![]() ![]() ( E) Relative mRNA expression of CMTM6 was analyzed by qRT-PCR in different chemotherapy nonresponder (CT nonresponder) OSCC tumors as compared with CT responder tumors (median, n = 11 for CT responder and n = 23 for CT nonresponder). ( D) Relative mRNA (fold change) CMTM6 expression was analyzed by qRT-PCR in indicated cells (mean ± SEM, n = 3), * P < 0.05 by 1-way ANOVA. ( C) Cell lysates from indicated resistant and sensitive OSCC cells were isolated and subjected to immunoblotting ( n = 3) against CMTM6 and β-actin antibodies. ( B) Relative mRNA (fold change) CMTM6 expression was analyzed by quantitative real-time PCR (qRT-PCR) in indicated cells (mean ± SEM, n = 3), * P < 0.05 by 1-way ANOVA. ( A) Cell lysates from indicated resistant and sensitive OSCC cells were isolated and subjected to immunoblotting ( n = 3) against CMTM6 and β-actin antibodies. SCX, strong cation exchange and LC-ESI, liquid chromatography electrospray ionization. CMTM6 is the top-ranked upregulated genes in 4M and 8M cisplatin-resistant groups. ( D) Volcano plot indicating deregulated genes in proteome profiling of sensitive and cisplatin-resistant cells. ( C) Principal component analysis (PCA) of global proteomic profiling sensitive, early (4M), and late resistant cells (8M). 0R11 and 0R12 are biological replicates of the H357CisS group, 4R11: 4R12 and 4R2 are technical and biological replicates of the H357CisR4M group, and 8R11: 8R12 and 8R2 are technical and biological replicates of H357CisR8M group. The schematic diagram depicts the iTRAQ labeling strategy for proteomic analysis. ( B) The lysates were isolated from parental sensitive (H357CisS), early (H357CisR4M), and late (H357CisR8M) cisplatin-resistant cells and subjected to global proteomic profiling. ![]() The establishment of sensitive, early, and late resistant cells is described in Methods. ( A) Schematic representation of sensitive, early, and late cisplatin-resistant OSCC line for global proteomic profiling. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.Ĭell Biology Head and neck cancer Molecular biology Oncology Signal transduction. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT-glycogen synthase kinase-3β. ![]() The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatin-induced cell death and tumor burden substantially. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Therefore, identifying causative factors for chemoresistance is of high importance. Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance.
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