Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential
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Jason J. Kwon1, Jeffrey A. Willy2, Kayla A. Quirin1, Ronald C. Wek1,2, Murray Korc2,3,4,5, Xiao-Ming Yin6, Janaiah Kota1,4,5
1Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
3Department of Medicine, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
4The Melvin and Bren Simon Cancer Center, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
5Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA
6Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
Janaiah Kota, email: email@example.com
Keywords: pancreatic cancer, autophagy, gemcitabine, metastasis, miR-29
Received: February 16, 2016 Accepted: August 24, 2016 Published: September 10, 2016
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.
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