1596P - miR-7 modulates pancreatic cancer progression by interfering with aerobic glycolysis via inhibition of autophagy

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Dian-na Gu
Citation Annals of Oncology (2016) 27 (6): 545-551. 10.1093/annonc/mdw393
Authors D. Gu1, L. Tian1, Q. Huang2
  • 1Institute Of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School Of Medicine; Shanghai Key Laboratory Of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School Of Medicine, 1st Shanghai People's Hospital, 201620 - Shanghai/CN
  • 2Shanghai Key Laboratory Of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School Of Medicine; Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School Of Medicine, 1st Shanghai People's Hospital, 201620 - Shanghai/CN

Abstract

Background

Pancreatic cancers have abnormally high basal autophagy even under fed conditions, and are commonly addicted to aerobic glycolysis for survival and growth. This suggests that oncogenic events create inherent metabolic stress necessitating autophagy activation to sustain tumor cell survival. Thus, autophagy inhibition may exert the potential of antitumor. Recently, we and others described miR-7 acted as a tumor suppressor. However, the role of miR-7 in the context of pancreatic ductal adenocarcinoma (PDAC) remains unknown. Here, we investigated the biological functions of miR-7 in PDAC, and explored the underlying mechanism of miR-7 regulatory network related to autophagy and aerobic glycolysis.

Methods

The level of intracellular glucose, LDH activity and lactate production were detected by corresponding kits. A dual-luciferase reporter assay system was use to determine miR-7 target genes.

Results

Inhibition of autophagy by hydroxychloroquine or 3-methlyadenine could down-regulate the intracellular glucose levels, LDH activity and lactate. In contrast, induction of autophagy by glucose or serum starvation, could increase the level of glycolysis. These findings indicated that pancreatic cancer cells made use of autophagy as a survival strategy to provide essential glucose required for glycolysis. Importantly, overexpression of miR-7 inhibited the level of Torin-1 or starvation-induced autophagy, intracellular glucose and glycolytic metabolism. ciRS-7, a sponge of miR-7, could enhance autophagy and increase intracellular glucose. To address the underlying mechanism, we explored the pathway of autophagy, glycolysis and their related signaling. Intriguingly, miR-7 repressed autophagy through suppressing LKB1, ULK2, ATG4A and ATG7 to reduce the intracellular glucose supply to glycolysis in PDAC. Furthermore, we demonstrated that miR-7 inhibited pancreatic cancer cell growth and metastasis in vitro and in vivo.

Conclusions

These findings indicate that miR-7 acts as a tumor suppressor in PDAC and is a crucial regulator in autophagy-derived pools of glucose to suppress PDAC progress. Thus, exogenous overexpression of miR-7 might be a promising strategy for PDAC treatment by targeting autophagy.

Clinical trial identification

Legal entity responsible for the study

Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai/CHINA

Funding

The National Science Foundation of China

Disclosure

All authors have declared no conflicts of interest.