title: Metformin decreases IL-22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma.
abstract: Epidemiological, preclinical and cellular studies in the last 5 years have shown that metformin exerts anti-tumoral properties, but its mode of action in cancer remains unclear. Here, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and tumor-associated T cell immune responses. Oral metformin administration led to a significant reduction of tumor growth, which was accompanied by decreased interleukin-22 (IL-22). Meanwhile, IL-22-induced STAT3 phosphorylation and upregulation of downstream genes Bcl-2 and cyclin D1 were inhibited by metformin. At the cellular level, metformin attenuated Th1- and Th17-derived IL-22 production. Furthermore, metformin inhibited de novo generation of Th1 and Th17 cells from naive CD4(+) cells. These observations were further supported by the fact that metformin treatment inhibited CD3/CD28-induced IFN-γ and IL-17A expression along with the transcription factors that drive their expression (T-bet [Th1] and ROR-γt [Th17], respectively). The effects of metformin on T cell differentiation were mediated by downregulated STAT3 and STAT4 phosphorylation via the AMP-activated kinase-mammalian target of rapamycin complex 1 pathway. Notably, metformin led to a reduction in glucose transporter Glut1 expression, resulting in less glucose uptake, which is critical to regulate CD4(+) T cell fate. Taken together, these findings provide evidence for the growth-inhibitory and immune-modulatory effects of metformin in HCC and thus, broaden our understanding about the action of metformin in liver cancer treatment.
authors.affiliation: Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhao
authors.forename: Xi-Dai
authors.initials: XD
authors.lastname: Long
authors.forename: Tian-Fei
authors.initials: TF
authors.lastname: Lu
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Zhang
authors.forename: Yi-Xiao
authors.initials: YX
authors.lastname: Liu
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Cui
authors.forename: Hui-Juan
authors.initials: HJ
authors.lastname: Dai
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000187:drug effects; D000097043:Interleukin-22
chemical_list: D000970:Antineoplastic Agents; D007378:Interleukins; D008687:Metformin; D000097043:Interleukin-22
keywords: hepatocellular carcinoma; interleukin-22; metformin