DNA methylation-mediated repression of miR-181a/135a/302c expression promotes the microsatellite-unstable colorectal cancer development and 5-FU resistance via targeting PLAG1
DNA methylation-mediated repression of miR-181a/135a/302c expression promotes the microsatellite-unstable colorectal cancer development and 5-FU resistance via targeting PLAG1
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DNA甲基化介导的miR-181a/135a/302c表达抑制通过靶向PLAG1促进微卫星不稳定结直肠癌的发展和5-FU耐药
DOI：
10.1016/j.jgg.2018.04.003
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发表时间：
2018-04-20
影响因子：
5.9
通讯作者：
Han, Weidong
中科院分区：
文献类型：
--
作者：
Shi, Lu;Li, Xiang;Han, Weidong
微卫星不稳定性（Microsatellite instability， MSI）定义了一种具有典型临床病理特征的结直肠癌（CRC）亚型。伴有MSI的crc （MSI crc）经常会加速癌变和5-FU耐药，确切的潜在机制尚不完全清楚。我们之前的研究已经确定了microRNA （miRNA）在MSI crc中的表达谱。在本研究中，通过qRT-PCR验证了三个mirna （miR-181a， miR-135a和miR-302c）在67个CRC样本中显著降低。增殖和凋亡实验表明，miR-181a/135a/302c通过抑制PLAG1/IGF2信号传导而发挥肿瘤抑制作用。此外，我们提出了令人信服的证据，恢复miR-181a/135a/302c表达可促进MSI CRC细胞对5-FU治疗的敏感性。miR-181a/135a/302c通过减弱PLAG1的表达来影响化学耐药。值得注意的是，MSI CRC的高甲基化状态导致了miR-181a/135a/302c的降低。我们的研究结果有助于更好地理解MSI CRC的化疗耐药机制，并为挖掘CRC患者的生物标志物和治疗靶点提供线索。中国科学院遗传与发育生物学研究所，中国遗传学会版权所有爱思唯尔有限公司和科学出版社出版。版权所有。
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. Copyright (C) 2018, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.