhei Matsuoka, Bryan A. Ballif, Agata Smogorzewska et al. ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage Science 2007,316:1160-1166.
162、 Heisler, L.E., Evangelou, A., Lew, A.M., Trachtenberg, J., Elsholtz, H..P. &Brown, T..J.() Mol. Cell. Endocrinol. 1997,126:59-73.
163、 Hongyan Wang, Huichen Wang, Simon N. Powel et al. ATR Affecting Cell Radiosensitivity Is Dependent on Homologous Recombination Repair but Independent of Nonhomologous End Joining CANCER RESEARCH 2004,64:7139-7143.
164、 Mohammed S. Inayat. Damodaran Chendi, Mohammed Mohiuddin et al. Didox (A Novel Ribonucleotide Reductase Inhibitor) Overcomes bcl-2 Mediated Radiation Resistance in Prostate Cancer Cell Line PC-3 Cancer Biology & Therapy 2002,l(5):539-545.
165、 Zheng Wang,1 Ying Hao,l and Anson W. Lowe The Adenocarcinoma-Associated Antigen, AGR2, Promotes Tumor Growth, Cell Migration, and Cellular Transformation Cancer Res 2008,68(2): 492-497.
166、 Glen Kristiansen, Christian Pilarsky, Christoph Wissmann et al. Expression profiling of microdissected matched prostate cancer samples reveals CD166/MEMD and CD24 as new prognostic markers for patient survival J Pathol 2005, 205:359-376.
167、 David B. Miklos, Haesook T. Kim, Katherine H. Miller et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission BLOOD.2005,105:2973-2978.
168、 Peter Oettgen , Koen Kas , Antoinise Dube et al. Characterization of ESE-2, a Novel ESE-1 -related Ets Transcription Factor That Is Restricted to Glandular Epithelium and Differentiated Keratinocytes 1999,274(41):29439-29452,
169、 Javier A. Menendez and Ruth Lupu Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis nat ure reviews cancer 2007,7:763-777.
170、 Weiping Le a, Azfar S. Abbas a, Howard Sprecher et al. Long-chain acyl-CoA dehydrogenase is a key enzyme in themitochondrial L-oxidation of unsaturated fatty acids Biochimica et BiophysicaActa2000,1485:121-128.
1.Lubahn DB,Joseph DR,Sar M,Tan J,et al.The human androgen receptor:complementary deoxyribonucleic acid cloning,sequence analysis and gene expression in prostate[J].Mol Endocrinol, 1988,2(12): 1265-75
2. Cunha GR, Donjacour AA, Cooke PS, et al. The endocrinology and developmental biology of the prostate [J]. Endocr Rev, 1987, 8(3):338-62
3. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy [J]. Nat Med, 2004, 10:33 - 39
4. Shibata H, Spencer TE, Onate SA, et al. Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action [J]. Recent Prog Horm Res, 1997,52:141-64; discussion 164-5.
5. Xu L, Glass CK, Rosenfeld MG. Coactivator and corepressor complexes in nuclear receptor function [J]. Curr Opin Genet Dev, 1999, 9(2): 140-7
6. McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology [J]. Endocr Rev, 1999, 20 (3): 321-344
7 . http: //www3. interscience. wiley.com/ cgi-bin/ fulltext/113511967/HTMLSTART)
8. Chen H, Lin RJ, Schiltz RL, et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300 [J]. Cell, 1997, 90(3):569-80
9. Stallcup MR, Kim JH, Teyssier C, et al. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators [J]. J Steroid Biochem Mol Biol, 2003, 85(2-5):139-45
10. Gregory CW, He B, Johnson RT, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy [J]. Cancer Res, 2001, 61:4315-4319
11. Zhou HJ, Yan J, Luo W, et al. SRC-3 is required for prostate cancer cell proliferation and survival [J]. Cancer Res, 2005, 65:7976-7983
12. Halkidou K, Gnanapragasam VJ, Mehta PB, et al. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development [J]. Oncogene, 2003, 22(16):2466-77
13. Nishimura K, Ting HJ, Harada Y, et al. Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator [J]. Cancer Res, 2003,63: 4888-4894
14. Cunningham CC, Stossel TP, Kwiatkowski DJ. Enhanced motility in NIH 3T3 fibroblasts that overexpress gelsolin [A]. Science, 1991, 251(4998): 1233-1236
15. Taneja SS, Ha S, Swenson NK, et al. ART-27, an androgen receptor coactivator regulated in prostate development and cancer [J]. J Biol Chem, 2004,279(14):13944-13952
16. Hsiao PW, Lin DL, Nakao R, et al. The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator [J]. J Biol Chem, 1999, 274(29):20229-34
17. Li P, Yu X, Ge K, et al. Heterogeneous expression and functions of androgen receptor co-factors in primary prostate cancer [J]. Am J Pathol, 2002,161 (4): 1467-1474
18. Fujimoto N, Yeh S, Kang HY, et al. Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate [J]. J Biol Chem, 1999, 274(12):8316-8321
19. Miyoshi Y, Ishiguro H, Uemura H, et al. Expression of AR associated protein 55 (ARA55) and androgen receptor in prostate cancer [J]. Prostate, 2003,56(4):280-6.
20. Miyamoto H, Rahman MM, Chang C. Molecular basis for the antiandrogen withdrawal syndrome [J]. J Cell Biochem, 2004, 91(1):3-12
[1]A.Jemal,T Murray,E Ward,et al.Cancer statistics,CA Cancer J.Clin[J],2005,55(1):10-30
[2]C.Huggins,C.V.Hodges,Studies on prostate cancer:Ⅰ.The effect of castration,of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate,Cancer Res[J].1972,2:232-240
[3]C.Huggins,R.E.Stevens,C.V.Hodges.Studies on prostate cancer:Ii.The effects of castration on advanced carcinoma of the prostate gland,Arch.Surg.[J].1941,43:209
[4]G.N.Thalmann,P.E.Anezinis,S.M.Chang,et al.androgen-independent cancer progression and bone metastasis in the lncap model of human prostate cancer,Cancer Res[J].1994,54:2577-2581
[5]Blank,V.;Andrews,N.C.The Maf transcription factors:regulators of differentiation.Trends Biochem.Sci.[J]1997,22(11):437-41
[6]Qiu,Y.;Krishnan,V.;Zeng,Z.;et al.Isolation,characterization,and chromosomal localization of mouse and human COUP-TF Ⅰ and Ⅱ genes.Genomics[J].1995,29(1):240-6
[7]R.J.Jin,C.Kwak,S.G.Lee,et al.The application of an anti-angiogenic gene (thrornbospondin-1)in the treatment of human prostate cancer xenografts,Cancer Gene Ther[J]2000,7(12):1537-42
[8]M.Colombel,S.Filleur,R Fournier,et al.Androgens repress the expression of the angiogenesis inhibitor thrombospondin-1 in normal and neoplastic prostate,Cancer Res[J].2005,65:300-308
[9]Levesque E,Turgeon D,Carrier JS,et al.Isolation and characterization of the UGT2B28cDNA encoding a novel human steroid conjugating UDP-glucuronosyltransferase.Biochemistry [J].2001,40(13):3869-3881
[10]S.Funghini,M.A.Donati,E.Pasquini,et al.Structural Organization of the Human Carbamyl Phosphate Synthetase Ⅰ Gene(CPS1)and Identification of Two Novel Genetic Lesions [J].2003,22(4):340-1