超过 90% 的肝细胞癌 (HCC) 病例在存在纤维化或肝硬化的情况下发生，由于癌症相关成纤维细胞 (CAF) 和癌症干细胞 (CSC) 之间复杂的相互作用，使得 HCC 的肿瘤微环境 (TME) 与众不同，共同调节 HCC 进展。然而，CSC 在 HCC 发展过程中协调肿瘤基质动态的机制仍然难以捉摸。我们的研究揭示了 Sema3C 在纤维化肝脏、HCC 组织、HCC 患者外周血以及索拉非尼耐药组织和细胞中显着上调，其过度表达与 HCC 干性特性的获得相关。我们进一步确定 NRP1 和 ITGB1 是 Sema3C 的关键功能受体，激活下游 AKT/Gli1/c-Myc 信号通路，以支持 HCC 自我更新和肿瘤发生。此外，源自肝癌细胞的 Sema3C 促进细胞外基质 (ECM) 收缩和体内胶原蛋白沉积，同时还促进肝星状细胞 (HSC) 的增殖和活化。从机制上讲，Sema3C 与 HSC 中的 NRP1 和 ITGB1 相互作用，激活下游 NF-kB 信号传导，从而刺激 IL-6 的释放并上调 HMGCR 的表达，从而增强 HSC 中的胆固醇合成。此外，CAF 分泌的 TGF-β1 激活 AP1 信号传导，增强 HCC 细胞中 Sema3C 的表达，建立正反馈循环，加速 HCC 进展。值得注意的是，阻断 Sema3C 可有效抑制体内肿瘤生长并使 HCC 细胞对索拉非尼敏感。总之，我们的研究结果将 Sema3C 作为一种新型生物标志物，促进肝癌发生过程中 CSC 和基质之间的串扰，从而为提高 HCC 治疗效果和克服耐药性提供了一条有希望的途径。© 2024。作者。

More than 90% of hepatocellular carcinoma (HCC) cases develop in the presence of fibrosis or cirrhosis, making the tumor microenvironment (TME) of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs), which collectively regulate HCC progression. However, the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive. Our study unveils a significant upregulation of Sema3C in fibrotic liver, HCC tissues, peripheral blood of HCC patients, as well as sorafenib-resistant tissues and cells, with its overexpression correlating with the acquisition of stemness properties in HCC. We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C, activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation. Additionally, HCC cells-derived Sema3C facilitated extracellular matrix (ECM) contraction and collagen deposition in vivo, while also promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacted with NRP1 and ITGB1 in HSCs, activating downstream NF-kB signaling, thereby stimulating the release of IL-6 and upregulating HMGCR expression, consequently enhancing cholesterol synthesis in HSCs. Furthermore, CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Notably, blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. In sum, our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CSCs and stroma during hepatocarcinogenesis, thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.© 2024. The Author(s).