C1QBP通过调控YBX1活性调节肾癌细胞增殖的研究

Tumor cell proliferation plays an important role in cancer progression. It is well known that YBX1 is a key signaling molecule in tumor cell proliferation, but the molecular mechanism regulating YBX1 activity has not been clear. In our previous study, we have found that renal cell carcinoma (RCC) expressed a low level of C1QBP, and this low level is associated with the progression of RCC. While a high nuclear expression of YBX1 is correlated to tumor stage and metastasis. Using co-immunoprecipitate (CO-IP) and mass spectrometry (MS) analyses, we firstly confirmed that C1QBP can interact with YBX1. Meanwhile, the knockdown of C1QBP in RCC significantly enhanced the cell proliferation and promoted YBX1 nuclear accumulation. Thus, we hypothesize that C1QBP can regulate RCC cell proliferation by modulating YBX1 activity. In vitro, we will investigate the function of C1QBP in RCC proliferation and cell cycle progression, study the interaction between C1QBP and YBX1 and their role in regulating p53、PIK3CA transcriptional activity. In vivo, xenograft mouse model will be used to verify the effect of C1QBP on RCC proliferation. This study will light on a new mechanism that regulates RCC growth, and provide experimental evidence for novel anti-cancer drug for RCC.

细胞的增殖、分裂失调是肿瘤发生发展的基础。研究证实YBX1是肿瘤细胞增殖的关键分子，但调节YBX1活性的机制尚不清楚。本课题前期研究发现C1QBP随着肾癌的进展表达降低，YBX1在高级别和转移性肾癌的细胞核中表达增多；通过质谱结合免疫共沉淀技术首次发现C1QBP可与YBX1结合；降低C1QBP在肾癌细胞中的表达可促进细胞增殖及YBX1在细胞中核转位。我们认为：C1QBP可能通过调控YBX1来调节肾癌细胞的增殖。本项目将从体外试验研究C1QBP对肾癌细胞增殖和细胞周期的影响；通过蛋白组学结合分子生物学研究C1QBP与YBX1的相互作用及对p53、PIK3CA转录活性的调控；动物实验验证C1QBP在肾癌增殖中的作用。该研究有助于深入解析肾癌生长的分子机制，为发现新的抗肿瘤药物靶标提供理论基础。

癌细胞的增殖和转移是肿瘤的发生发展中的主要特征。已有研究表明C1QBP的过表达与多种肿瘤的进展相关，但有关C1QBP调节肾癌进展的研究目前未见报道。本项目通过蛋白组学结合分子生物学研究C1QBP与YBX1的相互作用；基因芯片检测C1QBP调控的基因及信号通路；体外试验研究C1QBP对肾癌细胞增殖、粘附、迁移及侵袭的影响，同时检测下游的信号通路；肾癌原位移植瘤模型验证C1QBP及YBX1在肾癌进展中的作用。结果显示，与其他肿瘤组织不同， C1QBP在肾癌组织中表达降低，C1QBP表达与患者临床组织学分期和术后生存率呈负相关。利用免疫共沉淀结合质谱分析首次发现了C1QBP与YBX1存在相互作用，C1QBP沉默促进YBX1的核转位及磷酸化；在临床标本中YBX1在肾癌组织中的表达增多；YBX1核表达随着肿瘤分期增高而增多，且预示患者预后不良；C1QBP的表达与YBX1核表达呈负相关。C1QBP降表达促进肾癌细胞的增殖及转移。YBX1降表达抑制肾癌的生长。C1QBP通过YBX1/AR信号通路调控肾癌的转移。通过基因芯片分析，C1QBP敲除会影响细胞黏附相关基因的表达，C1QBP通过Wnt通路调节L1CAM调控肾癌的黏附及转移。总之，在肾癌中C1QBP通过调控YBX1来调节肾癌的增殖及转移。C1QBP及YBX1在肾癌的进展中起重要作用。该研究有助于深入解析肾癌生长的分子机制，为发现新的抗肿瘤药物靶标提供理论基础。