TIP30启动子甲基化与结直肠癌Folfox方案疗效的关系
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摘要
研究背景：
近年来结直肠癌(colorectal cancer，CRC)的发病率不断升高，在恶性肿瘤死因中位居于前4位，是人类恶性肿瘤中最常见的一种。结直肠癌的复发转移是导致癌症患者死亡的主要原因，而其相对应的治疗及护理费用也在明显增张。今后相当长一段时间内我国的结直肠癌患者的发病率和死亡率将逐步上升。因此，对于结直肠癌的不断研究也一直是国外的医学热点。根据每例结直肠癌患者的具体情况，制定合适患者的个体化综合治理策略，是当今结直肠癌诊疗的发展方向。只有规范结直肠癌的临床诊疗路径，完善术后随访制度和加速肿瘤分子标记物的研究，才能达到实现个体化治疗从而使患者最大化获益的目的。作为TSG（tumor suppressor gene,抑癌基因）的TIP30，已经被众多实验研究证实了其与结直肠癌的发生、发展的关系。有关研究也已经证实，TIP30基因启动子甲基化是导致TIP30低表达的重要原因之一，且与结直肠癌细胞株对化疗药物敏感性密切相关。
目的：
本研究旨在探寻TIP30启动子甲基化状态与结直肠癌患者临床病理特征、预后及对化疗敏感性的关系，为其作为结直肠癌预后和预测指标提供理论基础，为结直肠癌个体化化疗提供新的途径。
研究方法：
采用甲基化特异性PCR（MSP）和甲基化测序PCR（BSP）方法检测230例结直肠癌组织及配对癌旁组织中TIP30基因启动子甲基化状态。使用SPSS13.0统计学软件进行统计学处理，采用χ2和Logrank检验分析TIP30基因启动子甲基化状态与患者临床病理特征（包括患者临床分期、病变部位、淋巴结转移等）的相关性。
结果：
1肿瘤组织TIP30启动子甲基化阳性率为35.22%，癌旁组织TIP30启动子甲基化阳性率为17.39%，二者间差异有统计学意义（P<0.05）。
2结肠癌患者中TIP30启动子甲基化阳性率为28.57%，直肠癌患者肿瘤组织中TIP30启动子甲基化阳性率为40.80%，二者间差异有统计学意义（P<0.05）。
3存在淋巴结转移的结直肠癌患者肿瘤组织TIP30启动子甲基化阳性率为41.57%，而淋巴结转移阴性患者肿瘤组织TIP30启动子甲基化阳性率为13.46%，二者间差异具有统计学意义（P<0.05）。
4Ⅱ期患者肿瘤组织中TIP30启动子甲基化阳性率为18.03%，Ⅲ期患者肿瘤组织中TIP30启动子甲基化阳性率为28.99%，Ⅳ期患者肿瘤组织中TIP30启动子甲基化阳性率为50.00%。Ⅱ期和Ⅲ期患者间TIP30启动子甲基化阳性率差异无统计学意义(P=0.144),而Ⅲ期和Ⅳ期患者相比，Ⅱ期和Ⅳ期患者相比，TIP30启动子甲基化阳性率差异皆具有统计学意义（P<0.05）。
5结直肠腺癌患者肿瘤组织TIP30启动子甲基化阳性率为33.54%，伴粘液腺癌及其他病理类型患者肿瘤组织TIP30启动子甲基化阳性率为39.13%，二者间差异无统计学意义（P=0.416）。
6在100例晚期结直肠癌患者中，结肠癌患者接受改良FOLFOX6方案化疗后临床获益率（PR+CR+SD）为67.39%，而直肠癌患者仅为46.29%，二者间差异具有统计学意义（P<0.05）。在130例结直肠癌根治术后辅助化疗患中，结肠癌患者中位DFS为28个月，直肠癌患者中位DFS为30个月，二者间差异无统计学意义（P=0.4644）。
7在100例晚期结直肠癌患者中，TIP30启动子甲基化阳性患者接受改良FOLFOX6方案化疗的临床获益率（PR+CR+SD）为54%，而TIP30启动子甲基化阴性患者接受改良FOLFOX6方案化疗的临床获益率为74%，二者间差异具有统计学意义（P<0.05）。在130例结直肠癌根治术后接受辅助化疗的患者中，TIP30启动子甲基化阳性患者中位DFS为25个月，而TIP30启动子甲基化阴性患者中位DFS为29个月，二者间差异无统计学意义（P=0.4644）。
结论:
TIP30启动子高甲基化与肿瘤位置、临床分期、复发转移相关，与病理类型无明显相关性。在化疗疗效方面，肿瘤位置及TIP30启动子甲基化状态与晚期结直肠癌患者化疗疾病控制率相关，而与术后辅助化疗患者DFS仅呈现相关趋势，无统计学意义。提示TIP30启动子甲基化是结直肠癌预后不良的指标之一，有望成为一种新的预后指标及化疗疗效预测指标，为肿瘤个体化治疗提供临床依据。
Background:
Colorectal cancer (CRC) is the most common malignant disease in the world. The incidence ofCRC has increased in recent years and the mortality lies in the fourth among human malignancies,therecurrence and metastasis are the main reasons leading to the death of patients with CRC, correspondingly,costs of thearopy and care also increased significantly. The morbidity and mortality of colorectal cancerwill gradually arise in quite a long period of time in the future in China. Therefore, the ongoing research forcolorectal cancer has also been a medical focus on the domestic and international. Today.,thecomprehensive strategy should be made individually and acted as the direction of patients with colorectalcancer. Only standardized treatment, improved postoperative follow-up system and the acceleration of theresearch of tumor molecular markers is achieved, the patients with CRC can be treated individually andgain the maximize benefits. TIP30,a tumor suppressor gene (TSG), has been confirmed its relationship tothe carcinogenesis and the evolution of colorectal cancer in numerous studies. the data has also showed thatTIP30gene promoter methylation is the main cause of low TIP30expression and is closely correlated tothe sensitivity to chemotherapeutic drugs in colorectal cancer cell lines.
Objective:
The purpose of this study was to explore the relationship between the status of TIP30promotermethylation and clinicopathological features, prognosis and chemosensitivity in patients with colorectalcancer and it provide an evidence to that TIP30act as a prognostic and predictive indicator theoritically andprovide a new way for individualized treatment in patients with colorectal cancer.
Material and methods:
The methylation status of TIP30between230cases of patients with CRC and the paired normalcolorectal samples was detected using Bisulfite DNA sequencing (BSP) and methylation-specific PCR(MSP). Statistical analysis was carried out using the Statistical Package for Social Sciences(SPSS)，version13.0, Chi－square test and Logrank Test were used to test the association between TIP30gene methylationand the clinicopathological features of patients (tumor gross type, tumor type, lymph node metastasis).
Results:
1In colorectal cancers, the rate of TIP30promoter methylation was35.22%and the rate ofadjacent tissue was17.39%, the difference was statistically significant (P <0.05).
2The rate of TIP30promoter methylation in patients with colon cancer was28.57%and therate in patients with rectal cancer was40.80%, the difference was statistically significant (P <0.05).
3the rate of TIP30promoter methylation in patients with lymph node metastasis was41.57%,while the rate in patients with lymph node metastasis-negative tumor was13.46%, the difference wasstatistically significant (P<0.05).
4the rate of TIP30promoter methylation in phase II patients was18.03%, while the rate inphase III patients is28.99%, and the rate in phase IV patients is50.00%.there was no statistically differencebetween Phase II and III patients (P=0.144), and there was statistically different between patients in stageⅢ and Ⅳ, and there was a significantly difference between patients in Phase II and IV (P <0.05).
5the rate of TIP30promoter methylation in patients with colorectal adenocarcinoma was33.54%, while the rate in patients with mucinous adenocarcinoma and other types was39.13%, there wasno significant difference between this two groups (P=0.416).
6In100patients with advanced colorectal cancer, the response rate (PR+CR+SD) in patientswith colon cancer received modified FOLFOX6regimen was67.39%, the rate of patients with rectal cancerwas46.29%, there was a statistically difference between the two groups. In130cases of colorectal cancer,the median DFS in patients with colon cancer suffered postoperative adjuvant chemotherapy was28months, while the median DFS in patients with rectal cancer was30months, there was no significantdifference between the two groups (P=.4644).
7in100patients with advanced colorectal cancer, the response rate in TIP30promotermethylation-positive patients receive modified FOLFOX6regimen was54%, while the rate in TIP30promoter methylation-negative patients was74%, there was a statistically significant difference betweenthe two groups (P <0.05). in130cases of colorectal cancer, the median DFS in TIP30promotermethylation-positive patients was25months, the median DFS in patients without TIP30promotermethylation was29months, there was not statistically different between the two groups.
Conclusions:
TIP30hypermethylation are associated with the location, stage, recurrence and metastasis oftumor and it has no correlation with its pathological characters. tumor location and TIP30promotermethylation status was associated with the disease control rate of chemotherapy in patients with advancedcolorectal cancer, while it only has trends in tumor location, TIP30promoter methylation status and theDFS received postoperative adjuvant chemotherapy, there is not statistically significant between them.theresults show that TIP30promoter methylation status is a poor prognosis indicator in patients with colorectalcancer and is expected to be a new prognostic indicator and a indicator to predict the efficacy ofchemotherapy to for individualized treatment in patients with colorectal cancer.
近年来结直肠癌(colorectal cancer，CRC)的发病率不断升高，在恶性肿瘤死因中位居于前4位，是人类恶性肿瘤中最常见的一种。结直肠癌的复发转移是导致癌症患者死亡的主要原因，而其相对应的治疗及护理费用也在明显增张。今后相当长一段时间内我国的结直肠癌患者的发病率和死亡率将逐步上升。因此，对于结直肠癌的不断研究也一直是国外的医学热点。根据每例结直肠癌患者的具体情况，制定合适患者的个体化综合治理策略，是当今结直肠癌诊疗的发展方向。只有规范结直肠癌的临床诊疗路径，完善术后随访制度和加速肿瘤分子标记物的研究，才能达到实现个体化治疗从而使患者最大化获益的目的。作为TSG（tumor suppressor gene,抑癌基因）的TIP30，已经被众多实验研究证实了其与结直肠癌的发生、发展的关系。有关研究也已经证实，TIP30基因启动子甲基化是导致TIP30低表达的重要原因之一，且与结直肠癌细胞株对化疗药物敏感性密切相关。
目的：
本研究旨在探寻TIP30启动子甲基化状态与结直肠癌患者临床病理特征、预后及对化疗敏感性的关系，为其作为结直肠癌预后和预测指标提供理论基础，为结直肠癌个体化化疗提供新的途径。
研究方法：
采用甲基化特异性PCR（MSP）和甲基化测序PCR（BSP）方法检测230例结直肠癌组织及配对癌旁组织中TIP30基因启动子甲基化状态。使用SPSS13.0统计学软件进行统计学处理，采用χ2和Logrank检验分析TIP30基因启动子甲基化状态与患者临床病理特征（包括患者临床分期、病变部位、淋巴结转移等）的相关性。
结果：
1肿瘤组织TIP30启动子甲基化阳性率为35.22%，癌旁组织TIP30启动子甲基化阳性率为17.39%，二者间差异有统计学意义（P<0.05）。
2结肠癌患者中TIP30启动子甲基化阳性率为28.57%，直肠癌患者肿瘤组织中TIP30启动子甲基化阳性率为40.80%，二者间差异有统计学意义（P<0.05）。
3存在淋巴结转移的结直肠癌患者肿瘤组织TIP30启动子甲基化阳性率为41.57%，而淋巴结转移阴性患者肿瘤组织TIP30启动子甲基化阳性率为13.46%，二者间差异具有统计学意义（P<0.05）。
4Ⅱ期患者肿瘤组织中TIP30启动子甲基化阳性率为18.03%，Ⅲ期患者肿瘤组织中TIP30启动子甲基化阳性率为28.99%，Ⅳ期患者肿瘤组织中TIP30启动子甲基化阳性率为50.00%。Ⅱ期和Ⅲ期患者间TIP30启动子甲基化阳性率差异无统计学意义(P=0.144),而Ⅲ期和Ⅳ期患者相比，Ⅱ期和Ⅳ期患者相比，TIP30启动子甲基化阳性率差异皆具有统计学意义（P<0.05）。
5结直肠腺癌患者肿瘤组织TIP30启动子甲基化阳性率为33.54%，伴粘液腺癌及其他病理类型患者肿瘤组织TIP30启动子甲基化阳性率为39.13%，二者间差异无统计学意义（P=0.416）。
6在100例晚期结直肠癌患者中，结肠癌患者接受改良FOLFOX6方案化疗后临床获益率（PR+CR+SD）为67.39%，而直肠癌患者仅为46.29%，二者间差异具有统计学意义（P<0.05）。在130例结直肠癌根治术后辅助化疗患中，结肠癌患者中位DFS为28个月，直肠癌患者中位DFS为30个月，二者间差异无统计学意义（P=0.4644）。
7在100例晚期结直肠癌患者中，TIP30启动子甲基化阳性患者接受改良FOLFOX6方案化疗的临床获益率（PR+CR+SD）为54%，而TIP30启动子甲基化阴性患者接受改良FOLFOX6方案化疗的临床获益率为74%，二者间差异具有统计学意义（P<0.05）。在130例结直肠癌根治术后接受辅助化疗的患者中，TIP30启动子甲基化阳性患者中位DFS为25个月，而TIP30启动子甲基化阴性患者中位DFS为29个月，二者间差异无统计学意义（P=0.4644）。
结论:
TIP30启动子高甲基化与肿瘤位置、临床分期、复发转移相关，与病理类型无明显相关性。在化疗疗效方面，肿瘤位置及TIP30启动子甲基化状态与晚期结直肠癌患者化疗疾病控制率相关，而与术后辅助化疗患者DFS仅呈现相关趋势，无统计学意义。提示TIP30启动子甲基化是结直肠癌预后不良的指标之一，有望成为一种新的预后指标及化疗疗效预测指标，为肿瘤个体化治疗提供临床依据。
Background:
Colorectal cancer (CRC) is the most common malignant disease in the world. The incidence ofCRC has increased in recent years and the mortality lies in the fourth among human malignancies,therecurrence and metastasis are the main reasons leading to the death of patients with CRC, correspondingly,costs of thearopy and care also increased significantly. The morbidity and mortality of colorectal cancerwill gradually arise in quite a long period of time in the future in China. Therefore, the ongoing research forcolorectal cancer has also been a medical focus on the domestic and international. Today.,thecomprehensive strategy should be made individually and acted as the direction of patients with colorectalcancer. Only standardized treatment, improved postoperative follow-up system and the acceleration of theresearch of tumor molecular markers is achieved, the patients with CRC can be treated individually andgain the maximize benefits. TIP30,a tumor suppressor gene (TSG), has been confirmed its relationship tothe carcinogenesis and the evolution of colorectal cancer in numerous studies. the data has also showed thatTIP30gene promoter methylation is the main cause of low TIP30expression and is closely correlated tothe sensitivity to chemotherapeutic drugs in colorectal cancer cell lines.
Objective:
The purpose of this study was to explore the relationship between the status of TIP30promotermethylation and clinicopathological features, prognosis and chemosensitivity in patients with colorectalcancer and it provide an evidence to that TIP30act as a prognostic and predictive indicator theoritically andprovide a new way for individualized treatment in patients with colorectal cancer.
Material and methods:
The methylation status of TIP30between230cases of patients with CRC and the paired normalcolorectal samples was detected using Bisulfite DNA sequencing (BSP) and methylation-specific PCR(MSP). Statistical analysis was carried out using the Statistical Package for Social Sciences(SPSS)，version13.0, Chi－square test and Logrank Test were used to test the association between TIP30gene methylationand the clinicopathological features of patients (tumor gross type, tumor type, lymph node metastasis).
Results:
1In colorectal cancers, the rate of TIP30promoter methylation was35.22%and the rate ofadjacent tissue was17.39%, the difference was statistically significant (P <0.05).
2The rate of TIP30promoter methylation in patients with colon cancer was28.57%and therate in patients with rectal cancer was40.80%, the difference was statistically significant (P <0.05).
3the rate of TIP30promoter methylation in patients with lymph node metastasis was41.57%,while the rate in patients with lymph node metastasis-negative tumor was13.46%, the difference wasstatistically significant (P<0.05).
4the rate of TIP30promoter methylation in phase II patients was18.03%, while the rate inphase III patients is28.99%, and the rate in phase IV patients is50.00%.there was no statistically differencebetween Phase II and III patients (P=0.144), and there was statistically different between patients in stageⅢ and Ⅳ, and there was a significantly difference between patients in Phase II and IV (P <0.05).
5the rate of TIP30promoter methylation in patients with colorectal adenocarcinoma was33.54%, while the rate in patients with mucinous adenocarcinoma and other types was39.13%, there wasno significant difference between this two groups (P=0.416).
6In100patients with advanced colorectal cancer, the response rate (PR+CR+SD) in patientswith colon cancer received modified FOLFOX6regimen was67.39%, the rate of patients with rectal cancerwas46.29%, there was a statistically difference between the two groups. In130cases of colorectal cancer,the median DFS in patients with colon cancer suffered postoperative adjuvant chemotherapy was28months, while the median DFS in patients with rectal cancer was30months, there was no significantdifference between the two groups (P=.4644).
7in100patients with advanced colorectal cancer, the response rate in TIP30promotermethylation-positive patients receive modified FOLFOX6regimen was54%, while the rate in TIP30promoter methylation-negative patients was74%, there was a statistically significant difference betweenthe two groups (P <0.05). in130cases of colorectal cancer, the median DFS in TIP30promotermethylation-positive patients was25months, the median DFS in patients without TIP30promotermethylation was29months, there was not statistically different between the two groups.
Conclusions:
TIP30hypermethylation are associated with the location, stage, recurrence and metastasis oftumor and it has no correlation with its pathological characters. tumor location and TIP30promotermethylation status was associated with the disease control rate of chemotherapy in patients with advancedcolorectal cancer, while it only has trends in tumor location, TIP30promoter methylation status and theDFS received postoperative adjuvant chemotherapy, there is not statistically significant between them.theresults show that TIP30promoter methylation status is a poor prognosis indicator in patients with colorectalcancer and is expected to be a new prognostic indicator and a indicator to predict the efficacy ofchemotherapy to for individualized treatment in patients with colorectal cancer.
引文
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[27] Xian H，Paihan V，Yang Y，et a1．TIP30has an intrinsic kinase activity required for up-regulationof asubset of apeptotic genes．The EMBO joumal，2000，19(5)：956-963
[28] Ei Ommi K，Bird LE，Nichols CE，et a1．Crystal structure0f CC3(TIP30)：implication for its rolea tumor suppressor．J Bid Chem，2005，280(18)：18229-18236
[29] TANG Bin，HE Chang.Expression of Tat Interacting Protein30in Colorectal Carcinomas and ItsClinical Significance.JOURNAL OF GUIYANG MEDICAL COLLEGE.2010,35(6):593-595
[30] ZHANG Xia，OUYANG Xue-nong, LI Xiao-dong，et al. Acad J Sec Mil Med Univ.2005,26(5):488-491
[31] Li X，Zhang Y，Cao S，et al．Reduction of TIP30correlates with poor prognosis of gastric cancerpatients and its restoration drastically inhibits tumor growth and metastasis． Int JCancer．2009,124(3)：713-21：356-360
[32] Ito M, Jiang C, Krumm K, et al. TIP30deficiency increases susceptibility to tumorigenesis[J].Cancer Res,2003,63(24):8763-8767
[33] Esteller M. Epigenetics in cancer[J]. N Engl J Med,2008,358(11):1148-1159.
[34] Cottrell SE, Laird PW. Sensitive detection of DNA methylation[J]. Ann N Y Acad Sci,2003,983:120-130.
[35] Plumb JA, Steele N, Finn PW, et al. Epigenetic approaches to cancer therapy[J]. Biochem Soc Trans,2004,32(Pt6):1095-1097.
[36] Worm J, Kirkin AF, Dzhandzhugazyan KN, et al. Methylation-dependent silencing of the reducedfolate carrier gene in inherently methotrexate-resistant human breast cancer cells[J]. J Biol Chem,2001,276(43):39990-40000.
[37] Ishii T, Fujishiro M, Masuda M, et al. A methylated oligonucleotide induced methylation of GSTP1promoter and suppressed its expression in A549lung adenocarcinoma cells[J]. Cancer Lett,2004,212(2):211-223.
[38] Frommer M, McDonald L E, Millar D S, et al. A genomic sequencing protocol that yields a positivedisplay of5-methylcytosine residues in individual DNA strands [J]. Proc Natl Acad Sci USA,1992,89:1827–1831.
[39]朱燕. DNA的甲基化的分析与状态检测[J].现代预防医学,2005,32(9):1070-1073.
[40] Herman J G, Graff J R, Myohanen S, et al. Methylation-specific PCR: a novel PCR assay formethylation status of CpG islands [J]. Proc Natl Acad Sci USA,1996, Sep3.93(18),9821-9826
[41]黄琼晓,金帆,黄荷凤.DNA甲基化的研究方法学[J].国外医学遗传学分册,2004,27(6):354-358.
[42]陈小兵．抑癌基因TIP30启动子甲基化与大肠癌侵袭和转移的关系[D]．河南：郑州大学，2010．
[1] Shtivelman E. A link between metastasis and resistance to apoptosis of variant small cell lungcarcinoma. Oncogene,1997,14:2167-2178
[2] Xiao H, Tao Y, Greenblatt J, et al. A cofactor, TIP30, specifically enhances HIV-1Tat-activatedtranscription. Proc Natl Acad Sci USA,1998,95:2146-2151
[3] Whitman S, Wang X, Shalaby R, et al. Alternatively spliced products CC3and TC3have opposingeffects on apoptosis. Mol Cell Biol,2000,20:583-593
[4] NicAmhlaoibh R, Shtivelman E. Metastasis suppressor CC3inhibits angiogenic properties of tumorcells in vitro. Oncogene,2001,20:270-275
[5] Liu Y, Thor A, Shtivelman E, et al. Systemic gene delivery expands the repertoire of effectiveantiangiogenic agents. J Biol Chem,1999,274:13338-13344
[6] Xian H，Paihan V，Yang Y，et a1．TIP30has an intrinsic kinase activity required for up-regulation ofasubset of apeptotic genes．The EMBO joumal，2000，19(5)：956-963．
[7] Ei Ommi K，Bird LE，Nichols CE，et a1．Crystal structure0f CC3(TIP30)：implication for its role atumor suppressor．J Bid Chem，2005，280(18)：18229-18236
[8] Zhang X, Ouyany XN, Xuenong O. The correlation between the expression of TIP30and of VEGF inhuman HCC tissues and its cell line. Chin J Clin Oncol,2005,32:489-492.
[9] Xiao H, Palhan V, Yang Y, et al. TIP30has an intrinsic kinase activity required for up2regulation of asubset of apoptotic genes. EMBO J,2000,19:956-963
[10] Xiao H, Tao Y, Greenblatt J, et al. A cofactor, TIP30, specifically enhances HIV21Tat2activatedtranscription. Proc Natl Acad Sci USA,1998,95:2146-2151
[11] Zhang X, Zhan J, Li XD, et al. Construction of adenovirus vector expressing TIP30gene and itstumor suppressing effects in vitro and in vivo. Chin J Oncol,2004,26:85-88
[12] Kuo PL, Chiang LC, Lin CC, et al. Resveratrol-induced apoptosis is mediated by p532dependentpathway in HepG2cells. Life Sci,2002,72:23-34
[13] Jiang ZM, Lu CT. Attenuated salmoneller mediated fusion genes inhibit tumor angiogenesis in BALB/c mice with human salivary adenoid cystic carcinoma. Acad J Sec Mil Med Univ,2005,26:609-612
[14] Shi W Y, Skeat h J B. The drosophila RCC1homolog, Bj1,regulates nucleocytoplasmic transport andneural differentiation during drosophila development [J]. Dev Biol,2004,270:106-121
[15] May E F. Nucleocytoplasmic t ransport in apoptosis [J]. Cell Death and Differentiation,2005,12:1263-1276
[16] King F W, Shtivelman E. Inhibition of nuclear import by theproapoptotic protein CC3[J]. Mol CellBiol,2004,24:7091-7101
[17] Zhang X, Tsukamoto T, Mizoshita T，el a1．Expression of ostepopontin and CDX2：indication ofphenotypes and prognosis in advanced gastric cancer．Oncol Rep，2009，2l(3)：609-613．
[18] Cho H，Kang ES，Kim YT，et a1．Diagnostic and prognostic impact of osteopontin expression inendometrial caner．Cancer Invest．2009，27(3)：313-323
[19] Korits PV, Wakai T，Shimi Y，et a1．Overexpreosion of osteopontin independently correlates withvascular invasion and poor prognosis in with hepatoeellular carcinoma．Hum Pathol，2008，39(12)：1777-1783
[20] Tong X， Li K，Luo z，el at. Decreased TIP30expression promotes tumor metastasis in lungcancer．Am J Path01．2009，174(5)：1931-1939
[21] Zhao J，Lu B，Xu H，et a1．Thirty-kilodahon Tat-interacting protein suppresses tumor metastasis byinhibition of osteopontin transcription in human hepatocellular carcinoma，Hepatology.2008.48(1)：265-275
[22] Jiang C，Pecha J，Hoshino I，et a1．TIP30mutant derived from hepatocellula carcinoma specimenspromotes growth of HepG2cells through up-regulation of N-canherin，Cancer Res，2007，67(8)：3574-3582
[23] Zhao J，Zhang X，Shi M, et a1．TIP30inhibits growth of HCC cell lines and inhibits HCC xenograftsin mice in combination with5-FU．Hepatology Baltimore，2006；44(1)：205-15．
[24] Jiang C，Pecha J，Hoshino I，et a1． TIP30mutant derived from hepatocellular carcinoma specimenspromotes growth of HepG2cells through up-regulation of N-cadherin．Cancer research,2007,67(8)：3574-82
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[30] ZHANG Xia，OUYANG Xue-nong, LI Xiao-dong, et al. Acad J Sec Mil Med Univ.2005,26(5):488-491
[31] Li X，Zhang Y，Cao S，et al．Reduction of TIP30correlates with poor prognosis of gastric cancerpatients and its restoration drastically inhibits tumor growth and metastasis． Int JCancer．2009,124(3)：713-21：356-360
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[11] Whitman S, Wang X, Shalaby R, et al. Alternatively spliced products CC3and TC3have opposingeffects on apoptosis. Mol Cell Biol,2000,20:583-593.
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[13] ZHANG Xia，OUYANG Xue-nong, LI Xiao-dong，et al.Acad J Sec Mil Med Univ.2005,26(5):488-491.
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[26] KW Suh，JH Kim，do Y Kim，et a1．Which gene is a dominant predictor of response duringFOLFOX chemotherapy for the treatment of metastatic colorectal cancer,the MTHFR or XRCClgene[J]．Ann Surg Oncol，2006,13(11)：1379-1385
[27] Xian H，Paihan V，Yang Y，et a1．TIP30has an intrinsic kinase activity required for up-regulationof asubset of apeptotic genes．The EMBO joumal，2000，19(5)：956-963
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[29] TANG Bin，HE Chang.Expression of Tat Interacting Protein30in Colorectal Carcinomas and ItsClinical Significance.JOURNAL OF GUIYANG MEDICAL COLLEGE.2010,35(6):593-595
[30] ZHANG Xia，OUYANG Xue-nong, LI Xiao-dong，et al. Acad J Sec Mil Med Univ.2005,26(5):488-491
[31] Li X，Zhang Y，Cao S，et al．Reduction of TIP30correlates with poor prognosis of gastric cancerpatients and its restoration drastically inhibits tumor growth and metastasis． Int JCancer．2009,124(3)：713-21：356-360
[32] Ito M, Jiang C, Krumm K, et al. TIP30deficiency increases susceptibility to tumorigenesis[J].Cancer Res,2003,63(24):8763-8767
[33] Esteller M. Epigenetics in cancer[J]. N Engl J Med,2008,358(11):1148-1159.
[34] Cottrell SE, Laird PW. Sensitive detection of DNA methylation[J]. Ann N Y Acad Sci,2003,983:120-130.
[35] Plumb JA, Steele N, Finn PW, et al. Epigenetic approaches to cancer therapy[J]. Biochem Soc Trans,2004,32(Pt6):1095-1097.
[36] Worm J, Kirkin AF, Dzhandzhugazyan KN, et al. Methylation-dependent silencing of the reducedfolate carrier gene in inherently methotrexate-resistant human breast cancer cells[J]. J Biol Chem,2001,276(43):39990-40000.
[37] Ishii T, Fujishiro M, Masuda M, et al. A methylated oligonucleotide induced methylation of GSTP1promoter and suppressed its expression in A549lung adenocarcinoma cells[J]. Cancer Lett,2004,212(2):211-223.
[38] Frommer M, McDonald L E, Millar D S, et al. A genomic sequencing protocol that yields a positivedisplay of5-methylcytosine residues in individual DNA strands [J]. Proc Natl Acad Sci USA,1992,89:1827–1831.
[39]朱燕. DNA的甲基化的分析与状态检测[J].现代预防医学,2005,32(9):1070-1073.
[40] Herman J G, Graff J R, Myohanen S, et al. Methylation-specific PCR: a novel PCR assay formethylation status of CpG islands [J]. Proc Natl Acad Sci USA,1996, Sep3.93(18),9821-9826
[41]黄琼晓,金帆,黄荷凤.DNA甲基化的研究方法学[J].国外医学遗传学分册,2004,27(6):354-358.
[42]陈小兵．抑癌基因TIP30启动子甲基化与大肠癌侵袭和转移的关系[D]．河南：郑州大学，2010．
[1] Shtivelman E. A link between metastasis and resistance to apoptosis of variant small cell lungcarcinoma. Oncogene,1997,14:2167-2178
[2] Xiao H, Tao Y, Greenblatt J, et al. A cofactor, TIP30, specifically enhances HIV-1Tat-activatedtranscription. Proc Natl Acad Sci USA,1998,95:2146-2151
[3] Whitman S, Wang X, Shalaby R, et al. Alternatively spliced products CC3and TC3have opposingeffects on apoptosis. Mol Cell Biol,2000,20:583-593
[4] NicAmhlaoibh R, Shtivelman E. Metastasis suppressor CC3inhibits angiogenic properties of tumorcells in vitro. Oncogene,2001,20:270-275
[5] Liu Y, Thor A, Shtivelman E, et al. Systemic gene delivery expands the repertoire of effectiveantiangiogenic agents. J Biol Chem,1999,274:13338-13344
[6] Xian H，Paihan V，Yang Y，et a1．TIP30has an intrinsic kinase activity required for up-regulation ofasubset of apeptotic genes．The EMBO joumal，2000，19(5)：956-963．
[7] Ei Ommi K，Bird LE，Nichols CE，et a1．Crystal structure0f CC3(TIP30)：implication for its role atumor suppressor．J Bid Chem，2005，280(18)：18229-18236
[8] Zhang X, Ouyany XN, Xuenong O. The correlation between the expression of TIP30and of VEGF inhuman HCC tissues and its cell line. Chin J Clin Oncol,2005,32:489-492.
[9] Xiao H, Palhan V, Yang Y, et al. TIP30has an intrinsic kinase activity required for up2regulation of asubset of apoptotic genes. EMBO J,2000,19:956-963
[10] Xiao H, Tao Y, Greenblatt J, et al. A cofactor, TIP30, specifically enhances HIV21Tat2activatedtranscription. Proc Natl Acad Sci USA,1998,95:2146-2151
[11] Zhang X, Zhan J, Li XD, et al. Construction of adenovirus vector expressing TIP30gene and itstumor suppressing effects in vitro and in vivo. Chin J Oncol,2004,26:85-88
[12] Kuo PL, Chiang LC, Lin CC, et al. Resveratrol-induced apoptosis is mediated by p532dependentpathway in HepG2cells. Life Sci,2002,72:23-34
[13] Jiang ZM, Lu CT. Attenuated salmoneller mediated fusion genes inhibit tumor angiogenesis in BALB/c mice with human salivary adenoid cystic carcinoma. Acad J Sec Mil Med Univ,2005,26:609-612
[14] Shi W Y, Skeat h J B. The drosophila RCC1homolog, Bj1,regulates nucleocytoplasmic transport andneural differentiation during drosophila development [J]. Dev Biol,2004,270:106-121
[15] May E F. Nucleocytoplasmic t ransport in apoptosis [J]. Cell Death and Differentiation,2005,12:1263-1276
[16] King F W, Shtivelman E. Inhibition of nuclear import by theproapoptotic protein CC3[J]. Mol CellBiol,2004,24:7091-7101
[17] Zhang X, Tsukamoto T, Mizoshita T，el a1．Expression of ostepopontin and CDX2：indication ofphenotypes and prognosis in advanced gastric cancer．Oncol Rep，2009，2l(3)：609-613．
[18] Cho H，Kang ES，Kim YT，et a1．Diagnostic and prognostic impact of osteopontin expression inendometrial caner．Cancer Invest．2009，27(3)：313-323
[19] Korits PV, Wakai T，Shimi Y，et a1．Overexpreosion of osteopontin independently correlates withvascular invasion and poor prognosis in with hepatoeellular carcinoma．Hum Pathol，2008，39(12)：1777-1783
[20] Tong X， Li K，Luo z，el at. Decreased TIP30expression promotes tumor metastasis in lungcancer．Am J Path01．2009，174(5)：1931-1939
[21] Zhao J，Lu B，Xu H，et a1．Thirty-kilodahon Tat-interacting protein suppresses tumor metastasis byinhibition of osteopontin transcription in human hepatocellular carcinoma，Hepatology.2008.48(1)：265-275
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