YB1上调EphA2促进转移性肾癌舒尼替尼耐受的机制及功能研究

The patients with metastatic renal cancers have high mortality and poor prognosis. The treatment of metastatic renal cancers is the focus of attention and hot spots for clinicians. Sunitinib, a tyrosine kinase inhibitor, is the first-line drug for patients with metastatic renal cancers, but the current understanding on the mechanism of Sunitinib tolerance and regulatory pathways remains unclear. Previously applicants have found that high expression of EphA2 promoted metastasis and was related with Sunitinib tolerance in renal cancers. TCGA analysis showed that YB1 was positively correlated with EphA2 and up-regulated in Sunitinib-resistant cells. YB1 could up-regulate EphA2 expression in renal cancer cell lines. Accordingly, it is proposed that the YB1 / EphA2 signaling pathway may be a key signaling pathway for the tolerance of Sunitinib in patients with metastatic renal cancer. This project determines to analyze the expression of YB1 and EphA2 and their correlation in the clinical specimens of renal cancers. The Sunitinib-resistant renal cancer cell lines and nude mice in situ tumor model were selected for observing the effects of YB1 / EphA2 on the tolerance of Sunitinib in metastatic renal cancers. The regulatory mechanism of YB1 / EphA2 signaling pathway was also observed. This study may provide new strategies and ideas for the treatment of metastatic renal cancers.

转移性肾癌患者死亡率高，预后差，其治疗是临床的难点和热点问题。舒尼替尼（Sunitinib）等酪氨酸激酶抑制剂是转移性肾癌的一线治疗药物，但目前对Sunitinib耐受机制和调控通路的理解仍不透彻。申请者前期研究发现：在肾癌中EphA2高表达促进肾癌的转移和Sunitinib耐药，TCGA分析发现耐药相关基因YB1与EphA2呈正相关且在Sunitinib耐受细胞中表达上调，YB1正向调控EphA2的表达。据此提出YB1/EphA2信号通路是转移性肾癌病人对Sunitinib治疗耐受的关键信号通路。本项目拟分析肾癌临床标本中YB1和EphA2的表达及其相关性，在Sunitinib耐受肾癌细胞系及裸鼠原位瘤模型中，观察YB1/EphA2对转移性肾癌Sunitinib耐受的影响，并研究YB1/EphA2信号通路的调控机制，期望为转移性肾癌Sunitinib治疗耐受提供新的治疗策略和思路。

肾细胞癌（Renal cell carcinoma, RCC, 简称肾癌）是泌尿系统中致死性最强的恶性肿瘤，约占成人恶性肿瘤的2%-3%和肾脏恶性肿瘤的80%-90%。透明细胞肾细胞癌（clear cell renal cell carcinoma, ccRCC）是肾癌亚型中最常见的一种，预后差，转移性强且对传统的放疗和化疗不敏感。局限于肾脏的肾癌患者经历手术治疗后，5-10年生存率达到95%，而转移性肾癌（metastatic renal cell carcinoma, mRCC）患者在1年内死于该病的概率接近80%。目前转移性肾癌采用以内科为主的综合治疗。NCCN、EAU已经将酪氨酸激酶抑制剂（Tyrosine kinase inhibitor, TKI）类治疗药物（索拉菲尼、舒尼替尼等）作为转移性肾癌的一线治疗用药。然而，由于原发性或获得性耐药的存在，大大限制了许多mRCC患者使用这些分子靶向药物。舒尼替尼（Sunitinib）等TKI药物适用于转移性或晚期RCC患者，作为mRCC治疗的最主要药物，患者一旦出现对TKI的耐受，临床上将面临巨大的困境。 因此，本研究拟对转移性肾癌TKI耐药的机制做更全面而深入的研究，以期发现新的治疗靶点，提高转移性和晚期肾癌患者的生存率和生存时间。通过对组织和细胞中YB1和EphA2表达的检测及YB1调控EphA2机制的研究，我们发现以下研究结果：1.YB1在ccRCC组织中高表达且与肿瘤的分期分级正相关，并预示着更差的预后；2.在ccRCC组织中，EphA2与YB1呈正相关，且EphA2是YB1下游的靶基因；3.YB1通过上调EphA2的表达来促进肾癌的迁移和侵袭；4.YB1通过维持EphA2蛋白稳定性促进肾癌的TKI耐药和进展。通过本研究的结果，我们发现YB1和EphA2是肾癌TKI耐药和进展的潜在靶点，为以后临床针对这些靶点的药物研发提供理论基础。