GDF15在口腔鳞癌TPF诱导化疗和调控AKT/ERK信号通路中的机制研究

诱导化疗药物通过诱导癌细胞的凋亡发挥疗效，但在口腔鳞癌的临床应用中还存在争议。GDF15参与AKT/ERK信号通路，但在细胞凋亡中的机制尚不清楚。项目组在建立口腔黏膜上皮细胞体外癌变模型和基因组学研究的基础上，发现GDF15在口腔鳞癌发生发展中起重要作用，并且与AKT/ERK磷酸化和细胞凋亡相关；检测口腔鳞癌TPF诱导化疗临床试验的部分患者活检组织中GDF15表达，发现GDF15低表达的患者对TPF诱导化疗的有效率和预后，比GDF15高表达的患者好。本研究旨在结合分子机制研究和临床试验，围绕GDF15与AKT/ERK信号通路相关的细胞凋亡和GDF15抵抗TPF药物作用的分子机制，结合口腔鳞癌患者活检组织中GDF15表达作为预测性生物标志物选择TPF诱导化疗的临床试验，阐述GDF15在口腔鳞癌细胞凋亡中调控AKT/ERK信号通路的分子作用机制和作为预测性生物标志物的口腔鳞癌个体化治疗新策略。

Although induction chemotherapy agents could be used to treat malignancies by inducing the apoptosis of cancer cells, there are still debates on the clinical application of induction chemotherapy in oral squmaous cell carcinoma (OSCC). Growth differentiation factor 15 (GDF1) has been reported to be involved in the AKT/ERK pathways; however, the molecular role of GDF15 in cellular apoptosis is still unclear. Based on our previously established in vitro cellular carcinogenesis model of OSCC and genomic analysis, we found that GDF15 played an important role in progression of OSCC, it also correlated with the phosphorylation of AKT and ERK as well as cellular apoptosis; detection of GDF15 in biopsy samples from 256 OSCC patients in a clincial trial focusing on TPF induction chemotherpay shew that the patients with a low GDF15 expression had a significantly better survival, they also had a better response to TPF induction chemotherapy. However, in the literatures, there are few studies reporting the molecular mechanism of GDF15 expression on cellular apoptosis through AKT and ERK pathways, there are either few studies reporting the mechanism of treatment resistance in patients with GDF15 overexpression against TPF induction chemotherapy; so, there are still a lot of unknown mechanisms to be further investigated. Our present study will use the combination of basic machanism investigations and clincial trials to reveal the molecular mechanism of GDF15 on cellular apoptosis through AKT and ERK pathways and the molecular mechanism of treatment resistance of GDF15 overexpression against TPF induction chemotherapy in OSCC; a new clinical trial of GDF15 expression as a predictive biomarker for selecting TPF induction chemotherpay will also be designed and excuted based on the retrospective results of GDF15 anslysis in OSCC patients from the previous TPF trial. The aim of this study is to clarify the molecular mechanism of GDF15 in cellular apoptosis through AKT and ERK pathways, and a personalized treatment strategy based on predictive biomarker in patients with OSCC.