A cancer-promoting role of fibrogenesis in the liver has long been speculated; however, the molecular mechanisms regarding this phenomenon are largely unknown. We demonstrated in our previous study that macrophage-derived S100A4 promotes liver fibrosis via activation of hepatic stellate cells; however, whether and how S100A4 directly contributes to the development of fibrosis-associated liver cancer remains elusive. High expression of S100A4 in the fibrotic region was observed in human liver tumor tissues which associated with advanced disease severity. Through an established hepatocarcinogenesis model involving apparent liver fibrogenesis, we found that S100A4-deficient mice developed significantly less and smaller liver tumor nodules, with no change in the liver inflammation but decreased liver fibrosis and expression of stem cell markers in hepatocellular carcinoma (HCC) tissues. Mechanistically, S100A4 directly promoted stem cell-associated genes signatures in a way synergistic with its interacting protein, extracellular matrix component collagen I. This process is dependent on the receptor of advanced glycation end products (RAGE) and β-catenin signaling. Furthermore, the liver tumor sphere formation in vitro and tumor growth in vivo were greatly enhanced only when the cancer cells were pretreated with both S100A4 and collagen I. Our work firstly demonstrated a key role of S100A4 in synergy with extracellular matrix in the promotion of hepatocellular carcinoma by affecting the stemness of cancer cells.

中文翻译：

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S100A4通过增强纤维化相关的癌细胞干性来促进肝细胞癌变。

长期以来，人们一直推测肝中纤维生成具有促进癌症的作用。然而，有关这种现象的分子机制在很大程度上尚不清楚。我们在先前的研究中证明巨噬细胞来源的S100A4通过激活肝星状细胞促进肝纤维化。然而，S100A4是否以及如何直接促进与纤维化相关的肝癌的发展尚不清楚。在人肝肿瘤组织中观察到S100A4在纤维化区域中的高表达，这与疾病的严重程度有关。通过建立的涉及明显肝纤维化的肝癌发生模型，我们发现S100A4缺陷小鼠的肝脏肿瘤结节明显减少，并且结节变小。肝炎症反应无变化，但肝纤维化和肝细胞癌（HCC）组织中干细胞标志物的表达降低。从机制上讲，S100A4以与其相互作用的蛋白质细胞外基质成分胶原蛋白I协同的方式直接促进干细胞相关基因的签名。此过程取决于高级糖基化终产物（RAGE）和β-catenin信号的受体。此外，仅当癌细胞同时用S100A4和胶原I预处理时，体外肝肿瘤球的形成和体内肿瘤的生长才会大大增强。我们的工作首先证明了S100A4在与细胞外基质协同作用中的关键作用是促进肝细胞通过影响癌细胞的干性来癌变。S100A4以与其相互作用蛋白，细胞外基质成分胶原蛋白I协同作用的方式直接促进干细胞相关基因的签名。该过程取决于高级糖基化终产物（RAGE）和β-catenin信号的受体。此外，仅当癌细胞同时用S100A4和胶原I预处理时，体外肝肿瘤球的形成和体内肿瘤的生长才会大大增强。我们的工作首先证明了S100A4在与细胞外基质协同作用中的关键作用是促进肝细胞通过影响癌细胞的干性来癌变。S100A4以与其相互作用蛋白，细胞外基质成分胶原蛋白I协同作用的方式直接促进干细胞相关基因的签名。该过程取决于高级糖基化终产物（RAGE）和β-catenin信号的受体。此外，仅当癌细胞同时用S100A4和胶原I预处理时，体外肝肿瘤球的形成和体内肿瘤的生长才会大大增强。我们的工作首先证明了S100A4在与细胞外基质协同作用中的关键作用是促进肝细胞通过影响癌细胞的干性来癌变。该过程取决于晚期糖基化终产物（RAGE）和β-catenin信号转导的受体。此外，仅当癌细胞同时用S100A4和胶原I预处理时，体外肝肿瘤球的形成和体内肿瘤的生长才会大大增强。我们的工作首先证明了S100A4在与细胞外基质协同作用中的关键作用是促进肝细胞通过影响癌细胞的干性来癌变。该过程取决于晚期糖基化终产物（RAGE）和β-catenin信号转导的受体。此外，仅当癌细胞同时用S100A4和胶原I预处理时，体外肝肿瘤球的形成和体内肿瘤的生长才会大大增强。我们的工作首先证明了S100A4在与细胞外基质协同作用中的关键作用是促进肝细胞通过影响癌细胞的干性来癌变。