复发性和/或转移性口腔鳞癌患者对顺铂耐药后预后极差，逆转顺铂耐药是提高患者生存率的关键。Hedgehog (Hh)/Gli通路与肿瘤干细胞干性和耐药密切相关，但其调控机制仍不明确。我们的前期研究发现：Sam68高表达促进口腔鳞癌进展和顺铂耐药；过表达Sam68上调Hh/Gli通路和干细胞相关转录因子表达；抑制Hh/Gli通路下调干细胞相关转录因子表达。据此我们提出假说：Sam68通过调控Hh/Gli通路维持口腔鳞癌干细胞干性促进顺铂耐药。本项目拟通过体内外实验，探讨Sam68通过调控Hh/Gli通路促进口腔鳞癌顺铂耐药的机制，明确Hh/Gli通路维持口腔鳞癌干细胞干性促进顺铂耐药的分子机制，并在口腔鳞癌组织样本中验证假说内容，明确Sam68/Hh/Gli通路的临床意义。本项目将揭示口腔鳞癌顺铂耐药的新机制，为确立Sam68/Hh/Gli通路作为逆转口腔鳞癌顺铂耐药的新靶点提供科学依据。

Cisplatin resistance poses a major challenge to patients with recurrent and/or metastatic (R/M) oral cavity squamous cell carcinoma, which leads to an extremely poor prognosis. Reversal of cisplatin resistance is crucial in improving survival of patients with R/M oral cavity squamous cell carcinoma. Hedgehog/Gli signaling pathway correlates with cancer stem cell maintenance and chemoresistance, whereas the molecular mechanism beneath is unclear. Sam68 is a multifunctional RNA binding protein, which regulates RNA alternative splicing and RNA 3’-end formation. It plays pivotal roles in cell cycle regulation, promoting tumorigenesis and progression in a variety of malignancies. Our previous study showed that the expression of Sam68 was upregulated in oral cavity squamous cell carcinoma, which was positively correlated with N classification and recurrence (P = 0.026, and 0.002, respectively), and also significantly associated with poor overall and disease-free survival rate (P = 0.009, and 0.002, respectively). Furthermore, overexpression of Sam68 significantly inhibited cisplatin-induced apoptosis in vitro and in vivo (published on J Exp Clin Cancer Res in 2016, IF = 5.189), while the molecular mechanism beneath was still unclear. Recently, Signal Transduction 45-Pathway Reporter Array performed on Sam68-overexpressed SCC-9 and SCC-25 cell lines indicated that cell apoptosis associated pathways were activated with top fold changes, including Hedgehog/Gli, Nanog/Nanog, and Notch/RBP-Jk signaling pathways. Overexpression of Sam68 upregulated the expression of signaling molecules of Hedgehog/Gli signaling pathway and stem cell associated transcription factors. Inhibition of Hedgehog/Gli signaling pathway downregulated stem cell associated transcription factors. In this study, we plan to investigate the functions and mechanisms of Sam68 in promoting stem cell maintenance and cisplatin resistance through regulation of Hedgehog/Gli signaling pathway in oral cavity squamous cell carcinoma both in vitro and in vivo. Finally, we will validate the above hypothesis in clinical specimen from patients with oral cavity squamous cell carcinoma and illuminate the role and clinical value of Sam68/Hh/Gli signaling pathway. Through this study, we will provide a novel mechanism of cisplatin resistance and potential novel targets for reversal of cisplatin resistance in patients with oral cavity squamous cell carcinoma.