1. N6-methyladenosine-modified circular RNA QSOX1 promotes colorectal cancer resistance to anti-CTLA-4 therapy through induction of intratumoral regulatory T cells.
- Author
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Liu Z, Zheng N, Li J, Li C, Zheng D, Jiang X, Ge X, Liu M, Liu L, Song Z, Bao L, Zhan Y, and Gao X
- Subjects
- Humans, RNA, Circular genetics, T-Lymphocytes, Regulatory metabolism, T-Lymphocytes, Regulatory pathology, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Carcinogenesis genetics, Adenosine, Cell Proliferation, Methyltransferases genetics, Methyltransferases metabolism, Oxidoreductases Acting on Sulfur Group Donors genetics, Oxidoreductases Acting on Sulfur Group Donors metabolism, MicroRNAs genetics, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism
- 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 m6 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: m6 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., Competing Interests: Conflicts of interests Each author declared no conflict of interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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