Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma

SIMPLE SUMMARY: Most treatment failures in head and neck squamous cell carcinoma (HNSCC) patients are due to the presence of resistant cells. Despite the chemotherapeutic advances that have taken place in recent decades, there are hardly new alternatives for HNSCC patients, with cisplatin being the most widely used chemotherapy drug. Therefore, it is urgent to propose new potential biomarkers and alternative therapeutic modalities capable of preventing the acquisition of resistance to treatment. We have conducted a RNA sequencing and proteomics study in cisplatin resistant and sensitive HNSCC cells with the aim of unravelling the molecular mechanisms involved in chemoresistance. Then, by an extensive literature search, in silico studies in cBioportal and in vitro experiments in biopsies from resistant and sensitive patients, we have listed potentially involved genes and proteins. Overall, the overexpression of MAGEB2 was identified in resistant tumours, revealing it as a novel protein targeting sensitised HNSCC resistant patients. ABSTRACT: To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma (HNSCC), we explored the expression profiles of the following cisplatin (CDDP) resistant (R) versus parental (sensitive) cell lines by RNA-sequencing (RNA-seq): JHU029, HTB-43 and CCL-138. Using the parental condition as a control, 30 upregulated and 85 downregulated genes were identified for JHU029-R cells; 263 upregulated and 392 downregulated genes for HTB-43-R cells, and 154 upregulated and 68 downregulated genes for CCL-138-R cells. Moreover, we crossed-checked the RNA-seq results with the proteomic profiles of HTB-43-R (versus HTB-43) and CCL-138-R (versus CCL-138) cell lines. For the HTB-43-R cells, 21 upregulated and 72 downregulated targets overlapped between the proteomic and transcriptomic data; whereas in CCL-138-R cells, four upregulated and three downregulated targets matched. Following an extensive literature search, six genes from the RNA-seq (CLDN1, MAGEB2, CD24, CEACAM6, IL1B and ISG15) and six genes from the RNA-seq and proteomics crossover (AKR1C3, TNFAIP2, RAB7A, LGALS3BP, PSCA and SSRP1) were selected to be studied by qRT-PCR in 11 HNSCC patients: six resistant and five sensitive to conventional therapy. Interestingly, the high MAGEB2 expression was associated with resistant tumours and is revealed as a novel target to sensitise resistant cells to therapy in HNSCC patients.