title: Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation.
abstract: The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor suppressor microRNA that functions to posttranscriptionally suppress the expression of oncogenes that regulate cell growth and motility. We show that H19 depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including Hmga2, c-Myc and Igf2bp3. This H19/let-7-dependent regulation is recapitulated in vivo where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19 via DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities.
authors.affiliation: 1] Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P. R. China [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yan
authors.affiliation: 1] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA [2] Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 1] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA [2] Department of Gynecology and Obstetrics, Chinese PLA General Hospital, Beijing, P. R. China.
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ghazal
authors.affiliation: Department of Chronic Diseases Epidemiology, Yale School of Public Health, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bellone
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA [2] Department of Obstetrics and Gynecology, Xiangya Hospital of Central South University, Changsha, Hunan, P. R. China.
authors.forename: N
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P. R. China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Santin
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: H
authors.initials: H
authors.lastname: Taylor
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D019175:DNA Methylation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C094335:H19 long non-coding RNA; D035683:MicroRNAs; D062085:RNA, Long Noncoding; C487931:mirnlet7 microRNA, human; D008687:Metformin
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