Hepatology 2011 Nov;54 (5): 1808-18. [IF:10.885]
Epimorphin promotes human hepatocellular carcinoma invasion and metastasis through activation of focal adhesion kinase/extracellular signal-regulated kinase/matrix metalloproteinase-9 axis.
Jia YL , Shi L , Zhou JN , Fu CJ , Chen L , Yuan HF , Wang YF , Yan XL , Xu YC , Zeng Q , Yue W , Pei XT .
Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing, China.
北京大学干细胞与再生生物学实验室，北京输血医学研究所
Abstract
The high incidence rate of hepatocellular carcinoma (HCC) is mainly the result of frequent metastasis and tumor recurrence. Unfortunately, the underlying molecular mechanisms driving HCC metastasis are still not fully understood. It has been demonstrated that tumor stroma cells contribute to primary tumor growth and metastasis. Within the HCC environment, activated hepatic stellate cells (HSCs) can release a number of molecules and enhance cancer cell proliferation and invasiveness in a paracrine manner. Here, for the first time, we demonstrate that epimorphin (EPM; also called syntaxin-2), an extracellular protein, is strongly elevated in activated HSCs within tumor stroma. We show that knockdown of EPM expression in HSCs substantially abolishes their effects on cancer cell invasion and metastasis. Ectopic expression of EPM in HCC cancer cells enhances their invasiveness; we demonstrate that the cells expressing EPM have markedly increased metastasis potential. Furthermore, EPM-mediated invasion and metastasis of cancer cells is found to require up-regulation of matrix metalloproteinase-9 (MMP-9) through the activation of focal adhesion kinase (FAK)/extracellular signal-regulated kinase (ERK) axis. Conclusion: Our results show that EPM, secreted by activated HSCs within HCC stroma, promotes invasion and metastasis of cancer cells by activating MMP-9 expression through the FAK-ERK pathway. (HEPATOLOGY 2011;).
摘要：
肝细胞肝癌（HCC）的高病死率主要是由于高转移率和肿瘤复发造成的。然而，肝癌转移的分子机制仍然没有完全被了解。目前已经有证据表明肿瘤基质细胞(tumor stroma cells)促进肿瘤生长和转移。在肝癌的环境中，激活肝星状细胞可以通过旁分泌的方式释放一些列分子物质提高肿瘤细胞的增殖和侵袭性。这里我们首次阐明表皮形态发生素(epimorphin,EPM,syntaxin-2),一个细胞外蛋白，在肿瘤基质细胞激活肝星状细胞后剧烈升高。敲除EPM表达的肝星状细胞基本上丧失了其对癌细胞的侵袭和转移作用。在肝细胞肝癌肿瘤细胞中异位表达EPM则增强其肿瘤侵袭性。我们证实细胞表达EPM会显著增加其转移潜能。进一步研究发现EPM介导的侵袭和转移是通过激活粘着斑激酶(FAK)/细胞外信号调节激酶(ERK)途径上调基质金属蛋白酶9(MMP-9)实现的。结论：肿瘤基质细胞激活肝星状细胞后分泌EPM，而EPM是通过FAK-ERK途径上调MMP-9表达从而促进肿瘤侵袭和转移。
