CircMUC16 promotes autophagy of epithelial ovarian cancer via interaction with ATG13 and miR-199a

Abstract

Background: Circular RNA (circRNA) has been proven to play a significant role in multiple types of cancer. However, the expression and role of circRNAs in epithelial ovarian cancer (EOC) remains elusive. Methods: CircRNA and mRNA expression profiles of EOC were screened with sequencing analysis. Gene silencing and over-expression were used to study circRNA function. Cell proliferation and Matrigel invasion assays were used to detect cell proliferation and invasion, respectively. The expression of circRNAs, mRNAs and miRNAs was detected using qPCR. The location of circRNAs was detected using FISH. The expression of proteins was detected using western blot and immunohistochemistry. Results: CircMUC16 had increased expression in EOC tissues as compared to healthy ovarian tissues. The expression of circMUC16 was linked to the progression in stage and grade of EOC. Hence, silencing circMUC16 suppressed autophagy flux of SKOV3 cells. In contrast, ectopic expression of circMUC16 promoted autophagy flux of A2780 cells. CircMUC16-mediated autophagy exacerbated EOC invasion and metastasis. Mechanistically, circMUC16 could directly bind to miR-199a-5p and relieve suppression of target Beclin1 and RUNX1. In turn, RUNX1 elevated the expression of circMUC16 via promotion of its transcription. CircMUC16 could directly bind to ATG13 and promote its expression. Conclusion: This study demonstrated that circMUC16 regulated Beclin1 and RUNX1 by sponging miR-199a-5p. The data suggested that circMUC16 could be a potential target for EOC diagnosis and therapy.

The emerging roles of circular RNAs in ovarian cancer

“…Moreover, highly expressed circ-MUC16 was reported to be positively associated with tumor stage and tumor grade. Gan et al revealed that circMUC16 mediated autophagic flux in OvCa by regulating the circMUC16-miR-199a-5p-Beclin1/RUNX1 axis, thereby accelerating the proliferation and invasion of OvCa cells [55]. In addition, several studies have revealed that transcription factors can modulate the expression of circRNAs, and circMUC16 is a typical example.…”

“…The expression of this circRNA was reported to be impacted by the downstream target runt-related transcription factor 1 (RUNX1) via transcriptional promotion. Gan et al discovered that overexpression of RUNX1 facilitated MUC16 promoter activity and increased the expression of circMUC16, while silencing RUNX1 inhibited MUC16 promoter activity and decreased circMUC16 expression [55].…”

Identification and Functional Validation of Differentially Expressed Micrornas in Ascites-derived Ovarian Cancer Cells Compared With Primary Tumour Tissue

“…The interaction network of noncoding RNAs is essential for tumour progression. Several noncoding RNAs, such as CircMUC16 (17), lncRNA LUCAT1 (18) and lncRNA NORAD (19) promote ovarian cancer progression through miR-199a-3p and miR-199a-5p. Pan et al reported that miR-126 was underrepresented in exosomes from the plasma of epithelial ovarian cancer patients compared with that of healthy women (20).…”

The Roles of ceRNAs-Mediated Autophagy in Cancer Chemoresistance and Metastasis

“…In ovarian carcinoma, circMUC16-mediated autophagy promotes metastasis by directly binding to ATG13 and enhancing its expression. Moreover, cirMUC16 could also function as a ceRNA for miR-199a-5p and relieve its inhibitory on Beclin-1 and RUNX1 [ 81 ]. Nevertheless, in breast cancer, the expression of autophagy-related genes negatively correlates with pre-metastasis signatures, and thereof restricts tumor metastasis [ 105 , 106 ].…”

“…RUNX1 facilitated circMUC16 expression in a positive feedback. circMUC16 is a promising prognostic biomarker for metastasis in ovarian carcinomas [ 81 ].…”