The telomere/telomerase binding factor PinX1 is a new target to improve the radiotherapy effect of oesophageal squamous cell carcinomas
The telomere/telomerase binding factor PinX1 is a new target to improve the radiotherapy effect of oesophageal squamous cell carcinomas
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DOI：
10.1002/path.4163
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发表时间：
2013-04-01
影响因子：
7.3
通讯作者：
Xie, Dan
中科院分区：
文献类型：
--
作者：
Qian, Dong;Zhang, Bin;Xie, Dan
放化疗(CRT)是晚期食管鳞癌的标准治疗方法。在端粒酶阳性的癌细胞中，端粒酶/端粒相互作用蛋白PinX1参与端粒的维持、肿瘤的发生，并影响DNA损伤剂诱导的凋亡反应。然而，PinX1在人胚胎干细胞中的临床和生物学意义尚不清楚。我们用免疫组织化学方法检测了接受特定放化疗(CRT)的ESCC患者的学习队列(n=98)和验证队列(n=59)中PinX1的表达动态。通过一系列体内和体外实验，探讨PinX1对ESCC细胞CRT反应的影响及其机制。PinX1基因敲除不影响ESCC细胞对5-氟尿嘧啶和顺铂的化疗敏感性，但显著提高了ESCC细胞的体内外放射治疗效果。异位过表达PinX1显著增强了ESCC细胞对放射治疗的耐药性。此外，我们还证明了PinX1对放射治疗(RT)的抵抗归因于PinX1通过RT诱导的有丝分裂突变(MC)维持端粒的稳定性，减少ESCC细胞的死亡。Pinx1的高表达与ESCC对CRT的耐药性呈正相关，是ESCC患者短期疾病特异性生存(DSS)的独立预测因子。我们的研究结果表明，PinX1可以作为ESCC患者CRT反应的一个新的预测因子，PinX1介导的端粒稳定途径可能代表一个新的靶点，以改善ESCC的RT效应。版权所有(C)2013年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Chemoradiotherapy (CRT) is a standard treatment for oesophageal squamous cell carcinoma (ESCC) in its advanced stages. The telomerase/telomere interacting protein PinX1 contributes to telomere maintenance, tumourigenicity, and influences the DNA damage agent-induced apoptotic response in telomerase-positive cancer cells. However, the clinical and biological significance of PinX1 in human ESCCs remains unclear. We examined the expression dynamics of PinX1 by immunohistochemistry in a learning cohort (n=98) and a validation cohort (n=59) of ESCC patients treated with definite chemoradiotherapy (CRT). A series of in vivo and in vitro assays were performed to elucidate the effect of PinX1 on ESCC cells' CRT response and underlying mechanisms. Knockdown of PinX1 did not affect ESCC cells' chemosensitivities to 5-fluorouracil and cisplatin, but substantially increased ESCC cells' therapeutic efficacy of radiation both in vitro and in vivo. Ectopic overexpression of PinX1 dramatically enhanced ESCC cells' resistance to radiotherapy. Furthermore, we demonstrated that PinX1 resistance to radiotherapy (RT) was attributed to PinX1 maintaining telomere stability, reducing ESCC cell death by RT-induced mitosis catastrophe (MC). High expression of Pinx1 correlated positively with ESCC's resistance to CRT, and was a strong and independent predictor for short disease-specific survival (DSS) of ESCC patients. Our data suggest that PinX1 could serve as a novel predictor for a CRT response to ESCC patients, and the pathway of PinX1-mediated telomere stability might represent a new target to improve the RT effect of ESCC. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.