Abstract
Long non-coding RNA antisense non-coding RNA in the INK4 locus (ANRIL) has been reported to promote tumorigenesis via regulating microRNA (miR)-99a in gastric cancer cells. However, the role of each component involved in it is still not well understood. This study aimed to verify the role of ANRIL in gastric cancer as well as the underlying mechanisms. ANRIL levels in clinical gastric cancer tissues and cell lines were tested by qPCR. Effects of ANRIL silence on cell viability, migration and invasion, apoptosis, and miR-99a expression in MKN-45 and SGC-7901 cells were measured using CCK-8, Transwell assay, flow cytometry, and qPCR assays, respectively. Then, effects of miR-99a inhibition on ANRIL-silenced cells were evaluated. B-lymphoma Mo-MLV insertion region 1 (BMI1) expression, after abnormal expression of ANRIL and miR-99a, was determined. Finally, expression of key proteins in the apoptotic, Notch, and mTOR pathways was assessed. ANRIL level was elevated in gastric cancer tissues and cell lines. Knockdown of ANRIL suppressed cell viability, migration, and invasion, and increased apoptosis through up-regulating miR-99a. Furthermore, ANRIL silence down-regulated BMI1 via up-regulating miR-99a. BMI1 silence down-regulated Bcl-2 and key kinases in the Notch and mTOR pathways and up-regulated p16 and cleaved caspases. We verified the tumor suppressive effects of ANRIL knockdown in gastric cancer cells via crosstalk with miR-99a. Together, we provided a novel regulatory mechanism for ANRIL in gastric cancer, in which ANRIL silence down-regulated BMI1 via miR-99a, along with activation of the apoptotic pathway and inhibition of the Notch and mTOR pathways.
Highlights
Gastric cancer is one of the most common malignancies worldwide, ranking second in terms of global cancer related mortality [1]
We identified the higher expression of long non-coding RNAs (lncRNAs) antisense non-coding RNA in the INK4 locus (ANRIL) in gastric cancer tissues than in corresponding non-tumor tissues, and it was up-regulated in MKN-45 and SGC-7901 cells compared with gastric epithelial cell GES-1 in vitro, indicating that the abnormal expression of ANRIL in gastric cancer could be a candidate biomarker in gastric cancer diagnosis
ANRIL belongs to the family of lncRNAs, which have been implicated in diverse functions of gene regulation that is mediated by RNA-RNA, RNA-DNA, or RNA-protein interactions [29,30]
Summary
Gastric cancer is one of the most common malignancies worldwide, ranking second in terms of global cancer related mortality [1]. Surgical resection therapy and chemotherapy have been practiced in patients with gastric cancer [2]. Gastric cancer is diagnosed at an advanced stage accompanied by malignant proliferation in most patients, with poor prognosis for advancedstage patients [3]. Gastric cancer is still a big burden for health resources and facilities [4]. Elucidating the molecular mechanisms underlying gastric carcinogenesis is essential for improving diagnosis and prognosis of gastric cancer. MicroRNAs (miRNAs, miRs) and long non-coding RNAs (lncRNAs), including miR148b, miR-10b, lncRNA H19 etc., have been identified as key factors for tumorigenesis of gastric cancer [5,6,7]
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