Circ_MAPK9 promotes STAT3 and LDHA expression by silencing miR-642b-3p and affects the progression of hepatocellular carcinoma.

Publisher: BioMed Central Country of Publication: England NLM ID: 101258412 Publication Model: Electronic Cited Medium: Internet ISSN: 1745-6150 (Electronic) Linking ISSN: 17456150 NLM ISO Abbreviation: Biol Direct Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2006-

Carcinoma, Hepatocellular*/genetics ; Liver Neoplasms*/genetics ; MicroRNAs*/genetics; Animals ; Mice ; Humans ; STAT3 Transcription Factor/genetics ; In Situ Hybridization, Fluorescence ; Mice, Nude ; Cell Proliferation ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic

Background: Aberrant expression and activation of circular RNAs (circRNAs) are closely associated with various cancers. The role of circ_MAPK9 (hsa_circ_0001566) in cancer progression remains unknown. This study aims to investigate the function, mechanism and clinical significance of circ_MAPK9 in hepatocellular carcinoma (HCC).
Methods: Circ_MAPK9 expression on the microarray of tumor from clinical HCC patients was detected by in situ hybridization (ISH). Circ_MAPK9 knockdown was achieved with siRNAs in SMMC-7721 and SK-Hep1 HCC cell lines. The biological function of circ_MAPK9 was verified in vitro by CCK8 test, colony formation assay, transwell assay, PI-Annexin V staining, and in vivo by xenograft tumor in nude mice. Fluorescent in situ hybridization (FISH), subcellular fractionation assay, a dual-luciferase reporter assay and rescue experiments were employed for further mechanistic investigation.
Results: The expression of circ_MAPK9 was significantly up-regulated in HCC tissues and cells, which was found to be associated with poor prognosis. Patients with high expression of circ_MAPK9 had a shorter overall survival and disease-free survival in comparison to those with low circ_MAPK9 expression. Functional assays showed that circ_MAPK9 knockdown suppressed cellular proliferation, migration, invasion and tumor growth in vivo, and promoted apoptosis in HCC cells. Moreover, we found that circ_MAPK9 knockdown could inhibit aerobic glycolysis by decreasing the production of adenosine triphosphate (ATP) and lactic acid, which was mediated by lactate dehydrogenase (LDHA). Mechanistically, circ_MAPK9 functioned as ceRNA via sponging miR-642b-3p and alleviated the inhibitory effect of miR-642b-3p on its target signal transducer and activator of transcription 3 (STAT3) and LDHA, thereby leading to STAT3 activation and LDHA expression.
Conclusions: Circ_MAPK9, as an oncogene, promotes HCC growth and metastasis through miR-642b-3p/STAT3-LDHA axis. Circ_MAPK9 could serve as a potential biomarker for HCC poor prognosis and diagnosis.
(© 2023. The Author(s).)

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82102813 National Natural Science Foundation of China; 81372634 National Natural Science Foundation of China; 2023A03J0416 Guangzhou Science and Technology Plan Project; 202201020157 Guangzhou Science and Technology Plan Project; A2021157 Guangdong Medical Research Foundation; 2021A1515010795, 2020A1515011255 General Project of Guangdong Natural Science Foundation

Keywords: Aerobic glycolysis; CeRNA; Circ_MAPK9; Hepatocellular carcinoma; Metastasis; Proliferation

0 (STAT3 Transcription Factor)
0 (MicroRNAs)
0 (STAT3 protein, human)

Date Created: 20240101 Date Completed: 20240103 Latest Revision: 20240104

20240104

PMC10759731

10.1186/s13062-023-00442-1

38163874