PTEN、Survivin在表皮肿瘤中的表达及意义
摘要
皮肤肿瘤的发病率相当高,严重地影响着人民健康乃至生命。根据国外某些肿瘤研究所的统计,皮肤肿瘤按病理诊断结果,病种分布以基底细胞上皮瘤为最高,其次为鳞状细胞癌,再次为原位癌。近十多年来我国皮肤肿瘤的发病率和死亡率也有增多趋势,故角质形成细胞来源的表皮肿瘤在皮肤肿瘤中的高发病率不容忽视。
皮肤肿瘤的发生、发展是一个多因素、多阶段、渐进的演变过程,特别是对原位癌或癌前病变患者,早期诊断对于患者的预后至关重要。由于原位癌(如增殖性红斑、Bowen病等)的临床表现与多种皮肤病皮疹特征相似,而且在临床上发病率不高,未能引起临床医生的足够重视,一旦误诊,它们将可能发展成鳞状细胞癌。由于良性与恶性肿瘤仅为相对概念,而且部分良性肿瘤(刺激型脂溢性角化病)、癌前病变(日光性角化病、增殖性红斑)仍有伴发其他表皮恶性肿瘤的高风险甚至发展成侵袭性癌的可能,所以上述表皮肿瘤的早期诊断具有很重要的价值。
目前表皮肿瘤的诊断方法有免疫学诊断、X线诊断、放射性核素扫描以及细胞学、组织病理学、免疫病理学诊断等。表皮肿瘤因发病于体表,故早期诊断主要是靠细胞学及病理学或免疫病理学的检查。但是尽管如此,仍有一些患者未能及时确诊,从而错失了最佳的治疗时机。此外,对于表皮肿瘤目前仍缺乏有效的治疗手段,且方法也比较单一。
因此,寻求新的诊断、治疗方法,提高表皮肿瘤早期诊断的技术水平是目前临床工作中亟待解决的问题。
目的:
探讨抑癌蛋白PTEN和凋亡抑制蛋白Survivin在表皮肿瘤(刺激型脂溢性角化病、日光性角化病、增殖性红斑、Bowen病、基底细胞上皮瘤、鳞状细胞癌)中的表达情况及二者相关性;了解PTEN和Survivin在早期诊断表皮肿瘤中的作用;为表皮肿瘤的发病机制和早期诊断提供理论依据。
方法:
选取吉林大学第二医院皮肤科门诊近16年(1995.03-2010.03)经临床及皮肤组织病理学诊断为刺激型脂溢性角化病、日光性角化病、增殖性红斑、Bowen病、基底细胞上皮瘤、鳞状细胞癌病例的石蜡包埋组织标本,应用免疫组织化学法,观察上述疾病PTEN及Survivin在组织中的表达情况。
结果:
1.PTEN蛋白阳性细胞染色主要分布于细胞核。PTEN在正常皮肤组织中有较多表达,除角质层外表皮全层均有表达。在表皮肿瘤组织中, PTEN蛋白阳性染色细胞散在分布或染色反应阴性。将20例正常皮肤组织作为对照组,其中PTEN阳性19例(95.0%),阴性l例(5.0%)。在刺激型脂溢性角化、日光性角化及增殖性红斑中,PTEN阳性率分别为81.8%,40.0%,100.0%,因样本例数较少,未与对照组行统计学分析;在34例BD中, PTEN阳性21例(61.8%),阴性13例(38.2%),与对照组比较有显著性差异(P<0.05);在37例BCC中, PTEN阳性13例(35.1%),阴性24例(64.9%),与对照组比较有显著性差异(P<0.05);在31例SCC中, PTEN阳性11例(35.5%),阴性20例(64.5%),与对照组比较有显著性差异(P<0.05)。
2.Survivin蛋白阳性细胞染色主要分布于细胞浆。在正常皮肤组织中,Survivin蛋白无表达,而在表皮肿瘤组织中则有较多的表达。在20例对照组中,Survivin全部为阴性(100%)。在刺激型脂溢性角化、日光性角化及增殖性红斑中,Survivin阳性率分别为81.8%,60.0%,100.0%,因样本例数较少,未与对照组行统计学分析;在34例BD中,Survivin阳性21例(61.8%),阴性13例(38.2%),与对照组比较有显著性差异(P<0.05);在37例BCC中,Survivin阳性14例(37.8%),阴性23例(62.2%),与对照组比较有显著性差异(P<0.05);在31例SCC中,Survivin阳性31例(100.0%),阴性0例(0.0%),与对照组比较有显著性差异(P<0.05)。
3.经统计学分析发现Survivin和PTEN蛋白在BD中的表达呈显著负相关,具有统计学意义(r=﹣0.370,P<0.05)。Survivin和PTEN蛋白在BCC和SCC中的表达呈无相关性,但是Survivin在BCC和SCC中异常高表达,PTEN在BCC和SCC中异常低表达。
结论:
1. Survivin和PTEN基因的异常表达可能参与了表皮肿瘤的发生、发展过程;
2.本研究中Survivin在正常皮肤组织中无表达,而在表皮肿瘤中显著表达,提示它可作为表皮肿瘤早期诊断的较为敏感指标,并为表皮肿瘤靶向生物治疗提供了一个新思路;
3.本研究中部分表皮肿瘤组织的Survivin蛋白和PTEN蛋白的表达有显著相关性,联合检测这两种蛋白对临床上早期诊断表皮肿瘤和判断恶性程度有一定的参考价值。
Background:
The incidence of epidermal cancers is extraordinaryly high according to lately researches, which significantly affects people’s health and even threats to people’s lives. Some foreign researches suggest that the most common cancer is BCC, the next is SCC, and then is cancers in situ. Meanwhile, China’s incidence of cutaneous cancers was increasing during the recent decade. It leads logically that epidermal cancers will be a chief conern in the medicine.
The genesis and development of epidermal cancers is a course with changing of multiple factors、steps、stages and genes. It is vital to early diagnosis, especially for those cancers in situ and precancerosis. It is difficult to identify cancers in situ (erythroplasia and Bowen’s disease) because they are rare and resemble other diseases in clinic. Consequencely they may develop into SCC. Besides, some of the benign cancers and precancerosis tend to become malignant cancers. Therefore it is valuable to diagnosis of previous cancers early.
At present, major diagnostic methods of epidermal tumors are clinical manifestation and histopathology. However, there are still some patients were too late to make a definite diagnosis, and thus losing the optimizing opportunity of treating. In addition, we lack of efficient means of therapy.
In conclusion, we need to seek new ways to improve the level of early diagnosis.
Objective:
This study was desgined to investgiate the location of PTEN and Survivin in epidermal cancers (stimulated seborrheic keratosis、solar keratosis、erythroplasia、Bowen’s disease、basal cell carcinoma and squamous cell carcinoma) and their correlation. And we research what characters PTEN and Survivin have take in developing epidermal cancers. We will provide reference for the pathogenesis and early diagnosis of epidermal cancers.
Methods:
Formalin-fixed, Paraffin-embedded blocks, which includes stimulated seborrheic keratosis、solar keratosis、erythroplasia、Bowen’s disease、basal cell carcinoma and squamous cell carcinoma, are from the Second Hospital of Jilin University dermatology clinic for the last 16 years (1995.03-2010.03) under the diagnosis of clinic and pathology. Subsequently all of them were detected by immunohistochemical technique streptavidin-peroxidase(SP). Rabbit/mouse anti-human polyclonal antibody PTEN and Rabbit/mouse anti-human polyclonal antibody Survivin were used in each group respectively to investigate the expression of Survivin and PTEN.
Results:
1 The positive staining cells of PTEN were mostly located in the nuclear. Except for keratoderma, the expression of PTEN was observed in nuclei throughout the whole epidermis in normal skin tissues. In cutaneous cancers, the positive staining cells of PTEN were found diffused distribution, or reaction of staining was negative. We regarded 20 cases of normal skin tissues as a control group. In control group, the positive expression rate of PTEN was 95%. The positive expression rate of PTEN in stimulated seborrheic keratosis、solar keratosis and erythroplasia tissues was 81.8%,40.0%,100.0% , respectively. Since the samples of those were insufficient, we didn’t analysis statistically; In 34 cases of BD, the positive expression rate of PTEN was 61.8%, and the statistic difference was significant(P<0.05);In 37 cases of BCC, the positive expression rate of PTEN was 35.1%, and the statistic difference was significant(P<0.05); In 31 cases of SCC, the positive expression rate of PTEN was 35.5%, and the statistic difference was significant (P<0.05),too.
2 The positive staining cells of Survivin were mostly located in the cytoplasm. In normal skin tissues, The Survivin positive cells were weakly or negative expressed. In contrast, the expression of the Survivin positive cells were increased in cutaneous cancers.The expression of PTEN in all the cases of normal skin tissues was negative. The positive expression rate of Survivin in stimulated seborrheic keratosis、solar keratosis and erythroplasia tissues was 81.8%,60.0%,100.0% , respectively. We didn’t analysis statistically for the samples of those were insufficient; In 34 cases of BD, the positive expression rate of PTEN was 61.8%, and the statistic difference was significant (P<0.05); In 37 cases of BCC, the positive expression rate of Survivin was 37.8%, and the statistic difference was significant(P<0.05); In 31 cases of SCC, the positive expression rate of PTEN was 100.0%, and the statistic difference was significant(P<0.05),too.
3 The expression of PTEN in BD was negatively correlated with the experssion of Survivin, and the statistic difference was significan(tr=﹣0.370,P<0.05). The expression of PTEN in BCC and SCC was not correlated with the experssion of Survivin, but the expression of the Survivin positive cells were increased in BCC and SCC, and the expression of the PTEN positive cells were decreased in BCC and SCC.
Conclusions:
1. In this study, the abnormal expression of PTEN and Survivin genes may contribute to the oncogenesis of epidermal cancers;
2. We found that Survivin is undetectable in normal skin tissues, in contrast, it is significantly increased in epidermal cancers. It suggests that Survivin can be one sensitive early diganostic markers of epidermal cancers,and may be developed as a new target of biological therapy for epidermal cancers.
3. Survivin protein and PTEN protein are significantly correlated with partial epidermal cancers. It is valuable to detection of Survivin and PTEN simultaneously for early diagnosis and evaluation of malignancy.
皮肤肿瘤的发生、发展是一个多因素、多阶段、渐进的演变过程,特别是对原位癌或癌前病变患者,早期诊断对于患者的预后至关重要。由于原位癌(如增殖性红斑、Bowen病等)的临床表现与多种皮肤病皮疹特征相似,而且在临床上发病率不高,未能引起临床医生的足够重视,一旦误诊,它们将可能发展成鳞状细胞癌。由于良性与恶性肿瘤仅为相对概念,而且部分良性肿瘤(刺激型脂溢性角化病)、癌前病变(日光性角化病、增殖性红斑)仍有伴发其他表皮恶性肿瘤的高风险甚至发展成侵袭性癌的可能,所以上述表皮肿瘤的早期诊断具有很重要的价值。
目前表皮肿瘤的诊断方法有免疫学诊断、X线诊断、放射性核素扫描以及细胞学、组织病理学、免疫病理学诊断等。表皮肿瘤因发病于体表,故早期诊断主要是靠细胞学及病理学或免疫病理学的检查。但是尽管如此,仍有一些患者未能及时确诊,从而错失了最佳的治疗时机。此外,对于表皮肿瘤目前仍缺乏有效的治疗手段,且方法也比较单一。
因此,寻求新的诊断、治疗方法,提高表皮肿瘤早期诊断的技术水平是目前临床工作中亟待解决的问题。
目的:
探讨抑癌蛋白PTEN和凋亡抑制蛋白Survivin在表皮肿瘤(刺激型脂溢性角化病、日光性角化病、增殖性红斑、Bowen病、基底细胞上皮瘤、鳞状细胞癌)中的表达情况及二者相关性;了解PTEN和Survivin在早期诊断表皮肿瘤中的作用;为表皮肿瘤的发病机制和早期诊断提供理论依据。
方法:
选取吉林大学第二医院皮肤科门诊近16年(1995.03-2010.03)经临床及皮肤组织病理学诊断为刺激型脂溢性角化病、日光性角化病、增殖性红斑、Bowen病、基底细胞上皮瘤、鳞状细胞癌病例的石蜡包埋组织标本,应用免疫组织化学法,观察上述疾病PTEN及Survivin在组织中的表达情况。
结果:
1.PTEN蛋白阳性细胞染色主要分布于细胞核。PTEN在正常皮肤组织中有较多表达,除角质层外表皮全层均有表达。在表皮肿瘤组织中, PTEN蛋白阳性染色细胞散在分布或染色反应阴性。将20例正常皮肤组织作为对照组,其中PTEN阳性19例(95.0%),阴性l例(5.0%)。在刺激型脂溢性角化、日光性角化及增殖性红斑中,PTEN阳性率分别为81.8%,40.0%,100.0%,因样本例数较少,未与对照组行统计学分析;在34例BD中, PTEN阳性21例(61.8%),阴性13例(38.2%),与对照组比较有显著性差异(P<0.05);在37例BCC中, PTEN阳性13例(35.1%),阴性24例(64.9%),与对照组比较有显著性差异(P<0.05);在31例SCC中, PTEN阳性11例(35.5%),阴性20例(64.5%),与对照组比较有显著性差异(P<0.05)。
2.Survivin蛋白阳性细胞染色主要分布于细胞浆。在正常皮肤组织中,Survivin蛋白无表达,而在表皮肿瘤组织中则有较多的表达。在20例对照组中,Survivin全部为阴性(100%)。在刺激型脂溢性角化、日光性角化及增殖性红斑中,Survivin阳性率分别为81.8%,60.0%,100.0%,因样本例数较少,未与对照组行统计学分析;在34例BD中,Survivin阳性21例(61.8%),阴性13例(38.2%),与对照组比较有显著性差异(P<0.05);在37例BCC中,Survivin阳性14例(37.8%),阴性23例(62.2%),与对照组比较有显著性差异(P<0.05);在31例SCC中,Survivin阳性31例(100.0%),阴性0例(0.0%),与对照组比较有显著性差异(P<0.05)。
3.经统计学分析发现Survivin和PTEN蛋白在BD中的表达呈显著负相关,具有统计学意义(r=﹣0.370,P<0.05)。Survivin和PTEN蛋白在BCC和SCC中的表达呈无相关性,但是Survivin在BCC和SCC中异常高表达,PTEN在BCC和SCC中异常低表达。
结论:
1. Survivin和PTEN基因的异常表达可能参与了表皮肿瘤的发生、发展过程;
2.本研究中Survivin在正常皮肤组织中无表达,而在表皮肿瘤中显著表达,提示它可作为表皮肿瘤早期诊断的较为敏感指标,并为表皮肿瘤靶向生物治疗提供了一个新思路;
3.本研究中部分表皮肿瘤组织的Survivin蛋白和PTEN蛋白的表达有显著相关性,联合检测这两种蛋白对临床上早期诊断表皮肿瘤和判断恶性程度有一定的参考价值。
Background:
The incidence of epidermal cancers is extraordinaryly high according to lately researches, which significantly affects people’s health and even threats to people’s lives. Some foreign researches suggest that the most common cancer is BCC, the next is SCC, and then is cancers in situ. Meanwhile, China’s incidence of cutaneous cancers was increasing during the recent decade. It leads logically that epidermal cancers will be a chief conern in the medicine.
The genesis and development of epidermal cancers is a course with changing of multiple factors、steps、stages and genes. It is vital to early diagnosis, especially for those cancers in situ and precancerosis. It is difficult to identify cancers in situ (erythroplasia and Bowen’s disease) because they are rare and resemble other diseases in clinic. Consequencely they may develop into SCC. Besides, some of the benign cancers and precancerosis tend to become malignant cancers. Therefore it is valuable to diagnosis of previous cancers early.
At present, major diagnostic methods of epidermal tumors are clinical manifestation and histopathology. However, there are still some patients were too late to make a definite diagnosis, and thus losing the optimizing opportunity of treating. In addition, we lack of efficient means of therapy.
In conclusion, we need to seek new ways to improve the level of early diagnosis.
Objective:
This study was desgined to investgiate the location of PTEN and Survivin in epidermal cancers (stimulated seborrheic keratosis、solar keratosis、erythroplasia、Bowen’s disease、basal cell carcinoma and squamous cell carcinoma) and their correlation. And we research what characters PTEN and Survivin have take in developing epidermal cancers. We will provide reference for the pathogenesis and early diagnosis of epidermal cancers.
Methods:
Formalin-fixed, Paraffin-embedded blocks, which includes stimulated seborrheic keratosis、solar keratosis、erythroplasia、Bowen’s disease、basal cell carcinoma and squamous cell carcinoma, are from the Second Hospital of Jilin University dermatology clinic for the last 16 years (1995.03-2010.03) under the diagnosis of clinic and pathology. Subsequently all of them were detected by immunohistochemical technique streptavidin-peroxidase(SP). Rabbit/mouse anti-human polyclonal antibody PTEN and Rabbit/mouse anti-human polyclonal antibody Survivin were used in each group respectively to investigate the expression of Survivin and PTEN.
Results:
1 The positive staining cells of PTEN were mostly located in the nuclear. Except for keratoderma, the expression of PTEN was observed in nuclei throughout the whole epidermis in normal skin tissues. In cutaneous cancers, the positive staining cells of PTEN were found diffused distribution, or reaction of staining was negative. We regarded 20 cases of normal skin tissues as a control group. In control group, the positive expression rate of PTEN was 95%. The positive expression rate of PTEN in stimulated seborrheic keratosis、solar keratosis and erythroplasia tissues was 81.8%,40.0%,100.0% , respectively. Since the samples of those were insufficient, we didn’t analysis statistically; In 34 cases of BD, the positive expression rate of PTEN was 61.8%, and the statistic difference was significant(P<0.05);In 37 cases of BCC, the positive expression rate of PTEN was 35.1%, and the statistic difference was significant(P<0.05); In 31 cases of SCC, the positive expression rate of PTEN was 35.5%, and the statistic difference was significant (P<0.05),too.
2 The positive staining cells of Survivin were mostly located in the cytoplasm. In normal skin tissues, The Survivin positive cells were weakly or negative expressed. In contrast, the expression of the Survivin positive cells were increased in cutaneous cancers.The expression of PTEN in all the cases of normal skin tissues was negative. The positive expression rate of Survivin in stimulated seborrheic keratosis、solar keratosis and erythroplasia tissues was 81.8%,60.0%,100.0% , respectively. We didn’t analysis statistically for the samples of those were insufficient; In 34 cases of BD, the positive expression rate of PTEN was 61.8%, and the statistic difference was significant (P<0.05); In 37 cases of BCC, the positive expression rate of Survivin was 37.8%, and the statistic difference was significant(P<0.05); In 31 cases of SCC, the positive expression rate of PTEN was 100.0%, and the statistic difference was significant(P<0.05),too.
3 The expression of PTEN in BD was negatively correlated with the experssion of Survivin, and the statistic difference was significan(tr=﹣0.370,P<0.05). The expression of PTEN in BCC and SCC was not correlated with the experssion of Survivin, but the expression of the Survivin positive cells were increased in BCC and SCC, and the expression of the PTEN positive cells were decreased in BCC and SCC.
Conclusions:
1. In this study, the abnormal expression of PTEN and Survivin genes may contribute to the oncogenesis of epidermal cancers;
2. We found that Survivin is undetectable in normal skin tissues, in contrast, it is significantly increased in epidermal cancers. It suggests that Survivin can be one sensitive early diganostic markers of epidermal cancers,and may be developed as a new target of biological therapy for epidermal cancers.
3. Survivin protein and PTEN protein are significantly correlated with partial epidermal cancers. It is valuable to detection of Survivin and PTEN simultaneously for early diagnosis and evaluation of malignancy.
引文
[1]Ambrosini G,Adida C,Altieri DC.A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma[J].NatMed,1997,3 (8):917-921.
[2]Salvesen GS, Duckett CS.IAP protein:blocking the road to death’s door[J].Nat Rev Mol Cell Biol,2002,3(6):401-410.
[3]都昌胡,徐军.凋亡蛋白抑制剂家族研究进展[ J ].世界华人消化杂志, 2005, 13 (13) : 1581 - 1589.
[4]Marzia Pennati, Marco Folini, Nadia Zaffaroni, et al. Targeting survivin in cancer therapy: fulfilled promises and open questions Carcinogenesis, 2007, 28(6):1133-1139.
[5]Conway EM, Pollefeyt S, Comelissen J, et al. Three differentially expressed survivin cDNA variants encode proteins with distinct antipoptotic functions[J]. Blood, 2000,95 (4):1435-1442.
[6]O′Connor DS,Grossman D ,Plescia J ,et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci U S A ,2000 ,1997 (24) :13 103-13107.
[7]Shin S, Sung BJ, Cho YS, et al. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7[J]. Biochemistry, 2001,40(4):1117-1123.
[8]Bolton MA, Lan W, Powers SE, et al. Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity is stimulated by survivin binding and phosp horylat ion[J].Mol Biol Cell,2002,13(9):3064-3077.
[9]Mesri M, Morales-Ruiz M. Suppression of vascular endothelial growth factor–medi ated endothelial cell protection by Survivin tar- geting. AmJ Path 2001; 158: 1757 - 1765.
[10]O’Conner DS, Schechner JS, Adida C, et al. Control of apoptosis during angiogenesis by surviving express in endothelial cell[J]. Am J Pathol,2000,156(2) :393-398.
[11]Tu SP,Jiang XH. Suppression of Survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. [J]Cancer Res 2003;15:63 (22) :7724- 7732.
[12]Ambrosini G,Adida C,Altieri DC. A novel anti-apoptosis gene ,survivin ,e- xpressed in cancer and lymphoma. Nat Med,1997 ,3 (8) :917-921.
[13]Altieri DC,Marchisio PC,Marchisio C. Survivin apoptosis: aninterloper between cell death and cell proliferation cancer.Lab Invest ,1999 , 79 (11): 1327-1333
[14]Gazzaniga P, GradiloneA, GiulianiL, et al. Expression and prognostic significance bladder cancer. Ann Oncol,2003,14:85-90.
[15]Grossman D , Kim PJ . Transgenic expression of Survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. J Clinical investigation 2001 ;108 (7) :991 - 999.
[16]Chiodino C, Cesinaro AM, Ottani D, et al. Expression of the novel inhibitor of apoptosis Survivin in normal and neoplastic skin. [J]Invest Dermatol 1999; 113: 15 - 418.
[17] Bowen AR, Hanks AN, Murphy KJ, et al. Proliferation, apoptosis, and survivin expression in keratinocytic neoplasms and hyperplasias[J] . Am JDermato-pathol, 2004, 26( 3) : 177-181.
[18]赵辩主编,临床皮肤病学[M].南京:江苏科学技术出版社,2001:1115-1117.
[19]Grossman D , Jennifer M, McNiff , et al. Expression of the apoptosis inhibitor , Survivin , in nonmelanoma skin cancer and gene targeting in a keratinocyte cell line. J Lab Investigation vol 1999 ;79(9) :1121 - 1126.
[20]Gradilone A,Gazzaniga P.Survivin, bcl-2,bax and bcl– x gene expression in lymph nodes from melanoma patients.[J]Clinical oncology 2003;21(2) :306 - 312.
[21]Sarela AI,Macadam RC,Farmery SM ,et al. Expression of the anti- apoptosis gene ,survi vin ,predicts death from recurrent colorectal carci-noma. Gut , 2000 , 46 (5) : 645-650.
[22]Monzo M ,Rosell R,Felip E,et al.A novel anti-apoptosis gene: Re-ex- pression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers.[J] Clin Oncol ,1999 ,17 (7) :2100-2104.
[23] Shapiro GI. Preclinical and clinical development of the cyclin 2 dependent kinase inhibitor flavopiridol [ J ] . Clin Cancer Res ,2004 ,10(12 Pt 2) :4270-4275.
[24]Olie RA , Simoes-Wust AP, Baumann B , et al. A novel antisenseoligonucle- otide target ing survivin expression induces apoptosis and sen-sitizeslung cancer cells to chem. otherapy. Cancer Res,2000 ,60 (11) : 2805-2809.
[25]Mesri M ,Wall NR,Li J ,et al. Cancer gene therapy using a surviving mutant adeno virus.[J] Clin Invest ,2001 ,108 (7):981-990.
[26]Reker S, Becker JC. HLA - B35 - restricted immune responses against Survivin in cancerpatients. IntJ Cancer 2004;108 (6) :937-941.
[27]Maehama T, et al. J Biol Chem, 1998; 273(22): 13375 -13378.
[28]Li J , et al.Cancer Res, 1998; 58(24) : 5667 - 5672.
[29]唐丽艳,张建兵,王东林.癌基因Survivin和PTEN在人类恶性肿瘤中的表达[J].Medical Recapitulate,December 2007;13:1790-1792.
[30]陈东主编.免疫组织化学及其组织学相关技术教程[M].吉林大学出版社,2004:20-21.
[31]Del Pizzo TJ, Borkowski A, Jacobs SC, et al. Loss of cell cyclic regulaters p27kip1 and cyclin E in transitional bladder correlates with tumor grade and patient survival. Am J Pathol.1999;155:1129-1136.
[32]Newcomb EW, Sosnow M, Demopoulos RI, et al. Expression of the cell cycle inhibitor p27kip1 is a new marker associated with survival in epithelial ovarian tumors. American Journal of Pathology.1999;154:119-125.
[33]Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma[J].NatMed,1997,3 (8):917-921.
[34]Shin S, Sung BJ, Cho YS. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and caspase-7. Biochemistry,2001,40:1117-1123.
[35]SuzukiaA, Ito T, Kawano H et al. Survivin initiates ptrocapse-3 p21 complex formation as result of interaction with CDK4 to resist Fas mediated cell death[J]. Oncog ene,2000,19(10):1346-1353.
[36]潘金飞.凋亡抑制因子Survivin与肿瘤关系研究进展.国外医学外科学分册,2003, 30:131-133.
[37]Laura S, et al. Exp Cell Res, 2001; 264 (1) : 29-41.
[38]Risinger JI, et al. Clin Cancer Res, 1998;(4) 12 : 3005 - 3010.
[39]张伟峰. PTEN基因的研究进展[J ].国外医学外科学分册,2003,30 (5): 294- 296.
[40]Sohna DM, Kima SY, Baeka MJ,et al. Expression of survivin and clinical correlation in patients with breast cancer[J]. Biomedi Pharmacother, 2006, 60(6):289-292.
[41]Sobczuk A, Smolarz B, Romanowicz-Makowska H, et al. MMAC/PTEN gene expression in epidermal cancer:RT-PCR studies[J].Pol J Pathol, 2006, 57(3)137-140.
[42]William G, et al. Cancer, 1975,36:1021-1028.
[43]Adida C, Crotty PL , Mograthj ,et al. Developemntally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation[J].AmJ Pathot ,1998 ,152 (1):43.
[44]Nasu S, Yagihashi A, Izawa A,et al. Survivin mRNA expression in patients with breast cancer.Anticancer Res,2002 ,22 (3) :1839-1843.
[45]Chiodino C,Cesinario AM, Ottani D, et al. Communication:expression of the novel inhibitor of apoptosis Survivin in nomal and neoplastic skin. Invest Dermatol 1999, 113:415-418.
[46]杨建峰,李文才,于建斌.鲍温病组织中PTEN和Survivin的检测[J].中国皮肤性病学杂志, 2007, 21(1) : 22- 23.
[2]Salvesen GS, Duckett CS.IAP protein:blocking the road to death’s door[J].Nat Rev Mol Cell Biol,2002,3(6):401-410.
[3]都昌胡,徐军.凋亡蛋白抑制剂家族研究进展[ J ].世界华人消化杂志, 2005, 13 (13) : 1581 - 1589.
[4]Marzia Pennati, Marco Folini, Nadia Zaffaroni, et al. Targeting survivin in cancer therapy: fulfilled promises and open questions Carcinogenesis, 2007, 28(6):1133-1139.
[5]Conway EM, Pollefeyt S, Comelissen J, et al. Three differentially expressed survivin cDNA variants encode proteins with distinct antipoptotic functions[J]. Blood, 2000,95 (4):1435-1442.
[6]O′Connor DS,Grossman D ,Plescia J ,et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci U S A ,2000 ,1997 (24) :13 103-13107.
[7]Shin S, Sung BJ, Cho YS, et al. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7[J]. Biochemistry, 2001,40(4):1117-1123.
[8]Bolton MA, Lan W, Powers SE, et al. Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity is stimulated by survivin binding and phosp horylat ion[J].Mol Biol Cell,2002,13(9):3064-3077.
[9]Mesri M, Morales-Ruiz M. Suppression of vascular endothelial growth factor–medi ated endothelial cell protection by Survivin tar- geting. AmJ Path 2001; 158: 1757 - 1765.
[10]O’Conner DS, Schechner JS, Adida C, et al. Control of apoptosis during angiogenesis by surviving express in endothelial cell[J]. Am J Pathol,2000,156(2) :393-398.
[11]Tu SP,Jiang XH. Suppression of Survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. [J]Cancer Res 2003;15:63 (22) :7724- 7732.
[12]Ambrosini G,Adida C,Altieri DC. A novel anti-apoptosis gene ,survivin ,e- xpressed in cancer and lymphoma. Nat Med,1997 ,3 (8) :917-921.
[13]Altieri DC,Marchisio PC,Marchisio C. Survivin apoptosis: aninterloper between cell death and cell proliferation cancer.Lab Invest ,1999 , 79 (11): 1327-1333
[14]Gazzaniga P, GradiloneA, GiulianiL, et al. Expression and prognostic significance bladder cancer. Ann Oncol,2003,14:85-90.
[15]Grossman D , Kim PJ . Transgenic expression of Survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. J Clinical investigation 2001 ;108 (7) :991 - 999.
[16]Chiodino C, Cesinaro AM, Ottani D, et al. Expression of the novel inhibitor of apoptosis Survivin in normal and neoplastic skin. [J]Invest Dermatol 1999; 113: 15 - 418.
[17] Bowen AR, Hanks AN, Murphy KJ, et al. Proliferation, apoptosis, and survivin expression in keratinocytic neoplasms and hyperplasias[J] . Am JDermato-pathol, 2004, 26( 3) : 177-181.
[18]赵辩主编,临床皮肤病学[M].南京:江苏科学技术出版社,2001:1115-1117.
[19]Grossman D , Jennifer M, McNiff , et al. Expression of the apoptosis inhibitor , Survivin , in nonmelanoma skin cancer and gene targeting in a keratinocyte cell line. J Lab Investigation vol 1999 ;79(9) :1121 - 1126.
[20]Gradilone A,Gazzaniga P.Survivin, bcl-2,bax and bcl– x gene expression in lymph nodes from melanoma patients.[J]Clinical oncology 2003;21(2) :306 - 312.
[21]Sarela AI,Macadam RC,Farmery SM ,et al. Expression of the anti- apoptosis gene ,survi vin ,predicts death from recurrent colorectal carci-noma. Gut , 2000 , 46 (5) : 645-650.
[22]Monzo M ,Rosell R,Felip E,et al.A novel anti-apoptosis gene: Re-ex- pression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers.[J] Clin Oncol ,1999 ,17 (7) :2100-2104.
[23] Shapiro GI. Preclinical and clinical development of the cyclin 2 dependent kinase inhibitor flavopiridol [ J ] . Clin Cancer Res ,2004 ,10(12 Pt 2) :4270-4275.
[24]Olie RA , Simoes-Wust AP, Baumann B , et al. A novel antisenseoligonucle- otide target ing survivin expression induces apoptosis and sen-sitizeslung cancer cells to chem. otherapy. Cancer Res,2000 ,60 (11) : 2805-2809.
[25]Mesri M ,Wall NR,Li J ,et al. Cancer gene therapy using a surviving mutant adeno virus.[J] Clin Invest ,2001 ,108 (7):981-990.
[26]Reker S, Becker JC. HLA - B35 - restricted immune responses against Survivin in cancerpatients. IntJ Cancer 2004;108 (6) :937-941.
[27]Maehama T, et al. J Biol Chem, 1998; 273(22): 13375 -13378.
[28]Li J , et al.Cancer Res, 1998; 58(24) : 5667 - 5672.
[29]唐丽艳,张建兵,王东林.癌基因Survivin和PTEN在人类恶性肿瘤中的表达[J].Medical Recapitulate,December 2007;13:1790-1792.
[30]陈东主编.免疫组织化学及其组织学相关技术教程[M].吉林大学出版社,2004:20-21.
[31]Del Pizzo TJ, Borkowski A, Jacobs SC, et al. Loss of cell cyclic regulaters p27kip1 and cyclin E in transitional bladder correlates with tumor grade and patient survival. Am J Pathol.1999;155:1129-1136.
[32]Newcomb EW, Sosnow M, Demopoulos RI, et al. Expression of the cell cycle inhibitor p27kip1 is a new marker associated with survival in epithelial ovarian tumors. American Journal of Pathology.1999;154:119-125.
[33]Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma[J].NatMed,1997,3 (8):917-921.
[34]Shin S, Sung BJ, Cho YS. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and caspase-7. Biochemistry,2001,40:1117-1123.
[35]SuzukiaA, Ito T, Kawano H et al. Survivin initiates ptrocapse-3 p21 complex formation as result of interaction with CDK4 to resist Fas mediated cell death[J]. Oncog ene,2000,19(10):1346-1353.
[36]潘金飞.凋亡抑制因子Survivin与肿瘤关系研究进展.国外医学外科学分册,2003, 30:131-133.
[37]Laura S, et al. Exp Cell Res, 2001; 264 (1) : 29-41.
[38]Risinger JI, et al. Clin Cancer Res, 1998;(4) 12 : 3005 - 3010.
[39]张伟峰. PTEN基因的研究进展[J ].国外医学外科学分册,2003,30 (5): 294- 296.
[40]Sohna DM, Kima SY, Baeka MJ,et al. Expression of survivin and clinical correlation in patients with breast cancer[J]. Biomedi Pharmacother, 2006, 60(6):289-292.
[41]Sobczuk A, Smolarz B, Romanowicz-Makowska H, et al. MMAC/PTEN gene expression in epidermal cancer:RT-PCR studies[J].Pol J Pathol, 2006, 57(3)137-140.
[42]William G, et al. Cancer, 1975,36:1021-1028.
[43]Adida C, Crotty PL , Mograthj ,et al. Developemntally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation[J].AmJ Pathot ,1998 ,152 (1):43.
[44]Nasu S, Yagihashi A, Izawa A,et al. Survivin mRNA expression in patients with breast cancer.Anticancer Res,2002 ,22 (3) :1839-1843.
[45]Chiodino C,Cesinario AM, Ottani D, et al. Communication:expression of the novel inhibitor of apoptosis Survivin in nomal and neoplastic skin. Invest Dermatol 1999, 113:415-418.
[46]杨建峰,李文才,于建斌.鲍温病组织中PTEN和Survivin的检测[J].中国皮肤性病学杂志, 2007, 21(1) : 22- 23.