转录因子TCF19促进肝细胞肝癌转移的生物学功能及分子机制

Hepatocellular carcinoma (HCC) is a common and aggressive cancer, with an increasing incidence globally, especially in China. It’s important to clarify the molecular mechanism and key regulators of HCC metastasis, which will effectively control the metastasis of HCC and improve the survival rate of HCC patients. Recently, We assessed the expression of TCF19 in multiple HCC cell lines and tissue, as well as the HCC dataset from TCGA. We found that TCF19 was overexpressed in HCC, and the overall expression level of TCF19 significantly correlated with lymph node metastasis (p<0.001) and distant metastasis (p<0.001), suggesting that TCF19 was involved in HCC metastasis. Furthermore, our preliminary data showed that overexpression of TCF19 induced epithelial-mesenchymal transition, inhibited apoptosis, promoted anchorage-independent growth. Further mechanism studies demonstrated that TCF19 could active the Wnt/β-Catenin pathway. These results suggested that TCF19 might play an important role in HCC metastasis. In the current project, we will combine in vivo and in vitro experimental systems, as well as clinical samples to clarify the molecular mechanism that TCF19 active the Wnt/β-Catenin pathway and clinical relevance. This work may identify novel indicator markers for HCC metastasis and also enrich the regulatory mechanism of Wnt/β-Catenin signaling pathway in HCC.

转移是肝细胞肝癌致死的关键原因，明确转移的分子机制，对于有效防控肝癌转移，提高患者存活率，具有重大意义。申请者通过分析TCGA公共数据库发现TCF19在肝癌中显著高表达，但其在肝癌中的功能尚未见报道。对140例肝癌样本进行免疫组化分析，显示TCF19与患者的复发转移呈显著正相关。进一步我们发现：过表达TCF19可诱导肝癌细胞发生EMT，增强肝癌细胞的侵袭迁移能力及抗凋亡和非锚定依赖性生长能力。相关机制研究提示TCF19通过上调Wnt/β-Catenin信号通路活性，在肝癌转移中发挥重要作用。据此，申请者拟深入研究TCF19激活Wnt/β-Catenin信号通路的分子机制，并结合临床样本研究TCF19及其调控分子与肝癌复发转移的相关性。以上研究结果有助于阐明TCF19促进肝癌复发转移的具体分子机制，提供新的临床预警分子，并丰富Wnt/β-Catenin信号通路在肝癌中异常激活的新的调控机制。

转移是引起肝细胞肝癌（hepatocellular carcinoma，HCC）患者死亡的关键原因之一，鉴定与HCC转移相关的分子并阐明其作用机制，对于有效防控HCC转移，提高患者存活率，具有重大意义。本项目围绕HCC侵袭转移进行深入研究，取得了一系列原创性成果。资助期间共发表SCI论文4篇，包括Briefings in Bioinformatics 1篇（一作，IF=11.622），cellular oncology 1篇 （一作，IF=6.73），Genomics 1篇 （一作，IF=5.736）和frontiers in pharmacology 1篇（参与，IF=5.811）。主要研究成果包括：（1）证实了转录因子TCF19能够显著促进HCC细胞的侵袭和增殖能力。相应的机制研究提示，TCF19通过转录上调wnt/β-catenin信号通路关键调控分子WNT9a和细胞周期关键调控蛋白CDK2发挥功能。（2）我们利用收集的具有详细临床信息的HCC样本和公共数据库中的HCC测序信息，联合癌和癌旁组织的基因表达谱对HCC患者进行分型和预后评估，并鉴定出7个与HCC转移、免疫逃逸和增殖密切相关的基因集。（3）揭示环状RNA circ-102166可发挥miRNA sponge的作用，通过吸附miR-182/miR-184，有效抑制HCC的侵袭和增殖。（4）较为全面的分析了MAGE蛋白家族在HCC中的表达情况及其表达量与HCC预后间的相关性，为HCC预后评估提供了新的靶标。