Role of COL6A2 in malignant progression and temozolomide resistance of glioma.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.