Identification of Docetaxel-Resistant Related Genes in Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) represents about 90% of all oral malignancies and docetaxel is one of the most effective anti-tumor agents currently available for OSCC [1,2]. However, resistance to docetaxel has become a major therapeutic obstacle for the successful treatment of OSCC. The purpose of this study was to investigate the molecular mechanism of docetaxel resistance in OSCC. We compared the gene expression profiles between the docetaxel-sensitive OSCC cell lines (HSC2, HSC3 and HSC4) and the docetaxel-resistant cell lines (HSC2/DOC, HSC3/DOC and HSC4/DOC) using an Agilent Human GE4 × 44K v2 Microarray. We established these docetaxel-resistant cell lines by exposing HSC2, HSC3 and HSC4 parental cells to increasing concentrations of docetaxel. Microarray analysis revealed that the expression levels of 662 genes were elevated and 414 genes were decreased in HSC2/DOC cell line compared to the parental HSC2. Similarly, the expression of 557 genes were up-regulated and 391 genes were down-regulated in HSC3/DOC, and 442 genes showed increased expression while 550 genes showed decreased expression in HSC4/DOC compared to the parental cell line. Interestingly, there was one gene only, Receptor transporter protein 3 (RTP3) that showed elevated expression in all three docetaxel-resistant cell lines. Western blot analysis confirmed increased expression of RTP3 protein in docetaxel-resistant cells compared with the parental cell lines. Moreover, Immunohistochemical staining showed that, positive staining for RTP3 is correlated with chemoresistance to docetaxel based combination therapy in 42 OSCC patients and the expression of RTP3 predicted the outcome of the patients who received docetaxel chemotherapy. Furthermore, siRNA-directed suppressed expression of the RTP3 resulted enhanced susceptibility to docetaxel-mediated apoptosis in docetaxel-resistant cell lines. These results suggest that RTP3 gene might have great potential for predicting the efficacy of docetaxel-based chemotherapy against OSCC. Global gene analysis of docetaxel- resistant cell lines may provide new insights into the mechanisms underlying clinical docetaxel resistance and improve the outcome of docetaxel based chemotherapy for human OSCC.

References:

1.  Harada K, Ferdous T, Ueyama Y.  Establishment of 5-fluorouracil-resistant oral squamous cell carcinoma cell lines with epithelial to mesenchymal transition changes. Int J Oncol. 2014 Apr; 44(4):1302-1308.

2.  Tamatani T, Ferdous T, Takamaru N, Hara K, Kinouchi M, Kuribayashi N, Ohe G, Uchida D, Nagai H, Fujisawa K, Miyamoto Y.  Antitumor efficacy of sequential treatment with docetaxel and 5-fluorouracil against human oral cancer cells. Int J Oncol. 2012 Sep; 41(3):1148-1156.