Autophagy-related CMTM6 promotes glioblastoma progression by activating Wnt/β-catenin pathway and acts as an onco-immunological biomarker

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal of Gene Medicine Pub Date : 2024-04-30 DOI:10.1002/jgm.3685

Lirui Dai, Jingjia Xiao, Xiang Li, Yiran Tao, Peizhi Zhou, Liang Lyu, Zimin Shi, Xianyin Liang, Ziyang Jia, Shu Jiang

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Abstract

Background

Glioblastoma multiforme (GBM) is identified as one of the most prevalent and malignant brain tumors, characterized by poor treatment outcomes and a limited prognosis. CMTM6, a membrane protein, has been found to upregulate the expression of programmed cell death 1 ligand 1 protein (PD-L1) and acts as an immune checkpoint inhibitor by inhibiting the programmed death 1 protein/PD-L1 signaling pathway. Recent research has demonstrated a high expression of CMTM6 in GBM, suggesting its potential role in influencing the pathogenesis and progression of GBM, as well as its association with immune cell infiltration in the tumor microenvironment. However, the underlying mechanism of CMTM6 in GBM requires further investigation.

Methods

Data from cancer patients in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas cohorts were consolidated for the current study. Through multi-omics analysis, the study systematically examined the expression profile of CMTM6, epigenetic modifications, prognostic significance, biological functions, potential mechanisms of action and alterations in the immune microenvironment. Additionally, the study investigated CMTM6 expression in GBM cell lines and normal cells using reverse transcription PCR and western blot analysis. The impact of CMTM6 on GBM cell proliferation, migration and invasion was evaluated using a combination of cell counting kit-8 assay, clone formation assay, 5-ethynyl-2′-deoxyuridine incorporation assay, wound healing assay and Transwell assay. In order to explore the mechanism of CMTM6, the Wnt/β-catenin signaling pathway and autophagy-related genes were further verified through western blot analysis.

Results

CMTM6 is highly expressed in multiple tumors, particularly GBM. CMTM6 has been shown to be a valuable diagnostic and prognostic biomarker by various bioinformatics approaches. Additionally, CMTM6 plays a pivotal role in the pathogenesis of cancer, specifically GBM, by modulating various biological processes such as DNA methyltransferase expression, RNA modification, copy number variation, genomic heterogeneity, tumor stemness and DNA methylation. The findings of the experiment indicate a significant correlation between elevated CMTM6 expression and the proliferation, invasion, migration and autophagy of GBM cells, with potential key roles mediated through the Wnt/β-catenin signaling pathway. Furthermore, CMTM6 is implicated in modulating tumor immune cell infiltration and is closely linked to the expression of various immune checkpoint inhibitors and immune modulators, particularly within the context of GBM. High levels of CMTM6 expression also enhance the responsiveness of GBM patients to radiotherapy and chemotherapy, thereby offering valuable insights for guiding treatment strategies for GBM.

Conclusions

Autophagy-related CMTM6 is highly expressed in various types of cancer, especially GBM, and it can regulate GBM progression through the Wnt/β-catenin signaling pathway and is capable of being used as an underlying target for the diagnosis, treatment selection and prognosis of patients with GBM.

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与自噬相关的 CMTM6 通过激活 Wnt/β-catenin 通路促进胶质母细胞瘤的发展，并成为一种肿瘤免疫生物标记物

背景多形性胶质母细胞瘤（GBM）被认为是最常见的恶性脑肿瘤之一，其特点是治疗效果差、预后有限。CMTM6是一种膜蛋白，已被发现能上调程序性细胞死亡1配体1蛋白（PD-L1）的表达，并通过抑制程序性死亡1蛋白/PD-L1信号通路而成为一种免疫检查点抑制剂。最近的研究表明，CMTM6 在 GBM 中高表达，提示其在影响 GBM 的发病机制和进展中的潜在作用，以及与肿瘤微环境中免疫细胞浸润的相关性。然而，CMTM6 在 GBM 中的潜在作用机制还需要进一步研究。方法本研究整合了癌症基因组图谱（The Cancer Genome Atlas）、基因表达总库（Gene Expression Omnibus）和中国胶质瘤基因组图谱（Chinese Glioma Genome Atlas）队列中的癌症患者数据。通过多组学分析，该研究系统地考察了 CMTM6 的表达谱、表观遗传修饰、预后意义、生物学功能、潜在作用机制以及免疫微环境的改变。此外，该研究还使用反转录 PCR 和 Western 印迹分析法研究了 CMTM6 在 GBM 细胞系和正常细胞中的表达。研究采用细胞计数试剂盒-8测定、克隆形成测定、5-乙炔基-2′-脱氧尿苷掺入测定、伤口愈合测定和Transwell测定相结合的方法，评估了CMTM6对GBM细胞增殖、迁移和侵袭的影响。为了探索 CMTM6 的作用机制，还通过 Western 印迹分析进一步验证了 Wnt/β-catenin 信号通路和自噬相关基因。结果 CMTM6在多种肿瘤尤其是GBM中高表达。各种生物信息学方法已证明 CMTM6 是一种有价值的诊断和预后生物标志物。此外，CMTM6 通过调节 DNA 甲基转移酶表达、RNA 修饰、拷贝数变异、基因组异质性、肿瘤干性和 DNA 甲基化等各种生物过程，在癌症（尤其是 GBM）的发病机制中发挥着关键作用。实验结果表明，CMTM6 表达的升高与 GBM 细胞的增殖、侵袭、迁移和自噬之间存在显著的相关性，其潜在的关键作用是通过 Wnt/β-catenin 信号通路介导的。此外，CMTM6 还与调节肿瘤免疫细胞浸润有关，并与各种免疫检查点抑制剂和免疫调节剂的表达密切相关，尤其是在 GBM 中。高水平的 CMTM6 表达还能提高 GBM 患者对放疗和化疗的反应性，从而为指导 GBM 的治疗策略提供有价值的见解。结论自噬相关的 CMTM6 在各种类型的癌症尤其是 GBM 中高表达，它能通过 Wnt/β-catenin 信号通路调控 GBM 的进展，可作为 GBM 患者诊断、治疗选择和预后判断的基础靶点。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.