Oncotarget

Research Papers:

miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1

She Tian, Xingjun Guo, Chao Yu, Chengyi Sun and Jianxin Jiang _

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Oncotarget. 2017; 8:11071-11082. https://doi.org/10.18632/oncotarget.14360

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Abstract

She Tian1,*, Xingjun Guo2,*, Chao Yu1,*, Chengyi Sun1, Jianxin Jiang3,4

1Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China

2Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

3Department of Hepatic-Biliary-Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan, China

4Hubei Key Laboratory of Digestive System Disease

*These authors contributed equally to this study

Correspondence to:

Jianxin Jiang, email: [email protected]

Chengyi Sun, email: [email protected]

Keywords: pancreatic cancer, miR-138-5p, autophagy, SIRT1

Received: November 16, 2016     Accepted: December 21, 2016     Published: December 29, 2016

ABSTRACT

The role of microRNA in the aberrant autophagy that occurs in pancreatic cancer remains controversial. Because hypoxia is known to induce autophagy, we screened for differentially expressed microRNAs using a miRNA microarray with pancreatic cancer cells cultured under normoxic and hypoxic conditions. We found that miR-138-5p was among the most downregulated miRNA in hypoxia-stimulated cells, and that overexpression of miR-138-5p substantially reduced expression of autophagy markers. In addition, western blot and immunofluorescence analyses and electron microscopy revealed that miR-138-5p inhibited autophagy in pancreatic cancer cells and blocked serum starvation-induced autophagic flux independently of the typical autophagic signaling pathway. miR-138-5p had no effect on ATG3, ATG5, or ATG7, three primary autophagy-associated genes. Instead, miR-138-5p specifically targeted the SIRT1 3′ untranslated region and suppressed autophagy by reducing the level of SIRT1, which acetylates FoxO1 and regulates autophagy via FoxO1/Rab7. SIRT1 or Rab7 knockdown blocked the SIRT1/FoxO1/Rab7 axis and suppressed autophagic inhibition by miR-138-5p. Finally, we found that miR-138-5p inhibited autophagy and tumor growth in vivo. These results indicate that miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1.


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