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

Zhihua Liu; Nanxin Zheng; Juan Li; Chao Li; Dan Zheng; Xue Jiang; Xiaoying Ge; Min Liu; Lianjie Liu; Zhen Song; Leilei Bao; Yangyang Zhan; Xianhua Gao

doi:10.1016/j.drup.2022.100886

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

Drug Resist Updat. 2022 Dec:65:100886. doi: 10.1016/j.drup.2022.100886. Epub 2022 Oct 21.

Authors

Zhihua Liu¹, Nanxin Zheng², Juan Li³, Chao Li¹, Dan Zheng⁴, Xue Jiang⁴, Xiaoying Ge⁴, Min Liu¹, Lianjie Liu², Zhen Song¹, Leilei Bao⁵, Yangyang Zhan⁶, Xianhua Gao⁷

Affiliations

¹ Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, China.
² Department of Colorectal Surgery, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai, China; Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
³ Department of Nephrology, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
⁴ Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China.
⁵ Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China. Electronic address: [email protected].
⁶ Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China. Electronic address: [email protected].
⁷ Department of Colorectal Surgery, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai, China; Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai, China. Electronic address: [email protected].

PMID: 36370665
DOI: 10.1016/j.drup.2022.100886

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 (m⁶A) 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 m⁶A 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: m⁶A-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.

Keywords: Anti-CTLA-4 therapy; CircQSOX1; Colorectal cancer; MiR-326; MiR-330–5p; PGAM1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine
Carcinogenesis / genetics
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Gene Expression Regulation, Neoplastic
Humans
Methyltransferases / genetics
Methyltransferases / metabolism
MicroRNAs* / genetics
Oxidoreductases Acting on Sulfur Group Donors / genetics
Oxidoreductases Acting on Sulfur Group Donors / metabolism
RNA, Circular / genetics
T-Lymphocytes, Regulatory / metabolism
T-Lymphocytes, Regulatory / pathology

Substances

RNA, Circular
MicroRNAs
Adenosine
METTL3 protein, human
Methyltransferases
QSOX1 protein, human
Oxidoreductases Acting on Sulfur Group Donors
IGF2BP2 protein, human
MIRN326 microRNA, human