Mis18β调控HJURP与CENP-A相互作用引起肾癌生物学行为变化的机制研究

肾癌是泌尿系常见肿瘤，发病机制不明，缺乏根治手段，寻找早期诊断和治疗的标记物十分重要。细胞周期中，HJURP参与细胞有丝分裂和活力维持，作为分子伴侣参与CENP-A从头合成和在着丝粒的聚集，对保持染色体稳定性起重要作用，Mis18复合物对该过程的调节十分关键。染色体不稳定性是肿瘤发生的首发事件，CENP-A表达异常与染色体不稳定性密切相关，HJURP与Mis18β交互作用是CENP-A聚集于着丝粒发挥作用的重要机制。我们前期研究证明HJURP在肾癌中发生明显改变并影响其生物学行为。因此，本研究拟采用肾癌细胞和组织，探索Mis18β调控HJURP与CENP-A相互作用从而引起肾癌生物学行为变化的机制，阐明Mis18β通过何种机制调节HJURP在着丝粒的聚集，从而影响CENP-A蛋白在着丝粒的装配，因此对肾癌的细胞周期等一系列生物学行为产生影响，为肾癌发生发展、早防早治提供实验依据。

Renal cell carcinoma is a common tumor of the urinary system. This is a heterogeneous disease and its natural course is still unpredictable. Morbidity and mortality in advanced renal cell carcinoma is high. In many tumors, biological markers can identify prognostic subgroups for individual treatment; however, at present, clinical use of biomarkers to predict outcome in renal cell carcinoma is not validated. It is very important to find markers that can diagnose and treat renal cell carcinoma at an early stage. In the cell cycle, Holliday junction recognition protein acts as a molecular chaperone to participate in de novo synthesis of centromere protein-A and aggregation in centromeres, which plays an important role in maintaining chromosome stability. The Mis18 complex recruits prenucleosomal centromere protein-A complex through directly binding between Mis18β and Holliday junction recognition protein. Mis18β governs the centromere loading of centromere protein-A by recruiting centromere protein-A chaperone Holliday junction recognition protein. Chromosomal instability is the first event of tumorigenesis. The abnormal expression of centromere protein-A is closely related to chromosomal instability. The interaction between Holliday junction recognition protein and Mis18β is an important mechanism for centromere protein-A to aggregate at the centromere. Our previous studies have shown that HJURP has undergone significant changes in renal cell carcinoma. This study intends to use renal cancer cells and tissues to explore the mechanism by which Mis18β regulates the interaction between Holliday junction recognition protein and centromere protein-A to cause changes in the biological behavior of renal cell carcinoma. This study define a novel molecular mechanism underlying the temporal regulation of centromere protein-A incorporation into the centromere by accurate Mis18β- Holliday junction recognition protein interaction in renal cell carcinoma.