MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer.
MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer.
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DOI：
10.18632/oncotarget.2281
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Chauhan SC
中科院分区：
文献类型：
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作者：
Khan S;Ebeling MC;Zaman MS;Sikander M;Yallapu MM;Chauhan N;Yacoubian AM;Behrman SW;Zafar N;Kumar D;Thompson PA;Jaggi M;Chauhan SC
胰腺癌由于诊断晚、综合治疗无效，预后差。MUC 13是一种跨膜粘蛋白，与胰腺癌的进展密切相关。因此，了解其调控分子机制可能为胰腺癌的预防/治疗提供新的治疗途径。在此，我们报告了一种新的microRNA（miR-145）介导的机制，调节胰腺癌中MUC 13的异常表达。我们报道了胰腺癌细胞和人类肿瘤组织中miR-145表达与MUC 13表达呈负相关。miR-145主要存在于正常胰腺组织和早期胰腺导管腺癌（PDAC）前体病变（PanIN I）中，并且在从PanIN II/III到晚期低分化PDAC的发展过程中逐渐受到抑制。我们证明miR-145靶向MUC 13的3′非翻译区，从而下调细胞中MUC 13蛋白的表达。有趣的是，miR-145的转染抑制细胞增殖、侵袭并增强吉西他滨敏感性。它导致HER 2，P-AKT，PAK 1减少和p53增加。当MUC 13被针对MUC 13的shRNA特异性抑制时，发现了类似的结果。此外，在异种移植小鼠中瘤内注射miR-145通过抑制MUC 13及其下游靶标HER 2来抑制肿瘤生长。这些结果表明miR-145是胰腺癌中MUC 13的一种新的调节剂。
Pancreatic cancer has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MUC13, a transmembrane mucin is highly involved in pancreatic cancer progression. Thus, understanding its regulatory molecular mechanisms may offer new avenue of therapy for prevention/treatment of pancreatic cancer. Herein, we report a novel microRNA (miR-145)-mediated mechanism regulating aberrant MUC13 expression in pancreatic cancer. We report that miR-145 expression inversely correlates with MUC13 expression in pancreatic cancer cells and human tumor tissues. miR-145 is predominantly present in normal pancreatic tissues and early Pancreatic Ductal Adenocarcinoma (PDAC) precursor lesions (PanIN I) and is progressively suppressed over the course of development from PanIN II/III to late stage poorly differentiated PDAC. We demonstrate that miR-145 targets 3′ untranslated region of MUC13 and thus downregulates MUC13 protein expression in cells. Interestingly, transfection of miR-145 inhibits cell proliferation, invasion and enhances gemcitabine sensitivity. It causes reduction of HER2, P-AKT, PAK1 and an increase in p53. Similar results were found when MUC13 was specifically inhibited by shRNA directed at MUC13. Additionally, intratumoral injections of miR-145 in xenograft mice inhibited tumor growth via suppression of MUC13 and its downstream target, HER2. These results suggest miR-145 as a novel regulator of MUC13 in pancreatic cancer.