Sam68在舒尼替尼诱导肾癌细胞凋亡中的作用及其分子机制的研究

Sunitinib is the first line treatment for late stage renal cell carcinoma (RCC). However, the low effectiveness rate and resistance are main problem for this medicine.Sam68 is a signal transduction and activation of RNA metabolism family protein. It plays roles in several biological processes. Our previous study found that Sam68 acts as an oncogene in the development of RCC. Subsequent study found that late stage RCC patients with high Sam68 expression benefit more from the treatment of Sunitinb. Sunitinib induce kidney cancer cells apoptosis in a Sam68 dependent way. Sunitinib can reduce the level of Sam68 phosphorylation. These results imply that Sunitinb induce cell apoptosis by reducing the level of Sam68 phosphorylation. However the molecular mechanism is not clear. The present study aims at detecting the association of the Sam68 level and cell apoptosis; revealing the impact of sunitinb treatment on the phosphorylation of Sam68 and the molecular mechanism; studying the impact of Sam68 in Sunitinib induced RCC cell apoptosis in Vivo; exploring the predictive role of Sam68 in the effectiveness of Sunitinb through large sample study.

舒尼替尼是晚期肾癌的一线治疗药物，但存在着有效率不高和耐药等问题。Sam68是信号传导和RNA结合蛋白，参与体内多种生物学过程。我们前期研究发现Sam68在肾癌发展中起到癌基因的作用（CEBP，2009）。后续研究发现舒尼替尼在Sam68高表达患者中的疗效明显优于Sam68低表达患者; 进一步研究发现舒尼替尼诱导肾癌细胞凋亡依赖Sam68的表达，舒尼替尼能够降低肾癌细胞中Sam68的磷酸化水平，提示舒尼替尼通过降低Sam68的磷酸化水平诱导肾癌细胞凋亡，但具体分子机制及临床意义有待进一步阐明。本研究拟通过免疫共沉淀、免疫印迹等方法阐明舒尼替尼对Sam68磷酸化水平的影响的分子机制；通过动物模型验证体内Sam68的表达对舒尼替尼诱导肾癌细胞凋亡的影响；通过增大临床样本量验证Sam68对舒尼替尼疗效的预测价值。为发掘预判舒尼替尼疗效的分子指标提供科学依据，为晚期肾癌的治疗提供新的思路。

舒尼替尼是晚期肾癌的一线治疗药物，能抑制血管生成和细胞增殖，但存在着有效率不高和耐药等问题。Sam68是信号传导和RNA结合蛋白，参与体内多种生物学过程。我们前期研究发现Sam68在肾癌发展中起到癌基因的作用（CEBP，2009）。我们研究发现舒尼替尼在体内体外实验中都能抑制的表达；进一步发现舒尼替尼能够降低肾癌细胞中Sam68的磷酸化水平，进而影响PARP剪切并降低Cyclin D1和Survivin的表达，从而促进肾癌细胞凋亡；在Sam68干扰的肾癌细胞中，舒尼替尼促进肾癌细胞凋亡的能力明显下降；在晚期肾癌患者中，舒尼替尼在高表达Sam68患者中的疗效明显优于Sam68低表达患者。本研究为发掘预判舒尼替尼疗效的分子指标提供科学依据，为晚期肾癌的治疗提供新的思路。