乳腺癌组织中cIAP1、XIAP和caspase-3的表达及其临床意义
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摘要
目的:探讨cIAP1、XIAP、caspase-3在乳腺癌组织中的表达与患者临床病理参数及预后的关系。方法:应用免疫组化法检测cIAP1、XIAP、caspase-3蛋白分子在99例乳腺癌、10例乳腺纤维腺瘤及6例癌旁正常乳腺组织中的表达,结合Kaplan-MeierPlotter数据库中的乳腺癌患者资料,分析3种蛋白与乳腺癌临床病理参数及其预后的关系。结果:免疫组化结果显示,乳腺癌组织中cIAP1、XIAP、caspase-3蛋白的表达水平均明显高于各自在正常乳腺组织中的表达(均P<0.05),但3种蛋白表达水平在乳腺癌组织与乳腺纤维腺瘤组织中均无统计学差异,且在接受过与未接受过新辅助化疗乳腺癌患者的癌组织中也无统计学差异(均P>0.05)。cIAP1的表达与患者的月经状态、年龄明显有关,而XIAP的表达与Ki-67的表达强度明显有关(均P<0.05)。Kaplan-MeierPlotter数据库分析结果显示,cIAP1表达量与乳腺癌患者的无复发生存期关系不明显(P>0.05),XIAP高表达乳腺癌患者的无复发生存期长于低表达乳腺癌患者,而caspase-3高表达乳腺癌患者的无复发生存期短于caspase-3低表达乳腺癌患者(均P<0.05)。结论:cIAP1、XIAP和caspase-3的表达可能与乳腺癌的发生、发展密切相关,XIAP和caspase-3可作为评估乳腺癌预后的潜在指标。
Objective: To assess expressions of cIAP1, XIAP and caspase-3 in breast cancer tissue and their relations with clinicopathologic factors and prognosis. Methods: The protein expressions of cIAP1, XIAP and caspase-3 in 99 specimens of breast cancer tissue, 10 specimens of breast fibroadenoma tissue and 6 specimens of tumor-adjacent normal mammary tissue were determined by immunohistochemical staining. The relations of the 3 proteins with clinicopathologic features and prognosis of breast cancer patients were analyzed, by combination with the data of breast cancer patients in Kaplan-Meier Plotter database.Results: The results of immunohistochemical staining showed that the expression levels of cIAP1, XIAP and caspase-3 protein in breast cancer tissue were all significantly higher than those in normal mammary tissue(all P<0.05), while no significant differences were noted in the expression levels of the 3 proteins between breast cancer tissue and breast adenofibroma tissue, and between breast cancer tissues from patients undergoing and not undergoing neoadjuvant chemotherapy(all P>0.05). The expression of cIAP1 was significantly associated with the menstrual status and age of patients, and the expression of XIAP was significantly related to the expression intensity of Ki-67(all P<0.05). The results of Kaplan-Meier Plotter database analysis showed that the cIAP1 expression level exerted no significant influence on the relapse-free survival(RFS) time of breast cancer patients(P>0.05), while the RFS time in breast cancer patients with high XIAP expression level was longer than that in breast cancer patients with high XIAP expression level, and in patients with high caspase-3 expression level was shorter than that in those with low caspase-3 expression level(both P<0.05). Conclusion: The expressions of cIAP1, XIAP and caspase-3 may be closely related to the occurrence and development of breast cancer, and XIAP and caspase-3 may potentially be prognostic indicators for breast cancer.
Objective: To assess expressions of cIAP1, XIAP and caspase-3 in breast cancer tissue and their relations with clinicopathologic factors and prognosis. Methods: The protein expressions of cIAP1, XIAP and caspase-3 in 99 specimens of breast cancer tissue, 10 specimens of breast fibroadenoma tissue and 6 specimens of tumor-adjacent normal mammary tissue were determined by immunohistochemical staining. The relations of the 3 proteins with clinicopathologic features and prognosis of breast cancer patients were analyzed, by combination with the data of breast cancer patients in Kaplan-Meier Plotter database.Results: The results of immunohistochemical staining showed that the expression levels of cIAP1, XIAP and caspase-3 protein in breast cancer tissue were all significantly higher than those in normal mammary tissue(all P<0.05), while no significant differences were noted in the expression levels of the 3 proteins between breast cancer tissue and breast adenofibroma tissue, and between breast cancer tissues from patients undergoing and not undergoing neoadjuvant chemotherapy(all P>0.05). The expression of cIAP1 was significantly associated with the menstrual status and age of patients, and the expression of XIAP was significantly related to the expression intensity of Ki-67(all P<0.05). The results of Kaplan-Meier Plotter database analysis showed that the cIAP1 expression level exerted no significant influence on the relapse-free survival(RFS) time of breast cancer patients(P>0.05), while the RFS time in breast cancer patients with high XIAP expression level was longer than that in breast cancer patients with high XIAP expression level, and in patients with high caspase-3 expression level was shorter than that in those with low caspase-3 expression level(both P<0.05). Conclusion: The expressions of cIAP1, XIAP and caspase-3 may be closely related to the occurrence and development of breast cancer, and XIAP and caspase-3 may potentially be prognostic indicators for breast cancer.
引文
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[17]Wang J,Liu Y,Ji R,et al.Prognostic value of the X-linked inhibitor of apoptosis protein for invasive ductal breast cancer with triplenegative phenotype[J].Hum Pathol,2010,41(8):1186-1195.doi:10.1016/j.humpath.2010.01.013.
[18]Zhang Y,Zhu J,Tang Y,et al.X-linked inhibitor of apoptosis positive nuclear labeling:a new independent prognostic biomarker of breast invasive ductal carcinoma[J].Diagn Pathol,2011,6:49.doi:10.1186/1746-1596-6-49.
[19]Engels CC,Ruberta F,de Kruijf EM,et al.The prognostic value of apoptotic and proliferative markers in breast cancer[J].Breast Cancer Res Treat,2013,142(2):323-339.doi:10.1007/s10549-013-2748-y.
[20]吴至佛,汪灵,黄俊辉.三阴性乳腺癌的生物标记物研究进展[J].中国普通外科杂志,2017,26(11):1472-1477.doi:10.3978/j.issn.1005-6947.2017.11.016.Wu ZF,Wang L,Huang JH.Research progress on biomarkers of triple-negative breast cancer[J].Chinese Journal of General Surgery,2017,26(11):1472-1477.doi:10.3978/j.issn.1005-6947.2017.11.016.
[21]Kempkensteffen C,Hinz S,Christoph F,et al.Expression parameters of the inhibitors of apoptosis cIAP1 and cIAP2 in renal cell carcinomas and their prognostic relevance[J].Int J Cancer,2007,120(5):1081-1086.doi:10.1002/ijc.22416
[22]Lee EK,Jinesh GG,Laing NM,et al.A Smac mimetic augments the response of urothelial cancer cells to gemcitabine and cisplatin[J].Cancer Biol Ther,2013,14(9):812-822.doi:10.4161/cbt.25326.
[23]Che X,Yang D,Zong H,et al.Nuclear cIAP1 overexpression is a tumor stage-and grade-independent predictor of poor prognosis in human bladder cancer patients[J].Urol Oncol,2012,30(4):450-456.doi:10.1016/j.urolonc.2010.12.016.
[24]Chen YT,Tsao SC,Tsai HP,et al.The X-linked inhibitor of apoptosis protein is an independent prognostic marker for rectal adenocarcinoma after preoperative chemoradiotherapy[J].Virchows Arch,2016,468(5):559-567.doi:10.1007/s00428-016-1913-1.
[25]Moussata D,Amara S,Siddeek B,et al.XIAP as a radioresistance factor and prognostic marker for radiotherapy in human rectal adenocarcinoma[J].Am J Pathol,2012,181(4):1271-1278.doi:10.1016/j.ajpath.2012.06.029.
[26]Dubrez L,Berthelet J,Glorian V.IAP proteins as targets for drug development in oncology[J].Onco Targets Ther,2013,9:1285-1304.doi:10.2147/OTT.S33375.
[27]Mahadevan D,Chalasani P,Rensvold D,et al.Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma[J].Am J Clin Oncol,2013,36(3):239-243.doi:10.1097/COC.0b013e3182467a13.
[28]Lee FA,Zee BC,Cheung FY,et al.Randomized Phase II Study of the X-linked Inhibitor of Apoptosis(XIAP)Antisense AEG35156in Combination With Sorafenib in Patients With Advanced Hepatocellular Carcinoma(HCC)[J].Am J Clin Oncol,2016,39(6):609-613.doi:10.1097/COC.0000000000000099.
[29]Nestal de Moraes G,Delbue D,Silva KL,et al.FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance[J].Cell Signal,2015,27(12):2496-2505.doi:10.1016/j.cellsig.2015.09.013.
[30]Tamm I,Kornblau SM,Segall H,et al.Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias[J].Clin Cancer Res,2000,6(5):1796-1803.
[31]Carter BZ,Kornblau SM,Tsao T,et al.Caspase-independent cell death in AML:caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis[J].Blood,2003,102(12):4179-4186.doi:10.1182/blood-2003-03-0960.
[32]Ferreira CG,van der Valk P,Span SW,et al.Expression of X-linked inhibitor of apoptosis as a novel prognostic marker in radically resected non-small cell lung cancer patients[J].Clin Cancer Res,2001,7(8):2468-2474.
[33]Huang Q,Li F,Liu X,et al.Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy[J].Nat Med,2011,17(7):860-866.doi:10.1038/nm.2385.
[34]Zhou L,Li K,Luo Y,et al.Novel prognostic markers for patients with triple-negative breast cancer[J].Hum Pathol,2013,44(10):2180-2187.doi:10.1016/j.humpath.2013.03.021.
[35]李良宏.乳腺癌中HSP90和Caspase-3的表达及其与临床病理、预后关系的研究[J].疑难病杂志,2012,11(4):271-273.doi:10.3969/j.issn.1671-6450.2012.04.012.Li LH.The expression of HSP80 and Caspase-3 in breast cancer and the correlation with clinicopathologic and prognosis[J].Chinese Journal of Difficult and Complicated Cases,2012,11(4):271-273.doi:10.3969/j.issn.1671-6450.2012.04.012.
[36]Pu X,Storr SJ,Zhang Y,et al.Caspase-3 and caspase-8 expression in breast cancer:caspase-3 is associated with survival[J].Apoptosis,2017,22(3):357-368.doi:10.1007/s10495-016-1323-5.
[2]吴至佛,姚晓艺,汪灵,等.紫杉醇诱导三阴性乳腺癌细胞自噬相关蛋白LC3的表达及其作用[J].中国普通外科杂志,2018,27(6):732-739.doi:10.3978/j.issn.1005-6947.2018.06.012.Wu ZF,Yao XY,Wang L,et al.Paclitaxel induced expression of autophagy-associated protein LC3 in triple negative breast cancer cells and its action[J].Chinese Journal of General Surgery,2018,27(6):732-739.doi:10.3978/j.issn.1005-6947.2018.06.012.
[3]Hassan M,Watari H,AbuAlmaaty A,et al.Apoptosis and molecular targeting therapy in cancer[J].Biomed Res Int,2014,2014:150845.doi:10.1155/2014/150845.
[4]Fulda S,Vucic D.Targeting IAP proteins for therapeutic intervention in cancer[J].Nat Rev Drug Discov,2012,11(2):109-124.doi:10.1038/nrd3627.
[5]高宇哲,倪青,贾琦,等.紫杉醇联合曲妥珠单抗对人乳腺癌SKBR-3细胞移植裸鼠的治疗作用[J].中国普通外科杂志,2016,25(11):1608-1614.doi:10.3978/j.issn.1005-6947.2016.11.015.Gao YZ,Ni Q,Jia Q,et al.Therapeutic efficacy of paclitaxel plus trastuzumab chemotherapy in nude mice transplanted with human breast cancer SKBR-3 cells[J].Chinese Journal of General Surgery,2016,25(11):1608-1614.doi:10.3978/j.issn.1005-6947.2016.11.015.
[6]Bray F,Ferlay J,Soerjomataram I,et al.Global cancer statistics2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2018,68(6):394-424.doi:10.3322/caac.21492.
[7]常亮,户庄,周振宇,等.下调星形细胞上调基因1表达对乳腺癌细胞凋亡的影响[J].中国普通外科杂志,2018,27(5):575-580.doi:10.3978/j.issn.1005-6947.2018.05.008.Chang L,Hu Z,Zhou ZY,et al.Effect of down-regulating the expression of astrocyte elevated gene 1 on apoptosis of breast carcinoma cells[J].Chinese Journal of General Surgery,2018,27(5):575-580.doi:10.3978/j.issn.1005-6947.2018.05.008.
[8]Hanahan D,Weinberg RA.Hallmarks of cancer:the next generation[J].Cell,2011,144(5):646-674.doi:10.1016/j.cell.2011.02.013.
[9]Cossu F,Milani M,Mastrangelo E,et al.Targeting the BIRDomains of Inhibitor of Apoptosis(IAP)Proteins in Cancer Treatment[J].Comput Struct Biotechnol J,2019,17:142-150.doi:10.1016/j.csbj.2019.01.009.
[10]Pluta P,Jeziorski A,Cebula-Obrzut A P,et al.Expression of IAP family proteins and its clinical importance in breast cancer patients[J].Neoplasma,2015,62(4):666-673.doi:10.4149/neo_2015_080.
[11]Hussain AR,Siraj AK,Ahmed M,et al.XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis[J].BMCCancer,2017,17(1):640.doi:10.1186/s12885-017-3627-4.
[12]Xu YC,Liu Q,Dai JQ,et al.Tissue microarray analysis of X-linked inhibitor of apoptosis(XIAP)expression in breast cancer patients[J].Med Oncol,2014,31(3):764.doi:10.1007/s12032-013-0764-8.
[13]Yang X,Zhong DN,Qin H,et al.Caspase-3 over-expression is associated with poor overall survival and clinicopathological parameters in breast cancer:a meta-analysis of 3091 cases[J].Oncotarget,2018,9(9):8629-8641.doi:10.18632/oncotarget.23667.
[14]Zeleniuch-Jacquotte A,Afanasyeva Y,Kaaks R,et al.Premenopausal serum androgens and breast cancer risk:a nested case-control study[J].Breast Cancer Res,2012,14(1):R32.doi:10.1186/bcr3117.
[15]Dorgan JF,Stanczyk FZ,Kahle LL,et al.Prospective case-control study of premenopausal serum estradiol and testosterone levels and breast cancer risk[J].Breast Cancer Res,2010,12(6):R98.doi:10.1186/bcr2779.
[16]Goldhirsch A,Winer EP,Coates AS,et al.Personalizing the treatment of women with early breast cancer:highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013[J].Ann Oncol,2013,24(9):2206-2223.doi:10.1093/annonc/mdt303.
[17]Wang J,Liu Y,Ji R,et al.Prognostic value of the X-linked inhibitor of apoptosis protein for invasive ductal breast cancer with triplenegative phenotype[J].Hum Pathol,2010,41(8):1186-1195.doi:10.1016/j.humpath.2010.01.013.
[18]Zhang Y,Zhu J,Tang Y,et al.X-linked inhibitor of apoptosis positive nuclear labeling:a new independent prognostic biomarker of breast invasive ductal carcinoma[J].Diagn Pathol,2011,6:49.doi:10.1186/1746-1596-6-49.
[19]Engels CC,Ruberta F,de Kruijf EM,et al.The prognostic value of apoptotic and proliferative markers in breast cancer[J].Breast Cancer Res Treat,2013,142(2):323-339.doi:10.1007/s10549-013-2748-y.
[20]吴至佛,汪灵,黄俊辉.三阴性乳腺癌的生物标记物研究进展[J].中国普通外科杂志,2017,26(11):1472-1477.doi:10.3978/j.issn.1005-6947.2017.11.016.Wu ZF,Wang L,Huang JH.Research progress on biomarkers of triple-negative breast cancer[J].Chinese Journal of General Surgery,2017,26(11):1472-1477.doi:10.3978/j.issn.1005-6947.2017.11.016.
[21]Kempkensteffen C,Hinz S,Christoph F,et al.Expression parameters of the inhibitors of apoptosis cIAP1 and cIAP2 in renal cell carcinomas and their prognostic relevance[J].Int J Cancer,2007,120(5):1081-1086.doi:10.1002/ijc.22416
[22]Lee EK,Jinesh GG,Laing NM,et al.A Smac mimetic augments the response of urothelial cancer cells to gemcitabine and cisplatin[J].Cancer Biol Ther,2013,14(9):812-822.doi:10.4161/cbt.25326.
[23]Che X,Yang D,Zong H,et al.Nuclear cIAP1 overexpression is a tumor stage-and grade-independent predictor of poor prognosis in human bladder cancer patients[J].Urol Oncol,2012,30(4):450-456.doi:10.1016/j.urolonc.2010.12.016.
[24]Chen YT,Tsao SC,Tsai HP,et al.The X-linked inhibitor of apoptosis protein is an independent prognostic marker for rectal adenocarcinoma after preoperative chemoradiotherapy[J].Virchows Arch,2016,468(5):559-567.doi:10.1007/s00428-016-1913-1.
[25]Moussata D,Amara S,Siddeek B,et al.XIAP as a radioresistance factor and prognostic marker for radiotherapy in human rectal adenocarcinoma[J].Am J Pathol,2012,181(4):1271-1278.doi:10.1016/j.ajpath.2012.06.029.
[26]Dubrez L,Berthelet J,Glorian V.IAP proteins as targets for drug development in oncology[J].Onco Targets Ther,2013,9:1285-1304.doi:10.2147/OTT.S33375.
[27]Mahadevan D,Chalasani P,Rensvold D,et al.Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma[J].Am J Clin Oncol,2013,36(3):239-243.doi:10.1097/COC.0b013e3182467a13.
[28]Lee FA,Zee BC,Cheung FY,et al.Randomized Phase II Study of the X-linked Inhibitor of Apoptosis(XIAP)Antisense AEG35156in Combination With Sorafenib in Patients With Advanced Hepatocellular Carcinoma(HCC)[J].Am J Clin Oncol,2016,39(6):609-613.doi:10.1097/COC.0000000000000099.
[29]Nestal de Moraes G,Delbue D,Silva KL,et al.FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance[J].Cell Signal,2015,27(12):2496-2505.doi:10.1016/j.cellsig.2015.09.013.
[30]Tamm I,Kornblau SM,Segall H,et al.Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias[J].Clin Cancer Res,2000,6(5):1796-1803.
[31]Carter BZ,Kornblau SM,Tsao T,et al.Caspase-independent cell death in AML:caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis[J].Blood,2003,102(12):4179-4186.doi:10.1182/blood-2003-03-0960.
[32]Ferreira CG,van der Valk P,Span SW,et al.Expression of X-linked inhibitor of apoptosis as a novel prognostic marker in radically resected non-small cell lung cancer patients[J].Clin Cancer Res,2001,7(8):2468-2474.
[33]Huang Q,Li F,Liu X,et al.Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy[J].Nat Med,2011,17(7):860-866.doi:10.1038/nm.2385.
[34]Zhou L,Li K,Luo Y,et al.Novel prognostic markers for patients with triple-negative breast cancer[J].Hum Pathol,2013,44(10):2180-2187.doi:10.1016/j.humpath.2013.03.021.
[35]李良宏.乳腺癌中HSP90和Caspase-3的表达及其与临床病理、预后关系的研究[J].疑难病杂志,2012,11(4):271-273.doi:10.3969/j.issn.1671-6450.2012.04.012.Li LH.The expression of HSP80 and Caspase-3 in breast cancer and the correlation with clinicopathologic and prognosis[J].Chinese Journal of Difficult and Complicated Cases,2012,11(4):271-273.doi:10.3969/j.issn.1671-6450.2012.04.012.
[36]Pu X,Storr SJ,Zhang Y,et al.Caspase-3 and caspase-8 expression in breast cancer:caspase-3 is associated with survival[J].Apoptosis,2017,22(3):357-368.doi:10.1007/s10495-016-1323-5.