Abstract
Simple SummaryDrug resistance is the principal limiting factor to achieving good survival rates in patients with cancer. The identification of potential biomarkers for diagnosis and prognostic prediction, as well as the design of new molecular-targeted treatments, will be essential to improving head and neck squamous cell carcinoma (HNSCC) patient outcomes. In this sense, the sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. We conducted a proteomic study involving cisplatin-resistance and CSCs with the aim to unravel the molecular and cellular mechanisms by which tumor cells acquire resistance to chemotherapy. Syntenin-1 (SDCBP) was identified as an important protein involved in the chemoresistance and stemness of HNSCC tumors.To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeutic target for effectively eliminating CSCs and CDDP resistance.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world and can affect the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity, or salivary glands [1,2]
To gain insight into the mechanisms that govern head and neck squamous cell carcinoma (HNSCC) chemoresistance, we used a proteomic approach to compare the proteins differentially expressed in CCL-138 parental cells versus CCL-138-R cells and cancer stem cells (CSCs) [14]
To investigate whether SDCBP was involved in the acquisition of CDDP resistance in vivo, we generated a spontaneous model of CDDP resistance with tumors formed by CCL-138 and HTB-43 cells treated with CDDP (Figure S2A,B)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world and can affect the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity, or salivary glands [1,2]. HNSCC is generally curable when diagnosed early; patients are often diagnosed at an advanced and less curable stage, requiring more aggressive treatment and resulting in severe consequences and reduced life expectancy. 5-year survival rates for HNSCC patients have remained at ~50% over the last 40 years, largely due to frequent tumor recurrence and/or metastatic dissemination [3,4]. The identification of potential biomarkers for diagnosis and prognostic prediction, as well as the design of new molecular-targeted treatments, will be essential to improving HNSCC patient outcomes. The rapid evolution of HNSCC suggests the acquisition of resistance phenotypes by cancer cells, as well as the emergence of novel genetic/molecular alterations, in a dynamic, permanently active, and mutagenic tumor microenvironment [5]. CSC properties include the ability to self-renew, formation of tumorspheres in nonadherent culture conditions, expression of specific cell surface receptors (such as CD44 and CD133 in HNSCC), expression of transcription factors related to pluripotency
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