title: Upregulated miR-132 in Lgr5+gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway.
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.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China.
authors.forename: Lanfang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China.
authors.forename: Dezhong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China.
authors.forename: Shuping
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China.
authors.forename: Lanfang
authors.identifier: 0000-0002-7790-0061
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C116884:LGR5 protein, human; C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D043562:Receptors, G-Protein-Coupled; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D002945:Cisplatin
keywords: ABCG2; CREB; Lgr5+ gastric cancer stem cell-like cells; SIRT1; miR-132