TGF-β信号与CXXC5的相互调控及其在肝细胞癌早期发生中的功能

Hepatocellular carcinoma (HCC), the main form of liver cancer, is the third cause of cancer-related death worldwide. China is severely affected by HCC, and alone accounts for about 50% cases regarding occurrence and death. HCC usually occurs after a long period of hepatic fibrosis and cirrhosis, wherein TGF-β is often highly expressed and promotes chronic liver diseases, and finally plays a role in HCC development. Previously, we analyzed the direct target genes of TGF-β in early HCC cell lines by transcriptome sequencing (RNA-Seq), and identified the CXXC5 gene. Intriguingly, CXXC5 protein is in turn able to regulate TGF-β/Smad signal transduction. CXXC5, along with TET1/3, DNMT1 and others, belong to the CXXC zinc-finger protein family, but CXXC5 is less understood. In addition, the roles and mechanisms of TGF-β and CXXC5 in HCC need a better clarification. Based on the above observations and scientific questions, this project would start from high-throughput analysis and continue to study the functions of single genes, followed by analyses of clinical liver samples, aiming at understanding the roles and mechanisms of TGF-β and CXXC5 in early development of HCC. The results, on one hand, are anticipated to advance our understanding of the molecular mechanisms of HCC development, and on the other, may provide important clues for new diagnostic markers or therapeutic targets.

中国是肝细胞癌大国，其发生率与死亡率约占全世界的50%，严重影响国人健康。肝细胞癌发生往往会经历漫长的肝损伤，而TGF-β在此过程中通常表达显著升高，促进肝纤维化与肝硬化，并在肝细胞癌的发生中发挥作用。前期我们通过转录组测序大规模分析了TGF-β在早期肝细胞癌中的直接靶基因，并鉴定到了CXXC5基因；而且CXXC5蛋白能反馈调控TGF-β/Smad信号转导。CXXC5与TET1/3等同属CXXC锌指蛋白家族，但目前对CXXC5的了解有限；TGF-β与CXXC5在肝细胞癌中的作用与分子机制需要更深入的研究。基于以上科学问题，本项目拟从高通量数据分析入手，到单基因功能研究，试图阐明TGF-β与CXXC5在早期肝细胞癌中的生物学功能及其内在联系；并分析其在临床样本中的相关性。理论上，预期研究结果有助于理解肝细胞癌早期发生的分子机制；实践上，可能为早期诊断生物标志与新药物靶点的寻找提供有益的参考。

本项目旨在理解TGF-β信号在肝癌细胞中的调控机制及其在肝癌发展中的功能，项目研究进展顺利，成果较为丰富。本项目发现：（1）CXXC5是TGF-β在肝癌细胞中的一个新靶基因，它通过反馈机制促进TGF-β信号及其诱导的肝癌细胞生长抑制，而CXXC5基因表达下调促进肝癌发生；（2）KLF2蛋白能在肝癌细胞中抑制Smad蛋白转录活性和TGF-β靶基因表达，从而减弱肝癌细胞的运动能力；（3）肿瘤微环境脂肪细胞来源的G-CSF通过激活乳腺癌细胞内的STAT3信号通路，促进癌细胞恶性发展。此外，在J Genet Genom (2020)、Cells (2019)、J Cell Mol Med (2019)和Acta Biochim Biophys Sin (2018)期刊上综述了TGF-β信号的调控机制及其在肿瘤发展中发挥多重生物学功能的分子基础；作为客座编辑在Acta Biochim Biophys Sin期刊组织一期TGF-β细胞信号转导专刊，促进了国内外同行的交流，有助于提升国内专业期刊的国际影响力。人才培养方面，项目主持人严晓华博士聘为南昌大学“学科方向带头人”、江西省“双千计划”和省“青年井冈学者”，培养1名青年教师和多名研究生。