高糖状态下糖酵解酶HK2/PKM2调控舌鳞癌侵袭转移机制的研究

In our previous studies we had found that the prevalence rate of diabetes in tongue squamous cell carcinoma (TSCC) was significantly higher than that of general population. The poor prognosis was found in TSCC patients with diabetes. The deregulation of HK2 (Hexokinases II) and PKM2 (pyruvate kinase muscle) were related to the development、metastasis and poor prognosis of TSCC. There existed co-relationship between diabetes、expression of HK2 and PKM2。In order to further evaluate the role and mechanism of high glucose (diabetes)、HK2 and PKM2 in the metastasis of TSCC, at first we investigated the role of high glucose、HK2 and PKM2 in the metastasis of TSCC in vitro an in vivo; Then we investigated whether the migration and invasion of TSCC mediated by HK2 and PKM2 was related to H2O2-Slug pathway; and whether the migration and invasion of TSCC mediated by high glucose was related to miR138-AKT1(HK2)/PKM2-H2O2 pathway. Our study will clarify that diabetes、glycolytic enzyme (HK2/PKM2) play an important role in the development、metastasis and prognosis of TSCC. High glucose mediates the migration and invasion in TSCC though HK2/PKM2 pathway [miR138-AKT1(HK2)/PKM2-H2O2]. Thus, it is importance for us to control the glycemia in the treatment of TSCC patient with diabetes. At the same time, to clarify the mechanism of metastasis of TSCC is of great significance in looking for the molecular biomarker. These biomarkers may be therapeutic target of TSCC and have important application value in the diagnosis and prognosis prediction in TSCC. In future, this study is very important significance in improving the survival of patients with tongue cancer.

本课题组前期研究显示舌鳞癌患者的糖尿病患病率明显高于普通人群，且合并糖尿病的患者预后差；糖酵解酶HK2/PKM2的异常表达与舌鳞癌的发生发展及预后密切相关；糖尿病、HK2、PKM2三者之间存在相关关系。为了进一步研究高糖（糖尿病）状态下HK2/PKM2能否以及如何调控舌鳞癌的侵袭转移，本研究将开展：1、高糖、HK2/PKM2对舌鳞癌细胞侵袭转移的体内外研究；2、HK2/PKM2以及高糖状态下HK2/PKM2调控舌鳞癌细胞侵袭转移的机制。本研究结果阐明了糖尿病、异常糖酵解在舌鳞癌发生发展及预后中起重要作用，高糖可通过糖酵解酶HK2/PKM2调控舌鳞癌侵袭转移；该研究提示我们在治疗舌鳞癌的同时应积极治疗糖尿病；同时对舌鳞癌侵袭转移机理的阐明对寻找其侵袭转移分子标志物具有重要意义，在舌鳞癌的诊断、靶点治疗及预后预测中具有重要的应用价值，对提高舌鳞癌患者的生存率具有重要的意义。

目前研究显示高糖、糖酵解在恶性肿瘤的发生发展中起重要作用，为了研究高糖（糖尿病）状态下糖酵解酶HK2/PKM2能否以及如何调控舌鳞癌的侵袭转移，本项目将开展如下研究：①糖尿病、糖酵解酶HK2/PKM2与舌鳞癌发生发展、转移及预后相关性的研究；②高糖、HK2/PKM2调控舌鳞癌侵袭转移能力及其机理的研究。. 研究结果显示：① 糖酵解酶HK2/PKM2的异常表达与舌鳞癌的发生发展及预后密切相关：HK2/PKM2在舌鳞癌组织中显著高表达，并与临床分期和淋巴结转移相关，HK2/PKM2高表达患者具有较低的5年生存率，因此HK2/PKM2有望成为舌鳞癌的生物学标志物；② HK2/PKM2可通过SOD2-H2O2信号通路调控舌鳞癌细胞的体外增殖/侵袭转移能力和体内裸鼠移植瘤的生长速度和肺转移能力；③ 舌鳞癌患者具有较高的糖尿病(DM)患病率，其标准化患病率(SPR)为12.84%，显著高于普通人群的9.7%；高糖可促进舌鳞癌细胞的体外增殖侵袭转移能力和体内裸鼠移植瘤的增殖和肺转移能力；④舌鳞癌患者HK2/PKM2的表达与糖尿病患病存在相关关系，高糖可通过HK2/PKM2信号通路调控舌鳞癌侵袭转移，高糖还可通过miR-138靶向AKT1/PKM2，进一步激活miR-138-AKT1/PKM2-SOD2-H2O2信号通路，导致舌鳞癌的侵袭转移。. 本项目的研究成果提示我们：临床上在治疗合并糖尿病的舌鳞癌患者时应积极治疗其糖尿病，同时本项目对高糖、糖酵解在舌鳞癌侵袭转移中的作用及其调控机制的阐明，有望开发出舌鳞癌的靶点治疗药物，为将来舌鳞癌侵袭转移的早期诊断、预后预测提供可靠的分子标志物，对提高舌鳞癌患者的生存率具有重要的意义。