MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer

Abstract

// Sheema Khan 1 , Mara C. Ebeling 2 , Mohd S. Zaman 1 , Mohammed Sikander 1 , Murali M. Yallapu 1 , Neeraj Chauhan 1 , Ashley M. Yacoubian 3 , Stephen W. Behrman 4 , Nadeem Zafar 3 , Deepak Kumar 5 , Paul A. Thompson 2,6 , Meena Jaggi 1 and Subhash C. Chauhan 1 1 Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA 2 Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, USA 3 Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee , USA 4 Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee , USA 5 Department of Biological and Environmental Sciences, University of the District of Columbia, Washington, District of Columbia 6 Methodology and Data Analysis Center, Sanford Research, Sioux Falls, South Dakota, USA Correspondence: Subhash C. Chauhan, email: // Keywords : Pancreatic cancer, MUC13, MicroRNA, Tumor suppressor, Diagnostics, Therapeutics Received : June 14, 2014 Accepted : July 29, 2014 Published : July 30, 2014 Abstract 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.