circFN1 Mediates Sorafenib Resistance of Hepatocellular Carcinoma Cells by Sponging miR-1205 and Regulating E2F1 Expression

Abstract

In recent years, circular RNAs (circRNAs) have been shown to have critical regulatory roles in the resistance to anti-cancer drugs. However, the contributions of circRNAs to sorafenib resistance in hepatocellular carcinoma (HCC) remain largely unknown. The present study aims to explore the involvement of circFN1 in sorafenib resistance and how circFN1 is associated with the miR-1205/E2F1 pathway, which have been demonstrated to mediate this resistance in HCC cells. We investigated the expression of circRNAs in five paired sorafenib-sensitive HepG2 cells and sorafenib-resistant (SR)-HepG2 cells by microarray analysis. The quantitative real-time PCR analysis was used to investigate the expression pattern of circFN1 in HCC patient tissues and cell lines. Then, the effects of circFN1 on sorafenib resistance, cell proliferation, and apoptosis were assessed in HCC in vitro and in vivo . In this study, circFN1 was observed to be upregulated in HCC patient tissues and cell lines. Overexpression of circFN1 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival in patients with HCC. Our in vivo and in vitro data indicated that inhibition of circFN1 enhances the sorafenib sensitivity of HCC cells. Mechanistically, we found that circFN1 could promote the expression of E2F1 by sponging miR-1205. In summary, our study demonstrated that circFN1 contributes to sorafenib resistance by regulating the miR-1205/E2F1 signaling pathway. These results indicate that circFN1 may represent a potentially valuable target for overcoming sorafenib resistance for HCC.

Review on circular RNAs and new insights into their roles in cancer

“…A large number of studies performed on HCC patients have shown that hsa_circ_0000798 [174] hsa_circ_0027089 [175] and hsa_circ_0058124 [176] are upregulated in HCC tissues, whereas some circRNAs are downregulated, including hsa_circSMARCA5 [177] hsa_circ_0068669 [178] hsa_circ_0028502 [179] and hsa_circ_0076251 [179] . These circRNAs are supposed to serve as potential biomarkers for HCC.…”

The functional roles, cross-talk and clinical implications of m6A modification and circRNA in hepatocellular carcinoma

“…Therefore circRNA_101237 was an independent predictor of prognosis in HCC patients 102 . circFN1 (hsa_circ_0058124) was found to be able to promote the expression of E2F1 by acting as a miR-1205 sponge; thus, inhibition of circFN1 could enhance the sensitivity of HCC cells to sorafenib 103 . circARNT2 (hsa_circ_0104670) regulated cisplatin resistance through the miR-155-5p/PDK1 axis, while downregulation of circARNT2 inhibited cell proliferation and enhanced the sensitivity of HCC cells to cisplatin 104 .…”

Circular RNAs: characteristics, biogenesis, mechanisms and functions in liver cancer

“…Our group has made continuous progress in this field and found that circSORE participates in the process of HCC sorafenib resistance [ 52 , 53 ]. Additionally, circFN1 was reported to induce HCC sorafenib resistance by sponging miR-1205 and modulating E2F1 expression [ 101 ].…”