miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells

Mathieu Neault; Frédérick A Mallette; Stéphane Richard

doi:10.1016/j.celrep.2016.01.068

miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells

Cell Rep. 2016 Mar 1;14(8):1966-78. doi: 10.1016/j.celrep.2016.01.068. Epub 2016 Feb 18.

Authors

Mathieu Neault¹, Frédérick A Mallette², Stéphane Richard³

Affiliations

¹ 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.
² 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.
³ 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.

PMID: 26904954
DOI: 10.1016/j.celrep.2016.01.068

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Cell Line, Tumor
Cell Proliferation
Cellular Senescence / genetics
Fibroblasts / cytology
Fibroblasts / metabolism
Gene Expression Regulation, Neoplastic*
Gene Regulatory Networks
Genes, Reporter
HEK293 Cells
Humans
Jumonji Domain-Containing Histone Demethylases / genetics*
Jumonji Domain-Containing Histone Demethylases / metabolism
Luciferases / genetics
Luciferases / metabolism
Mice
MicroRNAs / genetics*
MicroRNAs / metabolism
Molecular Sequence Data
Oncogene Protein p21(ras) / genetics*
Oncogene Protein p21(ras) / metabolism
Osteoblasts / metabolism
Osteoblasts / pathology
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
RNA, Messenger / genetics
RNA, Messenger / metabolism
Retinoblastoma Protein / genetics*
Retinoblastoma Protein / metabolism
Signal Transduction
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism

Substances

MIRN137 microRNA, human
MicroRNAs
RNA, Messenger
Retinoblastoma Protein
Tumor Suppressor Protein p53
Luciferases
Jumonji Domain-Containing Histone Demethylases
KDM4A protein, human
Oncogene Protein p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding