Khan Sheema, Ebeling Mara C, Zaman Mohd S, Sikander Mohammed, Yallapu Murali M, Chauhan Neeraj, Yacoubian Ashley M, Behrman Stephen W, Zafar Nadeem, Kumar Deepak, Thompson Paul A, Jaggi Meena, Chauhan Subhash C
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, USA.
Oncotarget. 2014 Sep 15;5(17):7599-609. doi: 10.18632/oncotarget.2281.
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.
由于诊断较晚且多模态治疗效果不佳，胰腺癌的预后较差。MUC13是一种跨膜粘蛋白，高度参与胰腺癌的进展。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，我们报告一种新的微小RNA（miR-145）介导的机制，该机制调节胰腺癌中MUC13的异常表达。我们报告miR-145的表达与胰腺癌细胞和人类肿瘤组织中MUC13的表达呈负相关。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发展到晚期低分化PDAC的过程中逐渐受到抑制。我们证明miR-145靶向MUC13的3'非翻译区，从而下调细胞中MUC13蛋白的表达。有趣的是，转染miR-145可抑制细胞增殖、侵袭并增强吉西他滨敏感性。它导致HER2、P-AKT、PAK1减少，p53增加。当用针对MUC13的短发夹RNA（shRNA）特异性抑制MUC13时，也发现了类似的结果。此外，在异种移植小鼠中瘤内注射miR-145通过抑制MUC13及其下游靶点HER2来抑制肿瘤生长。这些结果表明miR-145是胰腺癌中MUC13的一种新型调节因子。
