Detailed Abstract
[Poster Exhibition]
[P127] Metformin inhibited pancreatic cancer growth by upregulating miR-143/145 cluster and suppressing MAPK signaling pathway
Yaolin XU1, Zizhen WU1, Peng YUAN2, Mofang LIU2, Wenhui LOU1
1General Surgery Department, Zhongshan Hospital Fudan University, China
2Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China
Introduction : Accumulating evidence suggests that metformin treatment is associated with decreased risk and better survival outcome of pancreatic cancer (PC) in patients with diabetes. Besides, our previous study revealed that miR-143 was as essential regulator of cancer glycolysis and miR-143/145 cluster was reported as a tumor suppressor in a range of cancer. The aim of present study was to investigate whether miR-143/145 cluster was associated with antitumor effect of metformin in PC and its potential mechanism.
Methods : We analyzed miRNA sequencing dataset of PC from NCBI (GSE37406) to identify miRNA that were differently expressed between metformin treatment and control group. MiR-143/145 expression level were determined by qRT-PCR, and expression level of target protein were detected by western blot. Potential target genes of miR-143/145 were identified by bioinformatic analyses and confirmed by luciferase reporter assays. Furthermore, biological consequences of miR-143/145 alternation and metformin treatment were examined by cell proliferation, invasion, and apoptosis assays in vitro and by patient derived xenograft models in vivo.
Results : MiR-143/145 was upregulated in metformin-treated PC. Overexpression of miR-143/145 inhibited proliferation and induce apoptosis of PC in vitro. Metformin inhibited tumor growth while downregulation of mir-143/145 cluster downstream of metformin treatment abrogated its antitumor effect both in vitro and vivo. Furthermore, miR-143/145 cluster directly targeted 3’-UTR of MAPK and AKT and repressed their expression. Low MAPK and AKT expression level correlated with better prognosis in PC.
Conclusions : Our data demonstrated the pivotal role of metformin/miR-143/145 cluster/MAPK axis and suggested miR-143/145 cluster as a candidate therapeutic target in PC.
Methods : We analyzed miRNA sequencing dataset of PC from NCBI (GSE37406) to identify miRNA that were differently expressed between metformin treatment and control group. MiR-143/145 expression level were determined by qRT-PCR, and expression level of target protein were detected by western blot. Potential target genes of miR-143/145 were identified by bioinformatic analyses and confirmed by luciferase reporter assays. Furthermore, biological consequences of miR-143/145 alternation and metformin treatment were examined by cell proliferation, invasion, and apoptosis assays in vitro and by patient derived xenograft models in vivo.
Results : MiR-143/145 was upregulated in metformin-treated PC. Overexpression of miR-143/145 inhibited proliferation and induce apoptosis of PC in vitro. Metformin inhibited tumor growth while downregulation of mir-143/145 cluster downstream of metformin treatment abrogated its antitumor effect both in vitro and vivo. Furthermore, miR-143/145 cluster directly targeted 3’-UTR of MAPK and AKT and repressed their expression. Low MAPK and AKT expression level correlated with better prognosis in PC.
Conclusions : Our data demonstrated the pivotal role of metformin/miR-143/145 cluster/MAPK axis and suggested miR-143/145 cluster as a candidate therapeutic target in PC.
SESSION
Poster Exhibition
Room E 4/6/2019 3:00 PM - 3:50 PM