DNA methylation-mediated repression of miR-181a/135a/302c expression promotes the microsatellite-unstable colorectal cancer development and 5-FU resistance via targeting PLAG1

Lu Shi; Xiang Li; Zhiqiang Wu; Xiaolei Li; Jing Nie; Mingzhou Guo; Qian Mei; Weidong Han

doi:10.1016/j.jgg.2018.04.003

Volume 45 Issue 4

Apr. 2018

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Article Navigation > Journal of Genetics and Genomics > 2018 > 45(4): 205-214

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DNA methylation-mediated repression of miR-181a/135a/302c expression promotes the microsatellite-unstable colorectal cancer development and 5-FU resistance via targeting PLAG1

doi: 10.1016/j.jgg.2018.04.003

a
Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100086, China
b
Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing 100086, China

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Corresponding author: E-mail address: meiqnn@hotmail.com (Qian Mei); E-mail address: hanwdrsw69@yahoo.com (Weidong Han)
Received Date: 2017-10-30
Accepted Date: 2018-04-08
Rev Recd Date: 2018-04-06

Available Online: 2018-04-13

Publish Date: 2018-04-20

Abstract

Abstract

Microsatellite instability (MSI) defines a subtype of colorectal cancer (CRC) with typical clinicopathologic characteristics. CRCs with MSI (MSI CRCs) frequently acquire accelerated carcinogenesis and 5-FU resistance, and the exact underlying mechanism remains incompletely understood. Our previous study has identified the microRNA (miRNA) expression profile in MSI CRCs. In this study, three miRNAs (miR-181a, miR-135a and miR-302c) were validated by qRT-PCR to be dramatically decreased in 67 CRC samples. Proliferation and apoptosis assays demonstrated that miR-181a/135a/302c function as tumor suppressors via repressing PLAG1/IGF2 signaling. Moreover, we presented compelling evidence that restoration of miR-181a/135a/302c expression promoted sensitivity of MSI CRC cells to 5-FU treatment. miR-181a/135a/302c exerted their effect on chemoresistance through attenuating PLAG1 expression. Notably, the hypermethylation status of MSI CRC accounts for the decrements of miR-181a/135a/302c. Our results contribute to a better understanding of the mechanism of chemoresistance in MSI CRCs, and provide a clue for digging the biomarkers and therapeutic targets for CRC patients.
- Colorectal cancer,
- Microsatellite instability,
- microRNA,
- Chemoresistance,
- 5-FU

These authors contributed equally to this study.

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References(46)

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