CircVPS13C promotes pituitary adenoma growth by decreasing the stability of IFITM1 mRNA via interacting with RRBP1

Abstract

CircRNAs play important roles in a variety of biological processes by acting as microRNA sponges and protein scaffolds or by encoding functional proteins. However, their functions and underlying mechanisms remain largely unknown. Distinctive circRNA patterns were explored by comparing nonfunctioning pituitary adenomas (NFPAs) and normal pituitary tissues with a circRNA array. The biological functions of selected circRNAs were determined in vitro and in vivo. RNA-seq and circRNA pulldown assays were applied to investigate the underlying mechanisms. The circRNA profile of NFPAs is tremendously different from that of normal pituitary tissues. CircVPS13C is significantly upregulated in NFPA samples and cell lines. Gain- and loss-of-function experiments demonstrate that silencing circVPS13C inhibits the proliferation of pituitary tumor cells in vitro and in vivo. Mechanistically, circVPS13C silencing increases the expression of IFITM1 and subsequently activates its downstream genes involved in MAPK- and apoptosis-associated signaling pathways. Rescue experiments show that IFITM1 overexpression partly reverses the biological effects of circVPS13C. Further studies reveal that circVPS13C inhibits IFITM1 expression through a novel mechanism mainly by competitively interacting with RRBP1, a ribosome-binding protein of the endoplasmic reticulum membrane, and thereby alleviating the stability of IFITM1 mRNA. Clinically, circVPS13C expression is markedly higher in high-risk NFPA samples and is downregulated in patient serum 7 days post-transsphenoidal adenoma resection. Our findings suggest that circVPS13C is a critical regulator in the proliferation and development of NFPAs through a novel mechanism, whereby regulating mRNA stability via interacting with ribosome-binding proteins on the endoplasmic reticulum membrane.