Medical School of Jingchu University of Technology, Jingmen 448000, China.
The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510900, China.
Cell Signal. 2023 Feb;102:110560. doi: 10.1016/j.cellsig.2022.110560. Epub 2022 Dec 12.
Gliomas are one of the most common primary malignant tumors of the central nervous system, and have an unfavorable prognosis. Even combining precise surgery, chemotherapy and radiotherapy, the survival rate is still unsatisfactory. Chemotherapy resistance is one of main reasons for its adverse prognosis. As shown by several studies, glioma stem cells (GSCs) were correlated with radiotherapy/chemotherapy resistance and high relapse rate. This study aimed to find a new biomarker related to GSCs and chemotherapy resistance.
TCGA, CGGA, GSE16011, GSE23806 and GDSC datasets were used to screen the genes related to GSCs, Temozolomide (TMZ) resistance, and survival. In the TCGA, GTEx, GSE16011 and CGGA datasets, mRNA level, prognostic value, and correlation with immune infiltration in the selected genes were analyzed through methods including Kaplan-Meier analysis, Cox analysis, the ESTIMATE algorithm, and the CIBERSORT algorithm. The expression of COL6A2 mRNA and protein in different groups was detected by RT-qPCR and western blot. A MTT assay and flow cytometry were used to measure the effect of COL6A2 on proliferation and apoptosis of glioma cells.
COL6A2 was positively correlated with glioma stemness and TMZ resistance. Its expression was up-regulated in GBM, and high expression was correlated with adverse prognosis. As shown by Cox analysis, COL6A2 was an independent prognostic factor for glioma. COL6A2 mRNA was increased with the glioma grade. It was over-expressed in MGMT non-methylation and IDH wild-type specimens. The results of in vitro experiments showed that COL6A2 promots proliferation of glioma cells and inhibits their apoptosis. Meanwhile, the expression of COL6A2 in TMZ-resistant glioma cells was significantly higher than that in ordinary glioma cells. As shown by GO and KEGG pathway analysis, COL6A2 was correlated with glioma proliferation, migration, invasion, and immunity. In particular, it was significantly positively correlated with PD-1, PD-L2, PD-L1, B7-H3, CTLA-4, IDO1 and TIM-3 expression, further verifying that it may play an important role in immune response. In addition, COL6A2 might influence immune cell infiltration in the glioma microenvironment.
COL6A2 high-expression is an indicator for adverse glioma prognosis, and is correlated with TMZ-resistant and immune response. Meanwhile, it may be a prospective biomarker for treatment.
神经胶质瘤是中枢神经系统最常见的原发性恶性肿瘤之一，预后不良。即使结合精确的手术、化疗和放疗，生存率仍然不理想。化疗耐药是其不良预后的主要原因之一。几项研究表明，神经胶质瘤干细胞（GSCs）与放疗/化疗耐药和高复发率有关。本研究旨在寻找与 GSCs 和化疗耐药相关的新生物标志物。
使用 TCGA、CGGA、GSE16011、GSE23806 和 GDSC 数据集筛选与 GSCs、替莫唑胺（TMZ）耐药和生存相关的基因。在 TCGA、GTEx、GSE16011 和 CGGA 数据集中，通过 Kaplan-Meier 分析、Cox 分析、ESTIMATE 算法和 CIBERSORT 算法等方法分析选定基因的 mRNA 水平、预后价值以及与免疫浸润的相关性。通过 RT-qPCR 和 Western blot 检测不同组中 COL6A2 mRNA 和蛋白的表达。使用 MTT assay 和流式细胞术测量 COL6A2 对神经胶质瘤细胞增殖和凋亡的影响。
COL6A2 与神经胶质瘤干细胞和 TMZ 耐药呈正相关。其在 GBM 中表达上调，高表达与不良预后相关。Cox 分析表明，COL6A2 是神经胶质瘤的独立预后因素。COL6A2 mRNA 随神经胶质瘤分级而增加。在 MGMT 非甲基化和 IDH 野生型标本中过度表达。体外实验结果表明，COL6A2 促进神经胶质瘤细胞的增殖并抑制其凋亡。同时，TMZ 耐药神经胶质瘤细胞中 COL6A2 的表达明显高于普通神经胶质瘤细胞。GO 和 KEGG 通路分析表明，COL6A2 与神经胶质瘤的增殖、迁移、侵袭和免疫相关。特别是，它与 PD-1、PD-L2、PD-L1、B7-H3、CTLA-4、IDO1 和 TIM-3 的表达呈显著正相关，进一步证实其可能在免疫反应中发挥重要作用。此外，COL6A2 可能影响神经胶质瘤微环境中免疫细胞的浸润。
COL6A2 高表达是不良神经胶质瘤预后的指标，与 TMZ 耐药和免疫反应相关。同时，它可能是治疗的有前途的生物标志物。
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