Abstract
A number of studies report that epithelial to mesenchymal transition (EMT) supports the generation and maintenance of cancer stem cells (CSCs), which show tumor seeding ability and drug resistance; however, the molecular mechanisms underlying induction of EMT-associated tumor malignancy remain unclear. The present study reports that oral cancer cells switch from expressing the CD44 variant form (CD44v) to expressing the standard form (CD44s) during acquisition of cisplatin-resistance, which resulted in EMT induction. CD44s induced an EMT phenotype in cisplatin resistant cells by up-regulating ZEB1, a transcriptional repressor of E-cadherin. More importantly, CD44s up-regulated ZEB1 by suppressing microRNA-200c, which is a non-coding RNA that directly represses the ZEB1 gene. These results demonstrate the importance of the association between platinum resistance and CD44s during EMT induction in oral cancer cells.
Highlights
Head and neck cancer is one of the most common malignancies, with more than 550,000 cases annually worldwide [1]
The present study reports that oral cancer cells switch from expressing the CD44 variant form (CD44v) to expressing the standard form (CD44s) during acquisition of cisplatinresistance, which resulted in epithelial to mesenchymal transition (EMT) induction
We demonstrated that CD44s induced ZEB1-mediated EMT induction in cis-diamminedichloroplatinum II (CDDP)-resistant head and neck squamous cell carcinoma (HNSCC) by suppressing miR-200c expression
Summary
Head and neck cancer is one of the most common malignancies, with more than 550,000 cases annually worldwide [1]. While research has succeeded in improving the quality of life of those with advanced head and neck squamous cell carcinoma (HNSCC), the recurrence and mortality rates remain high [2]. To improve the prognosis of post-operative HNSCC with high-risk features, patients often receive a combination of cisplatin [cis-diamminedichloroplatinum II (CDDP)] and radiotherapy (RT), which provides a survival benefit over RT alone [2]. Chemoradiotherapy (CRT) with CDDP is the standard treatment for post-operative HNSCC with a high risk of recurrence. One of the major obstacles to treatment of cancer patients is acquired resistance to anti-cancer agents [3]. In HNSCC, as for other types of cancer, intrinsic/acquired resistance to CDDP is a major obstacle, resulting in disease recurrence and a poor prognosis [4]
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