TMPRSS4 facilitates epithelial-mesenchymal transition of hepatocellular carcinoma and is a predictive marker for poor prognosis of patients after curative resection.
TMPRSS4 facilitates epithelial-mesenchymal transition of hepatocellular carcinoma and is a predictive marker for poor prognosis of patients after curative resection.
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DOI：
10.1038/srep12366
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发表时间：
2015-07-20
影响因子：
4.6
通讯作者：
Li T
中科院分区：
文献类型：
--
作者：
Wang CH;Guo ZY;Chen ZT;Zhi XT;Li DK;Dong ZR;Chen ZQ;Hu SY;Li T
TMPRSS4(跨膜蛋白酶丝氨酸4)在多种癌症中表达上调。然而，TMPRSS4对肝细胞癌的生物学作用及其相关机制还知之甚少。在本研究中，我们发现TMPRSS4的过表达显著促进了肝癌的侵袭、迁移、黏附和转移。此外，TMPRSS4通过激活Raf/MEK/ERK1/2而通过蜗牛和鼻涕介导肝癌细胞的EMT，其抑制ERK1/2的激活与减少细胞侵袭和逆转EMT有关。此外，我们还发现TMPRSS4显著抑制血管生成抑制因子RECK的表达，并显著诱导肿瘤血管生成和生长。更重要的是，在临床肝细胞癌组织中，TMPRSS4的表达与肿瘤分期显著相关，与E-钙粘蛋白和RECKS的表达呈负相关。TMPRSS4的表达与肝细胞癌的进展显著相关，是影响术后较差生存和复发的独立预后因素。综上所述，TMPRSS4作为Raf/MEK/ERK1/2通路的正向调节因子，通过诱导EMT和血管生成促进了肝癌的进展。TMPRSS4的表达升高可能是肝细胞癌进展的关键事件，可作为肝细胞癌潜在的预后指标。
TMPRSS4 (Transmembrane protease serine 4) is up-regulated in a broad spectrum of cancers. However, little is known about the biological effects of TMPRSS4 on hepatocellular carcinoma (HCC) and the related mechanisms. In the present study, we found that overexpression of TMPRSS4 significantly promoted the invasion, migration, adhesion and metastasis of HCC. Further more, TMPRSS4 induced EMT of HCC, which was mediated via snail and slug as a result of Raf/MEK/ERK1/2 activation, and inhibition of ERK1/2 activation by its inhibitor was associated with reduced cell invasion and reversion of EMT. In addition, we demonstrated that TMPRSS4 remarkably suppressed the expression of RECK, an inhibitor of angiogenesis, and drastically induced tumor angiogenesis and growth. More important, in clinical HCC specimens, TMPRSS4 expression was significantly correlated with tumor staging and was inversely correlated with E-cadherin and RECKS expression. Expression of TMPRSS4 is significantly associated with HCC progression and is an independent prognostic factor for postoperative worse survival and recurrence. In conclusion, TMPRSS4 functions as a positive regulator of Raf/MEK/ERK1/2 pathway and promotes HCC progression by inducing EMT and angiogenesis. The increase of TMPRSS4 expression may be a key event for HCC progression and may be regarded as a potential prognostic marker for HCC.