title: miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells.
abstract: Activating K-Ras mutations occurs frequently in pancreatic cancers and is implicated in their development. Cancer-initiating events, such as oncogenic Ras activation, lead to the induction of cellular senescence, a tumor suppressor response. During senescence, the decreased levels of KDM4A lysine demethylase contribute to p53 activation, however, the mechanism by which KDM4A is downregulated is unknown. We show that miR-137 targets KDM4A mRNA during Ras-induced senescence and activates both p53 and retinoblastoma (pRb) tumor suppressor pathways. Restoring the KDM4A expression contributed to bypass of miR-137-induced senescence and inhibition of endogenous miR-137 with an miRNA sponge-compromised Ras-induced senescence. miR-137 levels are significantly reduced in human pancreatic tumors, consistent with previous studies revealing a defective senescence response in this cancer type. Restoration of miR-137 expression inhibited proliferation and promoted senescence of pancreatic cancer cells. These results suggest that modulating levels of miR-137 may be important for triggering tumor suppressor networks in pancreatic cancer.
authors.affiliation: Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Segal Cancer Centre, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Departments of Oncology and Medicine, McGill University, Montréal, QC H3T 1E2, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Neault
authors.affiliation: Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada; Department of Medicine, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, QC H3C 3J7, Canada. Electronic address: fa.mallette@umontreal.ca.
authors.forename: Frédérick A
authors.initials: FA
authors.lastname: Mallette
authors.affiliation: Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Segal Cancer Centre, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Departments of Oncology and Medicine, McGill University, Montréal, QC H3T 1E2, Canada. Electronic address: stephane.richard@mcgill.ca.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D015689:Oncogene Protein p21(ras) / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D015689:Oncogene Protein p21(ras)