LDHA介导的miR-449a对肿瘤细胞有氧糖酵解的调控作用研究

Warburg effect(aerobic glycolysis) is an important characteristic of cancer. Understanding the mechanism of Warburg effect could potentially be exploited for cancer treatment. In our recent work on Warburg effect, we constructed a gene functional association network (gNET) and predicted glycolysis-related gene-miRNA pairs deregulated in lung cancer, and confirmed the regulation of miRNA-143 on hexokinase 2(HK2) and the functional effects of this regulation on tumor cells by laboratory tests. Nevertheless, further studies are needed to investigate the mechanisms that lead to the aberrant expression of other pivotal glycolytic enzymes in cancer development. Lactate dehydrogenase A(LDHA), which catalyzes the conversion of L-lactate and NAD+ to pyruvate and NADH in the final step of glycolysis, is found to be over-expressed in various tumors and down-regulation of LDHA would induce the inhibition of cell transformation and tumor progression. These findings raise the question whether any miRNA is involved in the deregulation of LDHA in cancer development. In this project, we will explore the influence of miR-449a, which was found by our previous study, on LDHA expression and the biological function of miR-449a and LDHA in cancer cells through molecular or cell biology experiments. Besides, we will also focus on the potential of miR-449a and LDHA to be biomarker for early dignosis and therapeutic targets for lung cancer. Our study would provide a further understanding for the molecular mechanism of Warburg effect and show new methods and targets for cancer diagnosis or treatment.

沃伯格效应是肿瘤发生的重要特征之一，对它的研究可为肿瘤的早期诊断和治疗提供理论依据和有效的靶点。前期我们在对沃伯格效应的研究中构建了一个功能相关基因的信息网络（gNET），预测出肺癌细胞中失调的miRNA-糖酵解酶基因配对，并证明了miR-143与己糖激酶HK2的调控关系及其在肿瘤发生中的功能。然而糖酵解途径在肿瘤发生发展过程中发生改变的机制及生物学意义尚需进一步的研究。乳酸脱氢酶A（LDHA）在肿瘤中多发生高表达，降低LDHA水平会抑制细胞的转化并滞后肿瘤的形成。本项目拟通过分子、细胞生物学等实验手段，阐明LDHA在肿瘤发生过程中的过表达与前期实验所发现miR-449a之间的调控关系以及二者在肿瘤细胞中功能的相关性，探究LDHA与miR-449a作为肿瘤分子标志物和治疗靶点的潜力。本研究将有助于进一步揭示沃伯格效应的分子机制，并为恶性肿瘤的诊断和治疗提供新的思路和方法。