CircRPN2 Inhibits Aerobic Glycolysis and Metastasis in Hepatocellular Carcinoma

Author:

Li Jia12,Hu Zhi-Qiang12,Yu Song-Yang12,Mao Li2,Zhou Zheng-Jun12,Wang Peng-Cheng12,Gong Yu12,Su Sheng12,Zhou Jian123,Fan Jia123,Zhou Shao-Lai12ORCID,Huang Xiao-Wu123

Affiliation:

1. 1Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University.

2. 2Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.

3. 3Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.

Abstract

Abstract Although circular RNAs (circRNA) are known to modulate tumor initiation and progression, their role in hepatocellular carcinoma (HCC) metastasis remains poorly understood. Here, three metastasis-associated circRNAs identified in a previous circRNA-sequencing study were screened and validated in two HCC cohorts. CircRPN2 was downregulated in highly metastatic HCC cell lines and HCC tissues with metastasis. Patients with HCC with lower circRPN2 levels displayed shorter overall survival and higher rates of cumulative recurrence. Mechanistic studies in vitro and in vivo revealed that circRPN2 binds to enolase 1 (ENO1) and accelerates its degradation to promote glycolytic reprogramming through the AKT/mTOR pathway, thereby inhibiting HCC metastasis. CircRPN2 also acted as a competing endogenous RNA for miR-183–5p, which increases forkhead box protein O1 (FOXO1) expression to suppress glucose metabolism and tumor progression. In clinical samples, circRPN2 expression negatively correlated with ENO1 and positively correlated with FOXO1, and expression of circRPN2, either alone or in combination with ENO1 and FOXO1, was a novel indicator of HCC prognosis. These data support a model wherein circRPN2 inhibits HCC aerobic glycolysis and metastasis via acceleration of ENO1 degradation and regulation of the miR-183–5p/FOXO1 axis, suggesting that circRPN2 represents a possible therapeutic target in HCC. Significance: The circRNA circRPN2 is a potential prognostic biomarker and therapeutic target in hepatocellular carcinoma that suppresses aerobic glycolysis and metastasis.

Funder

Ministry of Science and Technology

National Natural Science Foundation of China

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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