Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma
Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma
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DOI：
10.1038/labinvest.2010.161
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发表时间：
2011-02-01
影响因子：
5
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
--
作者：
Yoneda, Norihide;Sato, Yasunori;Nakanuma, Yasuni
细胞角蛋白（CK）19阳性的肝细胞癌（HCC）有报道预后不良。CK 19阳性HCC的发生机制仍有待进一步研究。为了阐明这一点，在体外实验中进行使用人肝癌细胞系（PLC-5，HepG 2），并与几种生长因子刺激后的表型变化进行了研究，使用定量逆转录酶PCR，蛋白质印迹，免疫荧光染色。还使用从总共78名患者获得的人HCC标本进行了体内实验和临床病理学分析。在所测试的生长因子中，表皮生长因子（EGF）对诱导PLC-5和HepG 2中的CK 19表达具有显著作用，这伴随着PLC-5中甲胎蛋白的表达减少。EGF刺激后CK 19表达的诱导伴随着c-Jun-N-末端激酶（JNK）/应激活化蛋白激酶的磷酸化，这被JNK抑制剂阻断。EGF还增加了HCC细胞系的增殖能力和侵袭性。78例HCC中9例（12%）CK 19免疫组化染色阳性。EGF、EGF受体（EGFR）和JNK的免疫组化阳性信号在CK-19阳性HCC中的表达程度明显强于CK-19阴性HCC。临床病理分析显示，CK 19阳性HCC门静脉浸润、肝外转移和早期复发的发生率高，且2年无瘤生存率低。这些结果表明EGF-EGFR信号通路的激活与CK 19阳性肝癌的发生相关，EGF诱导的肝癌生长能力的增强可能是患者预后不良的原因。实验室调查（2011）91，262-272; doi：10.1038/labinvest.2010.161; 2010年9月20日在线发表
Cytokeratin (CK) 19-positive hepatocellular carcinoma (HCC) has been reported to have a poor prognosis. The mechanism of the development of CK19-positive HCC remains to be studied. To clarify this, in vitro experiments were performed using human HCC cell lines (PLC-5, HepG2), and the phenotypic changes after stimulation with several growth factors were examined using quantitative reverse transcriptase PCR, western blotting, and immunofluorescence staining. In vivo experiments using human HCC specimens obtained from a total of 78 patients and clinicopathological analysis were also performed. Among the growth factors tested, epidermal growth factor (EGF) had prominent effects on inducing CK19 expression in PLC-5 and HepG2, which was accompanied by the reduced expression of alpha-fetoprotein in PLC-5. The induction of CK19 expression after EGF stimulation was accompanied by the phosphorylation of c-Jun-N-terminal kinase (JNK)/stress-activated protein kinase, which was blocked by the addition of JNK inhibitors. EGF also increased proliferative abilities and invasive properties of the HCC cell lines. In vivo, 9 (12%) of 78 HCC cases showed positive immunohistochemical staining of CK19. The extent of positive immunhistochemical signals of EGF, EGF receptor (EGFR), and JNK expression was significantly intense in CK-19-positive HCC than those of CK19-negative HCC. Clinicopathological analysis showed that CK19-positive HCC had a high incidence of portal vein invasion, extrahepatic metastasis and an early relapse, which was associated with the worsened 2-year disease free survival. These results indicate that the activation of the EGF-EGFR signaling pathway is associated with the development of CK19-positive HCC, and the EGF-induced increase in growth abilities of HCC may account for the poor prognosis of the patients. Laboratory Investigation (2011) 91, 262-272; doi:10.1038/labinvest.2010.161; published online 20 September 2010