MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer
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Sheema Khan1, Mara C. Ebeling2, Mohd S. Zaman1, Mohammed Sikander1, Murali M. Yallapu1, Neeraj Chauhan1, Ashley M. Yacoubian3, Stephen W. Behrman4, Nadeem Zafar3, Deepak Kumar5, Paul A. Thompson2,6, Meena Jaggi1 and Subhash C. Chauhan1
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
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
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.
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