Cell Oncol (Dordr). 2023 Oct;46(5):1333-1350.doi: 10.1007/s13402-023-00814-9. Epub 2023 Apr 26.

本文采用的英格恩产品: Entranter-R4000

Aberrant expression of circular RNA DHPR facilitates tumor growth and metastasis by regulating the RASGEF1B/RAS/MAPK axis in hepatocellular carcinoma

Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510000, P. R. China.
  • 2 Research Centre for Artificial Organ and Tissue Engineering & Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, P. R. China.
  • 3 Center of Pancreas, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, 510000, P. R. China.
  • 4 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510000, P. R. China.
  • 5 Department of General Surgery, Zhujiang hospital, Southern Medical University, Guangzhou, 510000, P. R. China.
  • 6 Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510000, P. R. China. gaoyi@smu.edu.cn.
  • 7 Research Centre for Artificial Organ and Tissue Engineering & Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, P. R. China. gaoyi@smu.edu.cn.
  • 8 Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510000, P. R. China. pmxwxy@sohu.com.
  • 9 Research Centre for Artificial Organ and Tissue Engineering & Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, P. R. China. pmxwxy@sohu.com.
  • 10 Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510000, P. R. China. fsj103@163.com.
  • 11 Research Centre for Artificial Organ and Tissue Engineering & Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, P. R. China. fsj103@163.com.

Abstract

Background: Circular RNAs (circRNAs) are noncoding RNAs. Accumulating evidence suggests that circRNAs play a critical role in human biological processes, especially tumorigenesis, and development. However, the exact mechanisms of action of circRNAs in hepatocellular carcinoma (HCC) remain unclear.

Methods: Bioinformatic tools and RT-qPCR were used to identify the role of circDHPR, a circRNA derived from the dihydropteridine reductase (DHPR) locus, in HCC and para-carcinoma tissues. Kaplan-Meier analysis and the Cox proportional hazard model were used to analyze the correlation between circDHPR expression and patient prognosis. Lentiviral vectors were used to establish stable circDHPR-overexpressing cells. In vitro and in vivo studies have shown that tumor proliferation and metastasis are affected by circDHPR. Mechanistic assays, including Western blotting, immunohistochemistry, dual-luciferase reporter assays, fluorescence in situ hybridization, and RNA immunoprecipitation, have demonstrated the molecular mechanism underlying circDHPR.

Results: CircDHPR was downregulated in HCC, and low circDHPR expression was associated with poor overall survival and disease-free survival rates. CircDHPR overexpression inhibits tumor growth and metastasis in vitro and in vivo. Further systematic studies revealed that circDHPR binds to miR-3194-5p, an upstream regulator of RASGEF1B. This endogenous competition suppresses the silencing effect of miR-3194-5p. We confirmed that circDHPR overexpression inhibited HCC growth and metastasis by sponging miR-3194-5p to upregulate the expression of RASGEF1B, which is regarded as a suppressor of the Ras/MAPK signaling pathway.

Conclusions: Aberrant circDHPR expression leads to uncontrolled cell proliferation, tumorigenesis, and metastasis. CircDHPR may serve as a biomarker and therapeutic target for HCC.

Keywords: Circular RNA; DHPR; Hepatocellular carcinoma; RASGEF1B; Ras/MAPK.

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