Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, China.
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.
Drug Resist Updat. 2022 Dec;65:100886. doi: 10.1016/j.drup.2022.100886. Epub 2022 Oct 21.
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.
Bioinformatics analyses were performed for circQSOX1expressions, specific binding sites, and N6-methyladenosine (mA) 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.
High circQSOX1 expression was associated with carcinogenesis and poor clinical outcome of CRC patients. METTL3-mediated RNA mA 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.
mA-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.
结直肠癌（CRC）是全球第三大常见癌症。环状 RNA（circRNA）是 CRC 的一种很有前途的新型生物标志物。调节性 T 细胞（Treg）表达细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）的免疫检查点受体，并促进肿瘤免疫耐受。因此，我们研究了 circQSOX1 在 CRC 肿瘤发生中的生物学功能和机制；circQSOX1 参与促进抗 CTLA-4 治疗中 Treg 细胞介导的 CRC 免疫逃逸。
对 circQSOX1 的表达、circQSOX1 的特异性结合位点和 N6-甲基腺苷（mA）基序进行了生物信息学分析，并通过一系列实验进行了进一步验证。在体外和体内研究了 circQSOX1 促进 CRC 发展、Treg 细胞介导的免疫逃逸和抗 CTLA-4 治疗反应的功能。
高 circQSOX1 表达与 CRC 患者的癌变和不良临床结局相关。METTL3 介导的 circQSOX1 RNA mA 修饰可被 CRC 细胞中的 IGF2BP2 读取。circQSOX1 通过调节 miR-326/miR-330-5p/PGAM1 轴促进 CRC 的发展。circQSOX1 调节糖酵解并促进 CRC 细胞的免疫逃逸，抑制 CRC 患者的抗 CTLA-4 治疗反应。
mA 修饰的 circQSOX1 通过海绵吸附 miR-326 和 miR-330-5p 促进 PGAM1 表达，从而促进 CRC 免疫逃逸，通过激活糖酵解和使 CRC 对抗 CTLA-4 治疗的反应失活来促进 CRC 免疫逃逸。sh-circQSOX1 与抗 CTLA-4 的联合治疗可能是克服 Treg 细胞介导的 CRC 免疫治疗耐药性的一种策略。
