MicroRNA-7 Impairs Autophagy-derived Pools Of Glucose To Suppress Pancreatic Cancer Progression

Pancreatic cancer commonly addicts to aerobic glycolysis,and abnormally activates autophagy to adapt the stringent metabolic microenvironment.micro RNAs(miRNAs)are evolutionarily conserved small non-coding RNAs that post-transcriptionally regulate gene expression through binding to the 3'-UTR of target m RNAs,and take vital roles in cancer initiation,development,progression and metastasis.micro RNA-7(miR-7)was supposed to modulate various gastrointestinal cancer progression.However,the potential role of miR-7 in pancreatic cancer remains largely unknown.Our previous study revealed that compared to normal pancreatic cells,autophagy and glycolysis metabolism were elevated in pancreatic cancer cells.Meanwhile,miR-7 could significantly block autophagy and inhibit the activity of glycolysis,and overexpression of miR-7 could arrest cancer cell-cycle as well as induce apoptosis.Thus,we wonder whether miR-7 could destroy the reprogrammed metabolic homeostasis in pancreatic cancer via modulating the level of autophagy,and further affect tumor proliferation and survival.Hereinafter,we firstly explored the effect of autophagy on glycolysis metabolism by using compounds or nutrient-starvation to inhibit or induce autophagy,and assessed the alteration of glycolytic metabolism and intracellular glucose by corresponding kits.We then further investigated whether miR-7 affect glycolysis via suppressing autophagy after establishing miR-7 stable cell lines and then detecting the glycolytic metabolism and intracellular glucose under Torin-1 or nutrition-starvation-induced autophagy.Moreover,we used the dual-luciferase reporter system to explore the underyling molecular mechanisms and determined the miR-7-target genes in the process of autophagy and glycolysis metabolism.In addition,we performed gain-and loss-of-function approaches to assess the effect of miR-7 on PDAC cell growth and metastasis in vitro and in vivo.At last,we evaluated its therapeutic potentials by injection of lentivirus-mediated miR-7 in pancreatic patient-derived xenograft(PDX)models.Herein,we first report that pancreatic cancer could take advantage of autophagy as a survival strategy to provide essential glucose required for glycolysis metabolism.Of note,under the stressful tumor microenvironment,miR-7 could repress autophagy through upregulation of LKB1-AMPK-m TOR signaling,and directly targeting ULK2,ATG4 A and ATG7 in the stages of autophagy induction or vesicle elongation to reduce the supply of intracellular glucose to glycolysis metabolism.Furthermore,miR-7 inhibited pancreatic cancer cell proliferation and metastasis in vitro and in vivo.Consistently,lentivirus-mediated miR-7 effectively reduced the growth of patient-derived xenograft by interfering glycolysis via inhibition of autophagy.Moreover,lower miR-7 expression was correlated with more advanced tumor stages and worse prognosis in pancreatic cancer.Taken together,these data suggested miR-7 might function as an important regulator to impair autophagy-derived pools of glucose to suppress pancreatic cancer progression.Our study also facilitated the improved understanding of underlying intricate molecular regulatory mechanisms of miR-7 in pancreatic cancer progression.Of note,miR-7 might be a prognostic biomarker in pancreatic cancer and also a potential anti-pancreatic cancer therapeutic target.