VHL-TGFBI活性在脱甲基化药物联合紫杉醇抑制肾癌增殖及转移中的机制研究

The prognosis of advanced renal cell carcinoma (RCC) is very poor, and RCC demonstrates a very low sensitivity to chemotherapy and radiotherapy. In previous study, we have found that demethylation drug (DAC) and paclitaxel (PTX) could synergisticly suppress the growth of RCC cells, and the synergy of DAC and PTX against RCC is associated with inhibiting the expression of TGFBI(BIGH3). Our results also suggested that TGFBI is a target of VHL, and the suppressing TGFBI by VHL is not via HIF pathways. In addition, results indicated that TGFBI participated in the adhesion, migration and invasion of RCC cells, which are dependent of the inactivation of VHL. So we speculated that high expression of TGFBI in RCC maybe associated with the inactivation of VHL, and VHL-TGFBI pathways is involved in the development and metastasis of RCC, TGFBI may acts as an important therapeutic target of DAC and PTX in RCC.In this study, we will further investigate the correlation between VHL activity and TGFBI expression in RCC, and reveal the fuctions of DAC and PTX modulating VHL-TGFBI activity and the metastasis ability of RCC cells, finally, we will detected the effect of VHL-TGFBI activity on the synergy of DAC and PTX combination chemotherapy.In brief, by analyzing the role of VHL-TGFBI pathways in this combination chemotherapy will provide theoretical basis for the personalized medical strategy to improve the prognosis of RCC patients in the future.

进展期肾癌的预后极差，且对放化疗不敏感。前期研究中我们发现脱甲基化药物DAC联合紫杉醇(PTX)对肾癌细胞的生长具有相乘抑制作用，基因芯片分析提示两种药物该相乘作用可能与抑制TGFBI(BIGH3)的表达有关。进一步分析我们证实TGFBI为VHL的下游靶基因，VHL失活后可增强TGFBI的表达并促进了肾癌细胞的粘附，游走和侵袭能力。因此我们推测肾癌组织中TGFBI的高表达很可能与VHL的失活有关，VHL-TGFBI通路参与了肾癌的的进展及转移，并且TGFBI可做为DAC与PTX联合化疗的一个重要治疗靶点。本研究中我们将进一步揭示肾癌组织中VHL活性与TGFBI表达水平的相关性，分析DAC联合PTX对VHL-TGFBI活性以及肿瘤细胞转移能力的调节作用，探讨VHL-TGFBI活性对DAC与PTX相乘作用的影响。通过研究VHL-TGFBI通路在该联合化疗中的作用将为开展个体化医疗提供理论依据。

进展期肾癌的预后极差，且对放化疗不敏感。前期研究中我们发现脱甲基化药物DAC联合紫杉醇(PTX)对肾癌细胞的生长具有相乘抑制作用，基因芯片分析提示两种药物该相乘作用可能与抑制TGFBI(BIGH3)的表达有关。进一步分析我们证实TGFBI为VHL的下游靶基因，VHL失活后可增强TGFBI的表达并促进了肾癌细胞的粘附，游走和侵袭能力。因此我们推测肾癌组织中TGFBI的高表达很可能与VHL的失活有关，VHL-TGFBI通路参与了肾癌的的进展及转移，并且TGFBI可做为DAC与PTX联合化疗的一个重要治疗靶点。本研究中我们进一步揭示了肾癌组织中VHL活性与TGFBI表达水平的相关性，分析DAC联合PTX对VHL-TGFBI活性以及肿瘤细胞转移能力的调节作用，探讨VHL-TGFBI活性对DAC与PTX相乘作用的影响。我们的研究成果表明TGFBI不但与促进肾癌细胞的增殖和转移有关，TGFBI也是DAC联合PTX抑制肾癌进展的一个重要的治疗靶点。VHL-TGFBI作为DAC联合PTX抑制肾癌进展的一个重要靶点，该两种药物的联合治疗模式似乎在VHL失活的肾癌患者中更有效。通过研究VHL-TGFBI通路在该联合化疗中的作用将为开展个体化医疗提供理论依据。