title: miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1.
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.
authors.affiliation: Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: She
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xingjun
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: Chengyi
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Hepatic-Biliary-Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.|Hubei Key Laboratory of Digestive System Disease, Wuhan, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Jiang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D018613:Microscopy, Confocal; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D020413:3' Untranslated Regions; D000071161:Forkhead Box Protein O1; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D020691:rab GTP-Binding Proteins
keywords: SIRT1; autophagy; miR-138-5p; pancreatic cancer