STK25通过mTOR通路调控肿瘤细胞糖酵解的分子机制

Metabolism is changed in tumor cells, compared with normal cells. In normal cells, the serine/ threonine protein kinase 25 (STK25) is involved in the metabolism of fat and glucose metabolism. However, the role of STK25 in tumor cells and its clinical significance is rarely known. In previous study, we identify the interaction between STK25 and GOLPH3. We also found GOLPH3 expression was elevated in CRC tissues compared with matched adjacent noncancerous tissues. GOLPH3 is associated with prognosis in CRC patients treated with postoperative 5-FU-based adjuvant chemotherapy. Based on our previous results, this study will focus on the regulation and the mechanism of glycolysis by the interaction of STK25 and GOLPH3 in cancer cells. Firstly, the effects of STK25 and GOLPH3 in glycolysis will be identified. Secondy, the interaction and regulation between STK25 and GOLPH3 will be explored. Thirdly, whether STK25 and GOLPH3 were involved in mTOR signaling pathway will be examined. Finally, we will determine the clinical significance and survival prediction of GOLPH3 and CENPH in colorectal cancer. The study will not only shed light on understanding the mechanism of STK25 and GOLPH3 in cancer glycolysis, but also provide potential targets for cancer diagnosis and treatment.

肿瘤细胞存在代谢异常。在正常细胞，丝氨酸/苏氨酸蛋白激酶25 (STK25) 参与脂肪代谢和糖代谢过程，而其在肿瘤中的作用及其临床意义目前鲜有报道。前期工作，我们发现STK25与GOLPH3存在相互作用。GOLPH3在结直肠癌组织存在高表达，其高表达提示病人对5-FU化疗敏感。本项目拟在前期工作基础上，探讨STK25与GOLPH3相互作用对肿瘤细胞糖酵解的作用及其分子机制。首先明确STK25和GOLPH3对肿瘤细胞糖酵解的作用；其次，探讨STK25与GOLPH3之间相互作用及其相互调节方式；再次，探讨STK25和GOLPH3对mTOR通路的作用；最后，通过对结肠癌临床组织样本的分析，明确STK25和GOLPH3在肿瘤组织中的表达水平及其临床意义。上述研究工作旨在阐明STK25和GOLPH3对肿瘤细胞能量代谢的作用以及相关的信号通路，从而为肿瘤诊疗提供新的潜在分子靶点，及可能的干预措施。

本项目进展过程中围绕着“STK25 通过mTOR 通路调控肿瘤细胞糖酵解的分子机制”开展了一系列研究工作。首先明确了STK25对肿瘤细胞增殖和糖酵解的作用。通过过表达或敲降细胞STK25水平，明确STK25对肿瘤细胞增殖的抑制作用，发现STK25抑制结肠癌细胞葡萄糖吸收和乳酸生成，且参与调控糖酵解的关键分子GLUT1和LDHA水平。同时，体内体外实验证明STK25和GOLPH3之间具有直接的相互作用。此外，明确了STK25对mTOR通路的调节作用，STK25通过下调磷酸化的pS6K和pAKT水平，参与调控mTORC1和mTORC2水平，从而影响mTOR通路。最后，数据库分析结果提示，STK25在结直肠癌肿瘤组织中呈低表达，其低表达提示肿瘤病人预后不良。由于GOLPH3对糖酵解的作用尚不确定，目前这部分工作仍在进一步开展中。综上，本项目明确了STK25通过mTOR信号通路调节结肠癌细胞糖酵解的作用。上述研究为深入了解STK25及GOLPH3在肿瘤发生发展中的作用及相关分子机制奠定了一定基础，具有一定的潜在应用价值。