Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis
Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis
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较高的基质硬度作为独立的引发剂触发上皮间质转化并促进 HCC 转移
DOI：
10.1186/s13045-019-0795-5
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发表时间：
2019-11-08
影响因子：
28.5
通讯作者：
Cui, Jiefeng
中科院分区：
文献类型：
--
作者：
Dong, Yinying;Zheng, Qiongdan;Cui, Jiefeng
背景肝硬度增加在肝细胞癌（HCC）恶性化和进展中发挥有害作用，并表明不良结局的高风险。然而，它仍然在很大程度上是未知的肝基质刚度作为一个独立的线索触发上皮间质转化（EMT），促进HCC metastasis.MethodsBuffalo大鼠肝癌模型与不同的肝硬度背景和体外Col I包被的细胞培养系统与可调刚度在研究中使用，以探讨基质刚度对EMT的发生及其潜在的分子机制的影响。肝硬度和硬化诱导EMT所需的关键分子的临床意义进行了验证，在HCC队列不同liverstiffic.ResultsHCC异种移植生长在较高的硬度肝表现出更差的恶性表型和更高的肺转移率，这表明，较高的肝硬度促进HCC的侵袭和转移。体外细胞实验表明，较高的基质硬度能够显著增强HCC细胞的恶性表型，并独立诱导EMT的发生，整合素介导的S100A11膜转位、eIF4E磷酸化和TGF β1自分泌等3条信号通路参与了Snail表达的硬度介导的EMT。此外，刚度诱导EMT所需的关键分子在肝癌患者的肿瘤组织中高度表达，肝硬度较高，与肿瘤分化差，复发率较高。结论较高的基质刚度作为启动子触发上皮间质转化（EMT）在肝癌细胞独立，和三个信号通路会聚在蜗牛表达有助于这一病理过程。这项工作强调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。
BackgroundIncreased 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.MethodsBuffalo 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.ResultsHCC 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.ConclusionsHigher 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.