International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China.
Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
Acta Pharmacol Sin. 2022 Nov;43(11):2917-2928. doi: 10.1038/s41401-022-00907-5. Epub 2022 May 4.
Non-alcoholic fatty liver disease (NAFLD) is emerging as an epidemic risk factor for hepatocellular carcinoma (HCC). The progression of NAFLD to HCC is closely associated with paracrine communication among hepatic cells. Vascular endothelial growth factor A (VEGFA) plays a key role in NAFLD and HCC; however, the cellular communication of VEGFA in the pathological transition from NAFLD to HCC remains unclear. Here, we found that VEGFA elevation was considerably distributed in hepatocytes of clinical and murine NAFLD-HCC specimens. Notably, progression from NAFLD to HCC was attenuated in hepatocyte-specific deletion of Vegfa (Vegfa) mice. Mechanistically, VEGFA activated human hepatic stellate cell (HSC) LX2 into a fibrogenic phenotype via VEGF-VEGFR signaling in fatty acid medium, and HSC activation was largely attenuated in Vegfa mice during NAFLD-HCC progression. Additionally, a positive correlation between VEGFA and hepatic fibrosis was observed in the NAFLD-HCC cohort, but not in the HBV-HCC cohort. Moreover, LX2 cells could be activated by conditioned medium from NAFLD-derived organoids, but not from HBV livers, whereas this activation was blocked by a VEGFA antibody. In summary, our findings reveal that hepatocyte-derived VEGFA contributes to NAFLD-HCC development by activating HSCs and highlight the potential of precisely targeting hepatocytic VEGFA as a promising therapeutic strategy for NAFLD-HCC.
非酒精性脂肪性肝病（NAFLD）正在成为肝细胞癌（HCC）的流行风险因素。NAFLD 向 HCC 的进展与肝实质细胞之间的旁分泌通讯密切相关。血管内皮生长因子 A（VEGFA）在 NAFLD 和 HCC 中起关键作用；然而，VEGFA 在从 NAFLD 到 HCC 的病理转化中的细胞通讯尚不清楚。在这里，我们发现 VEGFA 升高在临床和小鼠 NAFLD-HCC 标本的肝细胞中分布广泛。值得注意的是，在肝细胞特异性 Vegfa 缺失（Vegfa）小鼠中，NAFLD 向 HCC 的进展得到了抑制。从机制上讲，VEGFA 通过 VEGF-VEGFR 信号在脂肪酸培养基中激活人肝星状细胞（HSC）LX2 成为纤维生成表型，并且在 NAFLD-HCC 进展过程中，HSC 在 Vegfa 小鼠中的激活大大减弱。此外，在 NAFLD-HCC 队列中观察到 VEGFA 与肝纤维化之间存在正相关，但在 HBV-HCC 队列中则没有。此外，LX2 细胞可以被来自 NAFLD 类器官的条件培养基激活，但不能被来自 HBV 肝脏的条件培养基激活，而这种激活可以被 VEGFA 抗体阻断。总之，我们的研究结果表明，肝细胞来源的 VEGFA 通过激活 HSCs 促进 NAFLD-HCC 的发展，并强调了精确靶向肝细胞 VEGFA 作为治疗 NAFLD-HCC 的有前途的治疗策略的潜力。
