AUTHOR=Zou Changyan , Liao Jinrong , Hu Dan , Su Ying , Lin Huamei , Lin Keyu , Luo Xingguan , Zheng Xiongwei , Zhang Lurong , Huang Tao , Lin Xiandong 

TITLE=SNHG8 Promotes the Progression of Epstein–Barr Virus-Associated Gastric Cancer via Sponging miR-512-5p and Targeting TRIM28

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.734694

DOI=10.3389/fonc.2021.734694

ISSN=2234-943X

ABSTRACT=<p>SNHG8, a family member of small nucleolar RNA host genes (SNHG), has been reported to act as an oncogene in gastric carcinoma (GC). However, its biological function in Epstein–Barr virus (EBV)-associated gastric cancer (EBVaGC) remains unclear. This study investigated the role of SNHG8 in EBVaGC. Sixty-one cases of EBVaGC, 20 cases of non-EBV-infected gastric cancer (EBVnGC), and relative cell lines were studied for the expression of SNHG8 and BHRF1 (BCL2 homolog reading frame 1) encoded by EBV with Western blot and qRT-PCR assays. The relationship between the expression levels of SNHG8 and the clinical outcome in 61 EBVaGC cases was analyzed. Effects of overexpression or knockdown of <italic>BHRF1</italic>, SNHG8, or <italic>TRIM28</italic> on cell proliferation, migration, invasion, and cell cycle and the related molecules were determined by several assays, including cell proliferation, colony assay, wound healing assay, transwell invasion assay, cell circle with flow cytometry, qRT-PCR, and Western blot for expression levels. The interactions among SNHG8, miR-512-5p, and <italic>TRIM28</italic> were determined with Luciferase reporter assay, RNA immunoprecipitation (RIP), pull-down assays, and Western blot assay. The <italic>in vivo</italic> activity of SNHG8 was assessed with SNHG8 knockdown tumor xenografts in zebrafish. Results demonstrated that the following. (1) <italic>BHRF1</italic> and SNHG8 were overexpressed in EBV-encoded RNA 1-positive EBVaGC tissues and cell lines. <italic>BHRF1</italic> upregulated the expressions of SNHG8 and TRIM28 in AGS. (2) SNHG8 overexpression had a significant correlation with tumor size and vascular tumor thrombus. Patients with high SNHG8 expression had poorer overall survival (OS) compared to those with low SNHG8 expression. (3) SNHG8 overexpression promoted EBVaGC cell proliferation, migration, and invasion <italic>in vitro</italic> and <italic>in vivo</italic>, cell cycle arrested at the G2/M phase <italic>via</italic> the activation of <italic>BCL-2</italic>, <italic>CCND1</italic>, <italic>PCNA</italic>, <italic>PARP1</italic>, <italic>CDH1</italic>, <italic>CDH2 VIM</italic>, and <italic>Snail</italic>. (4) Results of dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assays indicated that SNHG8 sponged miR-512-5p, which targeted on <italic>TRIM28</italic> and promoted cancer malignant behaviors of EBVaGC cells. Our data suggest that BHRF1 triggered the expression of SNHG8, which sponged miR-512-5p and upregulated <italic>TRIM28</italic> and a set of effectors (such as <italic>BCL-2</italic>, <italic>CCND1</italic>, <italic>CDH1</italic>, <italic>CDH2 Snail</italic>, and VIM) to promote EBVaGC tumorigenesis and invasion. SNHG8 could be an independent prognostic factor for EBVaGC and sever as target for EBVaGC therapy.</p>