circCORO1C promotes the proliferation and metastasis of hepatocellular carcinoma by enhancing the expression of PD-L1 through NF-κB pathway

Abstract

Background: Circular RNA (circRNA) affects the occurrence and development of human cancers, but the specific mechanism of hepatocellular carcinoma (HCC) has not yet been fully understood.

Methods: CircRNAs were determined by human circRNA array analysis and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability, migration, invasion, and other indicators were used for cell function analysis. Knockdown and overexpression techniques were used to explore the mechanism of circCORO1C in the occurrence and development of HCC by RNA sequencing, qRT-PCR, western blot, and other methods.

Results: Among the thousands of circRNAs, 1238 circRNAs were significantly changed. As for the top 10 upregulated circRNAs, the expression of circRNAs, hsa_circ_0036412, hsa_circ_0036411, hsa_circ_0028071, hsa_circ_0036409, hsa_circ_0000437, hsa_circ_0021427, hsa_circ_0097182, hsa_circ_0028067, hsa_circ_0006852, and hsa_circ_0003620 were significantly increased. In regard to the top 10 downregulated circRNAs, the expression of hsa_circ_0123629, hsa_circ_0096121, hsa_circ_0038932, hsa-circRNA3310-44, hsa_circ_0045746, hsa_circ_0016836, hsa-circRNA10899-9, hsa_circ_0050116, hsa_circ_0035543, and hsa_circ_0092118 decreased significantly. About these circRNAs, the downregulation of hsa_circ_0006852 (circCORO1C) can inhibit the tumorigenesis of HCC cells in vivo and in vitro, and the overexpression of circCORO1C can enhance the proliferation and metastasis ability of HCC cells. Mechanistically, circCORO1C activated the NF-κB signaling pathway, increased P65 phosphorylation and upregulation of c-Myc and COX-2, leading to increased PD-L1 expression.

Conclusion: CircCORO1C upregulates c-Myc and COX-2 through NF-κB signaling pathway, leading to the upregulation of PD-L1, which jointly promotes the development of HCC, suggesting that circCORO1C is a promising biomarker and therapeutic target for HCC.

Keywords: NF-κB; PD-L1; circRNA; hepatocellular carcinoma.