Upregulated miR‐132 in Lgr5+ gastric cancer stem cell‐like cells contributes to cisplatin‐resistance via SIRT1/CREB/ABCG2 signaling pathway
- 2 May 2017
- journal article
- research article
- Published by Wiley in Molecular Carcinogenesis
- Vol. 56 (9), 2022-2034
- https://doi.org/10.1002/mc.22656
Abstract
Cisplatin resistance has long been a major problem that restricts its use. A novel paradigm in tumor biology suggests that gastric tumor chemo-resistance is driven by gastric cancer stem cell-like (GCSCs). Growing evidence has indicated that microRNAs (miRNAs) contributes to chemo-resistance in gastric cancer (GC). Here, Lgr5+ cells derived from gastric cancer cell lines displayed stem cell-like features. Flow cytometry demonstrated the presence of a variable fraction of Lgr5 in 19 out of 20 GC specimens. By comparing the miRNA expression profiles of Lgr5+ GCSCs and Lrg5- cells, we established the upregulation of miR-132 in Lgr5+ GCSCs. The enhanced miR-132 expression correlated chemo-resistance in GC patients. Kaplan–Meier survival curve showed that patients with low miR-132 expression survived obviously longer. Functional assays results indicated that miR-132 promoted cisplatin resistance in Lgr5+ GCSCs in vitro and in vivo. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-132. The expression of miR-132 was inversely correlated with SIRT1 in gastric cancer specimens. Furthermore, through PCR array we discovered ABCG2 was one of the downstream targets of SIRT1. Overexpression of SIRT1 down-regulated ABCG2 expression by promoting the de-acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Thus, we concluded that miR-132 regulated SIRT1/CREB/ABCG2 signaling pathway contributing to the cisplatin resistance and might serve as a novel therapeutic target against gastric cancer. This article is protected by copyright. All rights reservedKeywords
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