Department of Hepatobiliary Surgery, Fifth medical center, General Hospital of Chinese PLA, Beijing 100039, China.
Department of Hepatobiliary Medicine, 900 Hospital of the Joint Logistics Team, Fuzhou 350000, China.
Bull Cancer. 2022 Jul-Aug;109(7-8):795-804. doi: 10.1016/j.bulcan.2022.04.007. Epub 2022 Jun 6.
Tissue factor (TF) is an important predictor for poor prognosis of Hepatocellular carcinoma (HCC). TF can also upregulate the expression of BCL2, which is a key inhibitor of autophagy responses. This study aims to explore the role of BCL2-dependent autophagy in TF-regulated HCC carcinogenesis.
In this study, we explored the roles of TF in HCC using gene overexpression and silencing assays. Besides, we further identified the significance of BCL2-Beclin1-autophagy signaling on TF-regulated HCC tumorigenesis by combining TF silencing with pharmacological autophagy inhibitor (3-MA).
The experimental data showed that the overexpressed TF promoted BCL2 protein expression and inhibited the autophagy activity (shown as LC3 conversion rate, p62 expression and autophagosomes) while maintaining the survival in HCC cells. In contrast, the silent TF showed the completely opposite results. Furthermore, TF knockdown promoted the dissociation of Beclin1 from BCL2-Beclin1 complex. In addition, the enhanced autophagy and inhibited survival by TF knockdown could be reversed by autophagy inhibition with 3-MA or spautin-1 (Beclin1 specific inhibitor) in HCC cells. Xenografts assays also showed that TF-silencing HCC cells had stronger tumorigenicity in vivo, which was recovered by spautin-1 administration.
TF inhibits autophagy-related death by enhancing BCL2 expression, whereby promoting HCC tumorigenesis.
组织因子（TF）是肝细胞癌（HCC）预后不良的重要预测因子。TF 还可以上调 BCL2 的表达，BCL2 是自噬反应的关键抑制剂。本研究旨在探讨 BCL2 依赖性自噬在 TF 调节的 HCC 发生中的作用。
在这项研究中，我们使用基因过表达和沉默实验来探索 TF 在 HCC 中的作用。此外，我们通过将 TF 沉默与药理学自噬抑制剂（3-MA）结合，进一步确定了 BCL2-Beclin1-自噬信号在 TF 调节的 HCC 肿瘤发生中的意义。
实验数据表明，过表达的 TF 促进了 BCL2 蛋白的表达，抑制了自噬活性（表现为 LC3 转化率、p62 表达和自噬体），同时维持了 HCC 细胞的存活。相比之下，沉默的 TF 则显示出完全相反的结果。此外，TF 敲低促进了 Beclin1 从 BCL2-Beclin1 复合物中的解离。此外，用 3-MA 或 spautin-1（Beclin1 特异性抑制剂）抑制自噬可以逆转 TF 敲低增强的自噬和抑制 HCC 细胞的存活。异种移植实验也表明，TF 沉默的 HCC 细胞在体内具有更强的致瘤性，而 spautin-1 的给药则恢复了这种致瘤性。
TF 通过增强 BCL2 的表达抑制自噬相关死亡，从而促进 HCC 肿瘤的发生。
