Abstract
The discovery of circular RNA (circRNA) enormously complimented the repertoire of traditional gene expression theory. As a type of endogenous noncoding RNA, circRNA participates in the occurrence of many kinds of tumors in addition to regulating their development. The Warburg effect (aerobic glycolysis is taken with priority for cancer cells instead of oxidative phosphorylation) is one of the most important factors involved in the excessive proliferation of gastric cancer cells. Our data showed that circRNA circATP2B1 (also called hsa_circ_000826) was overexpressed in gastric cancer tissues instead of linear ATP2B1 mRNA, and it promoted aerobic glycolysis in gastric cancer cells. Bioinformatic Gene Ontology analysis showed that the potential downstream targets of circATP2B1 include the microRNA miR-326 gene cluster (miR-326-3p/miR-330-5p), which is functionally focused on cell growth and metabolic processes. The expressions of miR-326-3p/miR-330-5p were downregulated in gastric cancer, and circATP2B1 functionally targeted miR-326-3p/miR-330-5p in an RNA-induced silencing complex (RISC) dependent manner. Dual-luciferase reporter assays demonstrated that pyruvate kinase M2 (PKM2) was one of the targets of miR-326-3p/miR-330-5p. As a rate-limiting enzyme in the aerobic glycolytic pathway, PKM2 accelerated gastric cancer cells’ glucose uptake and increased cell viability. Taken together, circATP2B1 captured miR-326-3p/miR-330-5p and decreased the suppression of PKM2 by miR-326-3p/miR-330-5p, thus aiding the aerobic glycolysis and proliferation of gastric cancer cells. This study identified a novel molecular pathway in gastric cancer that may provide more targets for reversing cancer metabolic reprogramming, as well as a potential strategy for targeted therapy of gastric cancer.
Highlights
Gastric cancer is one of the most common gastrointestinal malignancies during which patients display no significant symptoms [1]
Our preliminary experiments showed that circATP2B1 exerted gastric cancer cells aerobic glycolysis
We examined glycolytic markers such as Glucose Transporter 1 (GLUT1), Glucose Transporter 3 (GLUT3), Llactate dehydrogenase A chain (LDHA), pyruvate kinase M2 (PKM2) in gastric tissues (GT), highly differentiated gastric adenocarcinoma cancer specimens (HDAC) and poorly differentiated gastric adenocarcinoma cancer specimens (PDAC)
Summary
Gastric cancer is one of the most common gastrointestinal malignancies during which patients display no significant symptoms [1]. Gastric cancer has poor sensitivity to chemotherapy and current targeted therapies. The pathogenesis of this type of cancer has been a great challenge in recent years, requiring novel approaches for targeted therapies. Aerobic glycolysis rates are 200 times as high compared to rates in normal tissues [3]. Aerobic glycolysis can induce oncogenesis and promote gastric cancer cell proliferation, as well as mediate resistance to chemotherapy drugs and targeted therapy of gastric cancer. The degree of aerobic glycolysis is closely related to the rate of gastric cancer progression
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