Increased liver stiffness exerts a detrimental role in driving hepatocellular carcinoma (HCC) malignancy and progression, and indicates a high risk of unfavorable outcomes. However, it remains largely unknown how liver matrix stiffness as an independent cue triggers epithelial-mesenchymal transition (EMT) and facilitates HCC metastasis. Buffalo rat HCC models with different liver stiffness backgrounds and an in vitro Col I-coated cell culture system with tunable stiffness were used in the study to explore the effects of matrix stiffness on EMT occurrence and its underlying molecular mechanism. Clinical significance of liver stiffness and key molecules required for stiffness-induced EMT were validated in HCC cohorts with different liver stiffness. HCC xenografts grown in higher stiffness liver exhibited worse malignant phenotypes and higher lung metastasis rate, suggesting that higher liver stiffness promotes HCC invasion and metastasis. Cell tests in vitro showed that higher matrix stiffness was able to strikingly strengthen malignant phenotypes and independently induce EMT occurrence in HCC cells, and three signaling pathways converging on Snail expression participated in stiffness-mediated effect on EMT including integrin-mediated S100A11 membrane translocation, eIF4E phosphorylation, and TGF β1 autocrine. Additionally, the key molecules required for stiffness-induced EMT were highly expressed in tumor tissues of HCC patients with higher liver stiffness and correlated with poor tumor differentiation and higher recurrence. Higher matrix stiffness as an initiator triggers epithelial-mesenchymal transition (EMT) in HCC cells independently, and three signaling pathways converging on Snail expression contribute to this pathological process. This work highlights a significant role of biomechanical signal in triggering EMT and facilitating HCC invasion and metastasis.

中文翻译：

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较高的基质刚度作为独立的引发剂会触发上皮-间质转化，并促进HCC转移。

肝硬度的增加在驱动肝细胞癌（HCC）恶性和进展中起有害作用，并指示不良后果的高风险。然而，很大程度上仍然未知的是，肝基质刚度作为独立的提示如何触发上皮-间质转化（EMT）并促进肝癌转移。本研究使用具有不同肝刚度背景的布法罗大鼠HCC模型和具有可调刚度的体外Col I包被的细胞培养系统来研究基质刚度对EMT发生的影响及其潜在的分子机制。在具有不同肝脏僵硬度的HCC队列中验证了肝脏僵硬和僵硬诱导的EMT所需的关键分子的临床意义。在较高硬度的肝中生长的HCC异种移植物表现出较差的恶性表型和较高的肺转移率，这表明较高的肝脏硬度会促进HCC的侵袭和转移。体外细胞测试显示，较高的基质刚度能够显着增强恶性表型并独立诱导HCC细胞中EMT的发生，并且收敛于Snail表达的三个信号通路参与了对EMT的刚度介导的作用，包括整联蛋白介导的S100A11膜易位，eIF4E磷酸化和TGFβ1自分泌。此外，刚度诱导的EMT所需的关键分子在肝硬度更高的HCC患者的肿瘤组织中高表达，并且与较差的肿瘤分化和更高的复发率相关。作为引发剂的较高的基质刚度独立地触发HCC细胞中的上皮-间质转化（EMT），并且会聚在Snail表达上的三个信号通路对此病理过程有所贡献。这项工作突出了生物力学信号在触发EMT和促进HCC侵袭和转移中的重要作用。