Semaphorin 3C (Sema3C) 重塑基质微环境,促进肝细胞癌的进展。

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Signal Transduction and Targeted Therapy Pub Date : 2024-07-03 DOI:10.1038/s41392-024-01887-0
Hao Peng, Meng Yang, Kun Feng, Qingpeng Lv, Yewei Zhang
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引用次数: 0

摘要

90%以上的肝细胞癌(HCC)病例是在纤维化或肝硬化的情况下发生的,这使得HCC的肿瘤微环境(TME)与众不同,因为癌症相关成纤维细胞(CAFs)和癌症干细胞(CSCs)之间存在着错综复杂的相互作用,它们共同调控着HCC的进展。然而,CSCs 在 HCC 发展过程中协调肿瘤基质动态的机制仍不明确。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的显著上调,其过表达与HCC干性特性的获得相关。我们进一步发现,NRP1和ITGB1是Sema3C的关键功能受体,可激活下游的AKT/Gli1/c-Myc信号通路,从而促进HCC的自我更新和肿瘤的发生。此外,HCC细胞衍生的Sema3C有助于体内细胞外基质(ECM)的收缩和胶原沉积,同时还能促进肝星状细胞(HSCs)的增殖和活化。从机制上讲,Sema3C与造血干细胞中的NRP1和ITGB1相互作用,激活下游的NF-kB信号,从而刺激IL-6的释放并上调HMGCR的表达,进而促进造血干细胞中胆固醇的合成。此外,CAF 分泌的 TGF-β1 可激活 AP1 信号,从而增强 HCC 细胞中 Sema3C 的表达,建立一个正反馈回路,加速 HCC 的进展。值得注意的是,在体内阻断 Sema3C 能有效抑制肿瘤生长并使 HCC 细胞对索拉非尼敏感。总之,我们的研究结果表明,Sema3C是一种新型生物标记物,可在肝癌发生过程中促进癌细胞干细胞与基质之间的串联,从而为提高HCC的治疗效果和克服耐药性提供了一种前景广阔的途径。
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Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression.

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.

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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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