Hsa_circ_0056686, derived from cancer-associated fibroblasts, promotes cell proliferation and suppresses apoptosis in uterine leiomyoma through inhibiting endoplasmic reticulum stress

Abstract

Abnormal expression of circular RNAs (circRNAs) in cancer-associated fibroblasts (CAFs) is involved in the tumor-promoting ability of CAFs. Hsa_ circ_ 0056686 has been reported to affect leiomyoma size. The purpose of this study is to investigate the regulatory role of hsa_circ_0056686 in CAFs on uterine leiomyoma (ULM). The primary CAFs and corresponding normal fibroblasts (NFs) were isolated from the tumor zones of ULM tissues and adjacent, respectively. Hsa_circ_0056686 level was higher in CAFs than NFs, and also higher in ULM tissues than in adjacent tissues. CAFs-CM significantly increased the proliferation and migration and inhibited apoptosis of ULM cells, as confirmed by CCK-8, transwell, and flow cytometry assays. Moreover, conditioned medium (CM) from CAFs transfected with hsa_circ_0056686 shRNA (CAFssh-circ_0056686-CM) abolished CAFs-mediated proliferation, migration and apoptosis of ULM cells. CAFs-CM suppressed the expression of endoplasmic reticulum stress (ERS) marker proteins and induced the expression of extracellular matrix (ECM) marker proteins, thus suppressing ERS and increasing ECM accumulation, which could be declined by CAFssh-circ_0056686-CM. Meanwhile, knockdown of hsa_circ_0056686 reversed the inhibitory effects of CAFs-CM on brefeldin A-induced cell apoptosis. Luciferase gene reporter and RNA pull-down assays indicated that miR-515-5p directly bound with hsa_circ_0056686. MiR-515-5p overexpression restored the hsa_circ_0056686-shRNA-mediated malignant biological behaviors of ULM cells. Hsa_circ_0056686 contributed to tumor-promoting effects of CAFs in ULM, manifested by promoting ULM cell proliferation and migration and reducing ERS-induced apoptosis through sponging miR-515-5p.

A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity

“…The most significant differences are observed in circRNAs hsa_circ_0083920 , hsa_circ_0056686 , hsa_circ_0062558 , hsa_circ_0020376 and hsa_circ_0043597 . In particular, hsa_circ_0056686 circRNA expression is higher in tumour-associated fibroblasts than in fibroblasts isolated from adjacent myometrial tissues and is associated with UL size, the regulation of proliferation, migration and apoptosis and endoplasmic reticulum stress [ 319 , 320 ].…”

Circulating circRNA: a social butterfly in tumors

“…For instance, hypoxia could induce secretion of exosomal circEIF3K from CAFs, and exosomal circEIF3K promoted colorectal cancer (CRC) progression via miR-214/PD-L1 axis (62). Hsa_circ_0056686, derived from CAFs, promoted cell proliferation and suppressed apoptosis in uterine leiomyoma through inhibiting endoplasmic reticulum stress (63). Moreover, breast cancer cells exposed to CAF-derived exosomes carrying circHIF1A display significantly increased stemness (64).…”