Inhibition of circRNA circVPS33B Reduces Warburg Effect and Tumor Growth Through Regulating the miR-873-5p/HNRNPK Axis in Infiltrative Gastric Cancer

Yizhuo Lu; Jia Cheng; Wangyu Cai; Huiqin Zhuo; Guoyang Wu; Jianchun Cai

doi:10.2147/OTT.S292575

Inhibition of circRNA circVPS33B Reduces Warburg Effect and Tumor Growth Through Regulating the miR-873-5p/HNRNPK Axis in Infiltrative Gastric Cancer

Onco Targets Ther. 2021 May 12:14:3095-3108. doi: 10.2147/OTT.S292575. eCollection 2021.

Authors

Yizhuo Lu¹, Jia Cheng², Wangyu Cai², Huiqin Zhuo², Guoyang Wu¹, Jianchun Cai²

Affiliations

¹ Department of General Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People's Republic of China.
² Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People's Republic of China.

Abstract

Background: Circular RNA VPS33B (circVPS33B) has been revealed to be upregulated in gastric cancer (GC) tissues. However, the role of circVPS33B in infiltrative GC is indistinct.

Methods: Expression of circVPS33B was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration, and invasion of infiltrative GC cells (XGC-1) were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT), plate clone, wound-healing, or transwell assays. Protein levels were detected by Western blotting. Measurements of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were executed using an XF96 extracellular flux analyzer. Glucose uptake and lactate production were analyzed by glycolysis assay. The regulatory mechanism of circVPS33B had been explored by bioinformatics analysis, dual-luciferase reporter assay, and/or RNA pull-down assay. In vivo tumorigenesis assay was executed to verify the oncogenicity of circVPS33B.

Results: CircVPS33B was upregulated in infiltrative GC tissues and cells. CircVPS33B silencing decreased tumor growth in vivo and inhibited proliferation, migration, invasion, EMT, and Warburg effect of infiltrative GC cells in vitro. Mechanically, circVPS33B regulated heterogeneous nuclear ribonucleoprotein K (HNRNPK) expression via sponging miR-873-5p. Furthermore, miR-873-5p inhibitor offset circVPS33B knockdown-mediated effects on malignant behaviors and Warburg effect of infiltrative GC cells. HNRNPK overexpression reversed the inhibitory impact of miR-873-5p mimic on malignant behaviors and Warburg effect of infiltrative GC cells.

Conclusion: CircVPS33B accelerated Warburg effect and tumor growth through regulating the miR-873-5p/HNRNPK axis in infiltrative GC, manifesting that circVPS33B might be a potential target for infiltrative GC treatment.

Keywords: HNRNPK; circVPS33B; infiltrative GC; miR-873-5p.

Grants and funding

This work was supported by grant from The National Natural Science Foundation of China (Nos. 81172283 and 81871979); the Natural Science Foundation of Fujian Province (no. 2020J011215); Fujian Provincial Medical Innovation Project (No. 2017-CXB-15); Guiding Project of Xiamen Science and Technology Plan (3502Z20149005 3502Z20174076); Young and Middle-aged Backbone Key Research Project of National Health and Family Planning Commission of Fujian Province (2017-ZQN-89).