N6-methyladenosine-modified circular RNA QSOX1 promotes colorectal cancer resistance to anti-CTLA-4 therapy through induction of intratumoral regulatory T cells. (December 2022)

• Record Type: Journal Article
• Authors: Liu, Zhihua; Zheng, Nanxin; Li, Juan; Li, Chao; Zheng, Dan; Jiang, Xue; Ge, Xiaoying; Liu, Min; Liu, Lianjie; Song, Zhen; Bao, Leilei; Zhan, Yangyang; Gao, Xianhua
• Is Part Of: Drug resistance updates. Volume 65(2022)
• Publication Date: 2022-12
• Subjects: Colorectal cancer -- CircQSOX1 -- Anti-CTLA-4 therapy -- MiR-326 -- MiR-330–5p -- PGAM1; Drug resistance in cancer cells -- Periodicals; Cancer -- Chemotherapy -- Periodicals; 616.994061
• DOI: 10.1016/j.drup.2022.100886
• Languages: English
• ISSNs: 1368-7646

Abstract

Abstract: Background: Colorectal cancer (CRC) is the 3rd most common cancer worldwide. CircRNAs are promising novel biomarkers for CRC. T regulatory (Treg) cells express the immune checkpoint receptor of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and promote tumor immunological tolerance. We therefore investigate the biological functions and mechanisms of circQSOX1 in CRC tumorigenesis; involvement of circQSOX1 in promoting Treg cell-mediated CRC immune escape in anti-CTLA-4 therapy. Methods: Bioinformatics analyses were performed for circQSOX1expressions, specific binding sites, and N6-methyladenosine (m 6 A) motifs of circQSOX1, thatwere further validated with a series of experiments. Functions of circQSOX1 in promoting CRC development, Treg cells-based immune escape, and anti-CTLA-4 therapy response were investigated both in vitro and in vivo . Results: High circQSOX1 expression was associated with carcinogenesis and poor clinical outcome of CRC patients. METTL3-mediated RNA m 6 A modification on circQSOX1 could be read by IGF2BP2 in CRC cells. CircQSOX1 promoted CRC development by regulating miR-326/miR-330–5p/PGAM1 axis. CircQSOX1 regulated glycolysis and promoted immune escape of CRC cells, and inhibits anti-CTLA-4 therapy response in CRC patients. Conclusion : m 6 A-modified circQSOX1 facilitated CRC tumorigenesis by sponging miR-326 and miR-330–5p to promotes PGAM1 expression, which further promoted CRC immune escape by activating glycolysis and inactivating the anti-CTLA-4 therapy response of CRC. Combined treatment with sh-circQSOX1 and anti-CTLA-4 could be a strategy to overcome Treg cell-mediated CRC immune therapy resistance.