Circular RNA MAT2B Promotes Glycolysis and Malignancy of Hepatocellular Carcinoma Through the miR‐338‐3p/PKM2 Axis Under Hypoxic Stress

Abstract

Glucose metabolism reprogramming, which is a well‐established characteristic of multiple cancers, demands a higher rate of glycolysis to meet the increasing demands for macromolecular synthesis and to maintain rapid proliferation in a hypoxic environment. However, the mechanism underlying this switch remains to be elucidated. In this study, we investigated the function of circular RNA MAT2B (circMAT2B) in hepatocellular carcinoma (HCC) glucose metabolism reprogramming and malignancy. CircMAT2B was identified by bioinformatics analysis of Gene Expression Omnibus data sets. CircMAT2B expression was up‐regulated in HCC tissues and cell lines. HCC patients with high circMAT2B expression had shortened overall survival. We analyzed the positive correlation between glycolysis and circMAT2B expression in HCC using a maximum standardized uptake value determined by preoperative positron emission tomography/computed tomography scanning combined with high‐performance liquid chromatography assessment of the metabolites of glycolysis and the citric acid cycle. The effect of circMAT2B on glycolysis was validated in vitro and in vivo under hypoxic (1% O2) conditions. Functional assays were performed in HCC cells, HCC organoids, and nude mice to explore the tumor‐promoting roles of circMAT2B in HCC. Biotin‐coupled probe pull‐down assays, biotin‐coupled microRNA capture, luciferase reporter assays, fluorescence in situ hybridization, and RNA immunoprecipitation assays were performed to confirm the interaction among different RNAs. Mechanistically, we demonstrated that circMAT2B up‐regulated expression levels of the microRNA (miR)‐338‐3p target gene PKM2, which encodes a key enzyme in the process of glycolysis, through “sponging” miR‐338‐3p; thus, glycolysis and HCC progression are promoted through this mechanism. Conclusion: CircMAT2B promoted HCC progression by enhanced glycolysis by activating the circMAT2B/miR‐338‐3p/PKM2 axis under hypoxia, which may provide a therapeutic target for HCC.

Circ_0072995 promotes cell carcinogenesis via up-regulating miR-149-5p-mediated SHMT2 in breast cancer

“…For example, circHIPK3 up-regulated BDNF expression by competitively binding with miR-107, thus facilitating cell viability and migration in gastric cancer [18]. CircMAT2B induced the glycolysis and malignancy in hepatocellular carcinoma via regulating PKM2 through sponging miR-338-3p [19]. Therefore, circRNAs are involved in the regulation of cell malignant phenotypes and metabolism, thus affecting the occurrence and development of cancers.…”

CircRNA circ_POLA2 promotes lung cancer cell stemness via regulating the miR‐326/GNB1 axis

“…Sponging miRNA is one of the most common regulatory mechanisms of circRNA. For example, circRNA CircFAT1 promotes the expression of YAP in osteosarcoma cells via sponging miR‐375 26 ; circRNA MAT2B promotes glycolysis and malignancy of hepatocellular carcinoma via sponging miR‐338‐3p under hypoxic stress 27 ; circRNA circ‐BANP promotes lung cancer progression via sponging miR‐503 28 . In the current work, we identified that the expression of circ_POLA2 was increased in lung cancer and high level of circ_POLA2 was negatively associated with the prognosis.…”

Circular RNA circ‑ACACA regulates proliferation, migration and glycolysis in non‑small‑cell lung�carcinoma via miR‑1183 and PI3K/PKB pathway

“…Alteration of energy metabolism, especially abnormal activation of the glycolysis pathway was observed in diverse human cancers (26,27). circRNAs are reported to be involved in the regulation of the Warburg effect in human cancers (28,29). Hence, the level of EcAR were checked in NScLc cells and it was found that circ-ACACA silencing reduced the glycolysis rate.…”