HIF-1α/Sirtuin1对话参与侵袭伪足形成在口腔鳞癌侵袭转移中的作用及其机制

淋巴结及远处转移是口腔鳞癌患者死亡的主要原因。现有研究已证实细胞外基质的降解是癌症转移中的“核心事件”。本课题组前期实验发现：口腔鳞癌细胞可通过形成侵袭伪足促进细胞外基质的降解，且该过程与皮动蛋白磷酸化和去乙酰化及HIF-1α、Sirtuin1表达上调有关。据此并结合文献，我们提出假设：HIF-1α/Sirtuin1对话协同调控cortactin磷酸化/乙酰化平衡诱导侵袭伪足形成促进口腔鳞癌侵袭转移。本课题旨在研究: (1) 皮动蛋白磷酸化/乙酰化平衡与侵袭伪足形成在口腔鳞癌转移过程中的作用; (2) 探讨HIF-1α、Sirtuin1在上述过程中的介导作用和具体分子机制；(3) 在此基础上以裸鼠及SCID/NOD小鼠模型为实验对象，探讨靶向抑制HIF-1α、Sirtuin1治疗口腔鳞癌远处转移的可行性。该项研究有可能进一步揭示口腔鳞癌转移的发病机制，并为开拓口腔鳞癌新疗法提供理论基础。

Lymph node and distant metastasis are main causes of death for patients with oral squamous cell carcinoma(oral cancer). Previous studies have demonstrated that the reduced extracellular matrix (ECM) is the key step of invasion and distant metastasis of cancer. Moreover, our preliminary researches indicate the formation of invadopodia in oral cancer cell, which may play important roles in the increase of ECM degradation and result from the up-regulation of HIF-1α, Sirtuin1 and destabilizing of cortactin acetylation and phosphorylation in oral cancer. Acorrding the results and previous studies, We put forward that HIF-1α/Sirtuin1 crosstalk can induce invadopodias via disturbing cortactin phosphorylation and acetylation balance, leading oral cancer invasion and metastasis. The aims of our project are as follows: (1) To uncover the roles of balance of cortactin acetylation and phosphorylation in the metastasis of oral cancer; (2) To investigate the effects of HIF-1α, Sirtuin1 in the above process; (3) To explore the feasibility of HIF-1α/Sirtuin1 targeting strategy to inhibit metastasis on the treatment of oral cancer using nude mice and SCID/NOD mice model of oral cancer. Our project may further clarify the pathogenesis of metastasis of oral cancer, and would be beneficial for developing novel therapeutic strategies against metastasis of oral cancer.