TD26调控肝癌代谢的机制及其作为治疗靶点的应用性研究

The insensitivity of liver cancer cells to drug therapy is one of the main causes for patients’ poor prognosis, which is also an important scientific problem to be solved. Though studies have shown that Metformin can inhibit the proliferation of liver cancer cells, the effect was not so promising, which may be related to the heterogeneity of tumor cells. Based on previous experiments, applicant found that TD26 can compete with AMPK for the combination with SREBP1, which further promoted the lipid metabolism and rapid proliferation of liver cancer cells. Metformin is the activator of AMPK and it is unclear whether the expression level of TD26 would affect the liver cancer’s sensitivity to Metformin. Pre-experimental results showed that TD26-highly-expressed hepatocarcinoma cells were more sensitive to the stimulation of Metformin. Further mechanism studies suggested that TD26 can up-regulate the expression of REDD1, which had a strong relationship with mTORC1 pathway. With above results, applicant speculated that TD26 may regulate mTORC1 pathway through REDD1 and influence the suppressing effect of Metformin to the proliferation of liver cancer. PDX model would be used to preliminarily explore the in vivo application of TD26-related metabolic pathway. The completion of this project will provide a new therapeutic target and experimental evidence for the precise treatment of liver cancer.

肝癌细胞对药物治疗不敏感是导致临床肝癌病人预后不佳的主要原因之一，也是亟待解决的重要科学问题。尽管有研究表明Metformin可抑制肝癌细胞增殖，但其效果并不显著，这可能与肝癌细胞的异质性有关。申请者前期研究发现，TD26可与AMPK竞争结合SREBP1促进肝癌细胞的脂代谢及快速增殖。Metformin是AMPK的激活剂，肝癌中TD26的表达水平是否会影响肝癌对Metformin的敏感性尚不明确。预实验结果显示，过表达TD26的肝癌细胞对Metformin更为敏感，TD26促进与mTORC1通路密切相关的REDD1的表达。基于以上结果，申请人推测TD26可能通过REDD1调控mTORC1通路，最终影响Metformin抑制肝癌增殖的效果。PDX模型将对TD26相关代谢通路的体内应用进行初步探索。通过本项目研究，可为肝癌精准治疗提供新的靶点及实验依据。

申请者前期研究发现，TD26可与AMPK竞争结合SREBP1促进肝癌细胞的脂代谢及快速增殖。Metformin是AMPK的激活剂，肝癌中TD26的表达水平是否会影响肝癌对Metformin的敏感性尚不明确。实验结果显示，过表达TD26的肝癌细胞对Metformin更敏感，TD26促进与mTORC1通路密切相关的REDD1的表达。基于以上结果，TD26可能通过REDD1调控mTORC1通路，最终影响Metformin抑制肝癌增殖的效果。PDX模型印证了上述结论。通过本项目研究，可为肝癌精准治疗提供新的靶点及实验依据。