干细胞基因Sox3在肝癌发生发展过程中的功能及其分子机制研究

Hepatocellular carcinoma (HCC) is a highly occurred malicious tumor with strong tendency of metastasis and poor prognosis. More and more research results suggest that tumor is a disease of dysfunction of stem cells and stem cell genes have strong correlation with tumorigenesis, metastasis and the recurrence of cancer. Sox3 is a stem cell gene with potential to promote cancer. Our preliminary data indicate that Sox3 is highly expressed in hepatocarcinoma tissues and Sox3 expression promotes hepatocarcinoma cell proliferation, migration and colonization with unknown mechanism. To explore the molecular mechanism, we propose to establish Sox3 knockout stable cell lines and further confirm the correlation between Sox3 gene expression with hepatocarcinoma cell proliferation and migration. We will utilize advanced biotechnology such as microarray and ChIP-seq etc. to identify Sox3-targeted genes and further explore the molecular mechanism of Sox3 function in hepatocarcinoma occurrence and metastasis. We project to analyze the affect of Sox3 expression on hepatocarcinoma initiation and metastasis in nude mouse models and eventually demonstrate the correlation of Sox3 expression with hepatocarcinoma occurrence, progression and survival analysis using tissue chip technology to detect and analyze Sox3 expression in human hepatocarcinoma tissues. This project will reveal the new mechanisms of hepatocarcinoma initiation, metastasis and reoccurrence and thus pointing to new targets and new therapy for preventing and curing HCC.

肝癌是常见的恶性肿瘤，易发生转移，且预后较差。越来越多的证据表明，肿瘤是干细胞疾病，而肿瘤干细胞基因与肿瘤发生发展、转移和复发存在一定关系。Sox3是干细胞基因，具有促癌潜能。预实验表明，Sox3在肝癌组织中高表达，且能促进肝癌细胞增殖、迁移和克隆形成，但其分子机制并不清楚。为了探索Sox3在肝癌发生发展中的功能及其分子机制，本项目试图利用筛选的Sox3基因敲除细胞株，进一步确证Sox3对肝癌细胞增殖和迁移的影响；利用基因表达谱芯片和ChIP-Seq等方法，分析鉴定Sox3的调控靶基因，并结合其它实验手段探讨Sox3在肝癌发生发展过程中的精细分子机制；利用裸鼠成瘤模型分析Sox3对肝癌细胞成瘤和转移的影响；最后利用人肝癌组织芯片检测方法，确认Sox3与肝癌分期、分级及生存期等的相关性。本项目的完成，将揭示肝癌发生发展、转移和复发相关的新机制，有望为肝癌防治提供潜在靶点和新思路。

肝癌是常见的恶性肿瘤,易发生转移，且预后较差。越来越多的证据表明，肿瘤是干细胞疾病，而肿瘤干细胞基因与肿瘤发生发展、转移和复发存在一定关系。Sox3是干细胞基因，具有促癌潜能。实验表明，Sox3在肝癌组织中高表达，且能促进肝癌细胞增殖、迁移和克隆形成，通过一系列筛选和验证实验，我们发现Sox3可以在mRNA水平上促进miR-203a-3p的表达，双荧光实验鉴定了生长抑制特异蛋白2（GAS2）为miR-203a-3p新的靶标,实验进一步证明Sox3可以通过miR-203a-3p/GAS2/p53信号通路调控肝癌细胞的生长过程。同时，Sox3可以通过调控AKT1的表达，通过AKT/mTOR信号通路调控肝癌细胞的迁移和侵袭能力。随后我们利用裸鼠成瘤模型验证了Sox3对肝癌细胞成瘤和转移的影响；最后利用人肝癌组织芯片检测方法，确认Sox3与肝癌的发生发展的相关性。本项目的完成，为揭示肝癌发生发展、转移和复发相关的新机制，有望为肝癌防治提供潜在靶点和新思路。