PDF(Pubmed)
Abstract：
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.
摘要：
超过90％的肝细胞癌（HCC）病例在纤维化或肝硬化的存在下发展，由于癌症相关成纤维细胞（CAFs）和癌症干细胞（CSC）之间复杂的相互作用，使HCC的肿瘤微环境（TME）变得与众不同，它们共同调节HCC的进展。然而,CSCs在HCC发展过程中协调肿瘤基质动力学的机制仍然难以捉摸。我们的研究揭示了Sema3C在纤维化肝脏中的显著上调，HCC组织，肝癌患者的外周血，以及抗索拉非尼的组织和细胞，其过度表达与肝癌干细胞特性的获得相关。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的自我更新和肿瘤发生。此外,肝癌细胞来源的Sema3C在体内促进细胞外基质（ECM）收缩和胶原蛋白沉积，同时还促进肝星状细胞（HSC）的增殖和活化。机械上,Sema3C与NRP1和ITGB1在HSC中相互作用，激活下游NF-kB信号，从而刺激IL-6的释放和上调HMGCR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信号增强Sema3C在肝癌细胞中的表达，建立加速HCC进展的正反馈回路。值得注意的是,Sema3C的阻断可有效抑制肿瘤生长，并使肝癌细胞在体内对索拉非尼敏感。总之,我们的研究结果聚焦Sema3C作为一个新的生物标志物促进CSC和基质之间的串扰在肝癌发生过程中，从而为提高HCC的治疗效果和克服耐药性提供了有希望的途径。
