SOX9 Elevation Acts with Canonical WNT Signaling to Drive Gastric Cancer Progression
SOX9 Elevation Acts with Canonical WNT Signaling to Drive Gastric Cancer Progression
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SOX9 升高与规范 WNT 信号传导共同驱动胃癌进展
DOI：
10.1158/0008-5472.can-16-1120
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发表时间：
2016-11-15
期刊：
影响因子：
11.2
通讯作者：
Matheu, Ander
中科院分区：
文献类型：
--
作者：
Santos, Juliana Carvalho;Carrasco-Garcia, Estefania;Matheu, Ander
胃癌仍然是全球癌症死亡的主要原因之一，由于治疗耐药，幽门螺杆菌（H。pylori）感染是主要的危险因素。在这项研究中，我们报告了细菌感染的人类胃炎和癌症样本中干细胞调节因子SOX 9升高的意义，与TNF α水平升高平行。在含有致病性显著的cagA + H菌株的样本中，SOX 9升高更强烈。幽门。值得注意的是，我们发现SOX 9是细菌诱导的胃癌细胞增殖、β-连环蛋白水平增加和获得干细胞样特性所必需的。对三个大型临床队列的分析显示，在具有晚期肿瘤阶段和较差患者存活率的胃癌中，SOX 9水平升高。在功能上，胃癌细胞中的SOX 9沉默增强了凋亡和衰老，同时阻断了自我更新和肿瘤启动能力。除了这些作用之外，我们还发现SOX 9介导与无病生存率降低相关的顺铂耐药性。SOX 9和β-连环蛋白表达之间的机制相互作用表明SOX 9靶向WNT经典途径的调节作用的存在。总之，我们的研究结果确立了SOX 9在胃癌病理生物学和异质性中的重要性，并暗示靶向WNT-SOX 9信号传导是一种合理的治疗策略。
Gastric cancer remains one of the leading causes of global cancer mortality due to therapy resistance, with Helicobacter pylori (H. pylori) infection being a major risk factor. In this study, we report the significance of an elevation of the stem cell regulator SOX9 in bacteria-infected human gastritis and cancer samples, paralleling increased levels of TNF alpha. SOX9 elevation was more intense in specimens containing the pathogenically significant cagA+ strains of H. pylori. Notably, we found that SOX9 was required for bacteria-induced gastric cancer cell proliferation, increased levels of beta-catenin, and acquisition of stem cell-like properties. Analysis of three large clinical cohorts revealed elevated SOX9 levels in gastric cancer with advanced tumor stage and poor patient survival. Functionally, SOX9 silencing in gastric cancer cells enhanced apoptosis and senescence, concomitantly with a blockade to self-renewal and tumor-initiating capability. Paralleling these effects, we also found SOX9 to mediate cisplatin chemoresistance associated with reduced disease-free survival. Mechanistic interactions between SOX9 and b-catenin expression suggested the existence of a regulatory role for SOX9 targeting the WNT canonical pathway. Taken together, our findings establish the significance of SOX9 in gastric cancer pathobiology and heterogeneity, with implications for targeting WNT-SOX9 signaling as a rational therapeutic strategy.