ARID1A suppresses malignant transformation of human pancreatic cells via mediating senescence-associated miR-503/CDKN2A regulatory axis

Zhao-Yun Li; Shan-Shan Zhu; Xian-Jun Chen; Jie Zhu; Qi Chen; Ya-Qiong Zhang; Chun-Ling Zhang; Ting-Ting Guo; Li-Ming Zhang

doi:10.1016/j.bbrc.2017.09.099

ARID1A suppresses malignant transformation of human pancreatic cells via mediating senescence-associated miR-503/CDKN2A regulatory axis

Biochem Biophys Res Commun. 2017 Nov 18;493(2):1018-1025. doi: 10.1016/j.bbrc.2017.09.099. Epub 2017 Sep 20.

Authors

Zhao-Yun Li¹, Shan-Shan Zhu¹, Xian-Jun Chen¹, Jie Zhu¹, Qi Chen¹, Ya-Qiong Zhang¹, Chun-Ling Zhang¹, Ting-Ting Guo¹, Li-Ming Zhang²

Affiliations

¹ Medical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China.
² Medical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China. Electronic address: [email protected].

PMID: 28942143
DOI: 10.1016/j.bbrc.2017.09.099

Abstract

ARID1A as a subunit of SWI/SNF chromatin complexes is frequently mutated in human pancreatic cancer, however its exact role in pancreatic tumorigenesis remain unclear. In this study, we investigated the effects of ARID1A loss on human pancreatic epithelial cell lines HPNE, BxPC-3 with KRAS mutant (KRAS^G12D) expression. We found that ARID1A knockdown promoted cell proliferation and colony formation in cooperation with active mutant KRAS^G12D. Function assay revealed that ARID1A knockdown accelerated cell cycle progression, and repressed KRAS^G12D-induced cell senescence. Transcriptome analysis revealed ARID1A knockdown led to miR-503 upregulation. CDKN2A was identified as a target of miR-503, which contributes to cell senescence. Thus, our data suggests that ARID1A deficiency promote KRAS^G12D-driven pancreatic tumorigenesis through miR-503/CDKN2A-mediated senescence.

Keywords: ARID1A; Pancreatic cancer; SWI/SNF; Senescence; miR-503; microRNA.

MeSH terms

Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinogenesis / pathology
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology*
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18 / genetics*
Cyclin-Dependent Kinase Inhibitor p18 / metabolism
DNA-Binding Proteins
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Humans
MicroRNAs / genetics*
MicroRNAs / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Pancreas / metabolism
Pancreas / pathology*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology*
Point Mutation
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
RNA Interference
RNA, Small Interfering / genetics
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

ARID1A protein, human
CDKN2A protein, human
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18
DNA-Binding Proteins
KRAS protein, human
MIRN503 microRNA, human
MicroRNAs
Nuclear Proteins
RNA, Small Interfering
Transcription Factors
Proto-Oncogene Proteins p21(ras)