口腔癌的侵袭和转移是一个连续复杂的生物学过程，其确切的分子机制仍不明确。研究表明，Ras基因突变与其密切相关。我们的前期研究显示：GGTase-I在K-ras基因突变诱导的恶性肿瘤中发挥重要作用，同时发现GGTase-I在炎症巨噬细胞的功能行使中的作用与传统的理论相违背，另一修饰酶RCE1也出现类似情形。这些修饰酶的具体作用机制有待进一步研究。我们设想：GGTase-I可能通过复杂的信号调控系统及信号分子对Rho家族发挥着尚未明确的作用；RhoA蛋白的异戊二烯化修饰过程包含相关重要的信号通路及信号分子的交叉对话；RhoA/p38MAPK是另一参与其中的重要信号通路。本研究拟采用基因敲除、基因芯片、免疫沉淀等技术，明确GGTase-I在K-ras基因突变诱导的舌癌RhoA蛋白修饰及在RhoA/p38MAPK通路中的作用，为头颈癌的分子靶向治疗、阐明其侵袭转移的分子机理提供新的实验依据和思路。

The invasion and metastasis of oral cancer is a continuous and complex process in which the involved mechanism is still unclear. It has been shown that this process is closely related with mutant Ras. Our previous investigation has shown that GGTase-I plays an important role in K-ras-induced cancer. Meanwhile, the experimental results on GGTase-I challenge the view that geranylgeranylation is essential for the activity and localization of Rho family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis. RCE1, another enzyme for Ras protein modification, works in a similar way as not expected. These data shows that some phenomena happening reversed to classical theory in the process of Ras protein modification and the detailed function of these enzymes needs to clarify. Based on our previous study, we hypothesize that GGTase-I effects on Rho family in an uncertain way and via complicated signal control system and siganl molecules and that there should be some crosstalks between a few related signal pathways in the process of RhoA geranylgeranylation and that RhoA/p38MAPK is also another important pathway for cancer's biological behaviors.In our current research, the technique of gene knockout and knockdown, DNA chip, and immune precipitation etc. will be applied. It is expected to be clarified that GGTase-I is crucial for RhoA protein modification and RhoA/p38MAPK signal pathway as well and that RhoA/p38MAPK pathway plays a critical role in biological behaviors of K-ras-induced tongue cancer. Our investigation will offer more and new experimental evidence and ideas for molecular targetting therapy and for mechanisms of cell invasion and metastasis involved in head and neck cancer.

口腔癌是世界范围内第6大常见癌症，而舌癌是口腔癌中最为常见的、恶性程度非常高的恶性肿瘤。舌癌具有较高的侵袭性和转移性，死亡率高。舌癌的形成、进展和转移与各种癌相关基因不可逆的积累突变和失调有关。人类肿瘤中Ras基因突变是最常见的癌基因异常。RhoA是Ras基因超家族的一个成员，属于Rho家族蛋白质，具有GTP酶活性，与肿瘤的发生、发展和转移密切相关。本研究主要通过体外实验验证RhoA及其他相关的Rho家族蛋白在口腔鳞状细胞癌中的高表达，通过RNA干扰验证RhoA在舌癌的增殖、侵袭和转移中的作用，并探讨其中可能的分子机制；同时检测GGTase-I酶在RhoA蛋白修饰过程的作用，验证GGTase-I对舌癌的增殖、侵袭的作用。此外，本研究对RAC1蛋白及RCE1酶对舌癌的作用进行了体外实验方面对的探讨。结果显示，RhoA、RhoB、RhoC等Rho家族蛋白在口腔鳞状细胞癌中高表达，RhoA与舌癌细胞的增殖、侵袭和转移呈正相关，通过Cyclin D1、p21、p27等细胞周期调控因子的调节参与细胞增殖的控制，通过调节Gal-3、β-catenin、MMP-9参与Wnt/β-catenin信号通路，从而调控舌癌细胞对的迁移、侵袭和转移。GGTase-I参与RhoA转录后的翻译修饰过程，同时降低GGTase-I表达可明显抑制舌癌的增殖、侵袭和转移。抑制RAC1蛋白及RCE1酶同样可显著抑制舌癌的增殖、侵袭和转移。GGTase-I是Ras蛋白翻译后修饰的三大重要酶之一。Ras蛋白的活化状态和能否正常发挥功能取决于GGTase-I等酶的活性。本研究证实了GGTase-I可作为舌鳞状细胞癌基因治疗的靶点，为舌癌的治疗提供了新的治疗思路；本研究初步探讨了RhoA及GGTase-I对舌鳞状细胞癌增殖和侵袭转移可能涉及的分子机制，为舌癌的靶向治疗提供了一定的理论依据。