Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential

// Jason J. Kwon 1 , Jeffrey A. Willy 2 , Kayla A. Quirin 1 , Ronald C. Wek 1, 2 , Murray Korc 2, 3, 4, 5 , Xiao-Ming Yin 6 , Janaiah Kota 1, 4, 5 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA 3 Department of Medicine, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA 4 The Melvin and Bren Simon Cancer Center, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA 5 Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA 6 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA Correspondence to: Janaiah Kota, email: jkota@iu.edu Keywords: pancreatic cancer, autophagy, gemcitabine, metastasis, miR-29 Received: February 16, 2016 Accepted: August 24, 2016 Published: September 10, 2016 ABSTRACT Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy that responds poorly to current therapeutic modalities. In an effort to develop novel therapeutic strategies, we found downregulation of miR-29 in pancreatic cancer cells, and overexpression of miR-29a sensitized chemotherapeutic resistant pancreatic cancer cells to gemcitabine, reduced cancer cell viability, and increased cytotoxicity. Furthermore, miR-29a blocked autophagy flux, as evidenced by an accumulation of autophagosomes and autophagy markers, LC3B and p62, and a decrease in autophagosome-lysosome fusion. In addition, miR-29a decreased the expression of autophagy proteins, TFEB and ATG9A, which are critical for lysosomal function and autophagosome trafficking respectively. Knockdown of TFEB or ATG9A inhibited autophagy similar to miR-29a overexpression. Finally, miR-29a reduced cancer cell migration, invasion, and anchorage independent growth. Collectively, our findings indicate that miR-29a functions as a potent autophagy inhibitor, sensitizes cancer cells to gemcitabine, and decreases their invasive potential. Our data provides evidence for the use of miR-29a as a novel therapeutic agent to target PDAC.