mTOR and P70S6 kinase expression in primary liver neoplasms
mTOR and P70S6 kinase expression in primary liver neoplasms
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DOI：
10.1158/1078-0432.ccr-04-0941
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发表时间：
2004-12-15
影响因子：
11.5
通讯作者：
Torbenson, M
中科院分区：
文献类型：
--
作者：
Sahin, F;Kannangai, R;Torbenson, M
目的：mTOR和P70 S6激酶（S6 K）在调节蛋白质翻译中起关键作用。尚未研究mTOR和S6 K在肝细胞癌中的作用，但该途径特别令人感兴趣，因为有一种有效的抑制剂雷帕霉素。本研究旨在确定mTOR通路激活在肝细胞癌中的患病率和临床病理学相关性，并确定雷帕霉素是否抑制细胞culture.Experimental Design中的通路：通过免疫组化研究了肝细胞癌（n = 73），纤维板层癌（n = 13）和肝腺瘤（n = 15）中总的和磷酸化的mTOR和S6 K蛋白的表达。结果与WHO定义的肿瘤生长模式（小梁、假腺/腺泡、致密和硬结）、肿瘤大小、Ki-67增殖指数和改良的Edmondson核分级（1 - 4级）相关。HepG 2和Hep 3B细胞系用雷帕霉素处理，看到增殖和S6 K磷酸化的效果。结果：总mTOR的表达增加被认为是在5%的肝细胞癌，而磷酸化mTOR的过度表达是明显的15%的肝细胞癌。磷酸化mTOR阳性与总S6 K表达增加相关，这在45%的病例中发现。总S6 K过表达与肿瘤核分级呈正相关，与肿瘤大小呈负相关，与增殖指数或WHO生长模式无关。雷帕霉素治疗的HepG 2和Hep 3B细胞系显着抑制细胞增殖，并减少S6 K磷酸化在两个细胞line.Conclusions：mTOR通路激活的肝细胞癌的一个子集。雷帕霉素可抑制细胞培养中的肿瘤性肝细胞增殖。
Purpose: mTOR and P70 S6 kinase (S6K) play a key role in regulating protein translation. The role of mTOR and S6K in hepatocellular carcinoma has not been investigated, but this pathway is of particular interest because an effective inhibitor, rapamycin, is available. This study was undertaken to determine the prevalence and clinicopathological correlates of mTOR pathway activation in hepatocellular carcinoma and to determine whether rapamycin inhibits the pathway in cell culture.Experimental Design: Total and phosphorylated mTOR and S6K protein expression were studied by immunohistochemistry in hepatocellular carcinomas (n = 73), fibrolamellar carcinomas (n = 13), and hepatic adenomas (n = 15). Results were correlated with tumor growth pattern as defined by the WHO (trabecular, pseudoglandular/acinar, compact, and scirrhous), tumor size, Ki-67 proliferation index, and the modified Edmondson nuclear grade, which has a scale of 1 to 4. HepG2 and Hep3B cell lines were treated with rapamycin to see the effect on proliferation and S6K phosphorylation.Results: Increased expression of total mTOR was seen in 5% of hepatocellular carcinoma, whereas overexpression of phospho-mTOR was evident in 15% of hepatocellular carcinoma. Phospho-mTOR positivity correlated with increased expression of total S6K, which was found in 45% of cases. Total S6K overexpression was positively correlated with tumor nuclear grade, inversely with tumor size, and was unassociated with the proliferation index or WHO growth pattern. Rapamycin treatment of HepG2 and Hep3B cell lines markedly inhibited cell proliferation and reduced S6K phosphorylation in both cell lines.Conclusions: The mTOR pathway is activated in a subset of hepatocellular carcinoma. Rapamycin can inhibit proliferation of neoplastic hepatocytes in cell culture.