Granulin-epithelin precursor overexpression promotes growth and invasion of hepatocellular carcinoma
Granulin-epithelin precursor overexpression promotes growth and invasion of hepatocellular carcinoma
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DOI：
10.1158/1078-0432.ccr-04-0960
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发表时间：
2004-11-15
影响因子：
11.5
通讯作者：
Fan, ST
中科院分区：
文献类型：
--
作者：
Cheung, ST;Wong, SY;Fan, ST
目的：颗粒上皮前体细胞（granulin - epithelial in precursor， GEP）是一种新型的生长因子。我们早期的cDNA芯片研究表明，GEP在肝细胞癌（HCC）中过表达。本研究的目的是探讨GEP表达的临床意义及其作为HCC治疗靶点的潜力。实验设计：共检查110对hcc及邻近非肿瘤肝组织，22对正常肝组织。采用定量逆转录pcr检测GEP RNA水平，免疫组织化学检测蛋白定位。转染实验检测GEP功能。结果：hcc组织的RNA水平明显高于非肿瘤肝组织和正常肝组织（P < 0.001）。肿瘤细胞质中可见GEP蛋白染色，hcc组织中GEP蛋白水平显著高于非肿瘤肝组织和正常肝组织（P < 0.001）。与邻近肝组织相比，大多数hcc表现出GEP蛋白上调[79(71.8%)/ 110]。在hcc中，GEP RNA与蛋白水平呈正相关（P < 0.01）。高表达的GEP与大肝癌、静脉浸润和早期肝内复发相关（P < 0.05）。对肝癌细胞系Hep3B的功能研究表明，GEP蛋白水平的降低导致裸鼠细胞增殖率、肿瘤侵袭能力、软琼脂中不依赖锚定生长和致瘤性降低（P < 0.05）。结论：GEP是肝癌生长、侵袭和转移的重要因素。GET具有作为肿瘤标志物和治疗靶点的潜力。
Purpose: Granulin-epithelin precursor (GEP) is a novel growth factor. Our earlier cDNA microarray study indicated that GEP was overexpressed in hepatocellular carcinoma (HCC). The aim of this study was to investigate the clinical significance of GEP expression and its potential as a therapeutic target in HCC.Experimental Design: A total of 110 pairs of HCCs and adjacent nontumor liver tissues, and 22 normal liver tissues were examined. The GEP RNA level was examined by quantitative reverse transcription-PCR, and protein localization by immunohistochemistry. The GEP function was examined by transfection experiments.Results: The RNA levels of the HCCs were significantly higher than those of the nontumor liver tissues and normal livers (P < 0.001). GEP protein staining was observed in tumor cytoplasm, and the GEP protein levels of the HCCs were also significantly higher than those of the nontumor liver tissues and normal livers (P < 0.001). The majority of HCCs demonstrated up-regulation of GEP protein compared with their adjacent liver tissues [79 (71.8%) of 110]. Positive correlation of GEP RNA with protein levels was observed in HCCs (P < 0.01). Strong GEP expression was associated with large HCCs, venous infiltration, and early intrahepatic recurrence (P < 0.05). Functional studies on the HCC cell line Hep3B demonstrated that reduction of GEP protein levels resulted in decreased cell proliferation rates, tumor invasion ability, anchorage-independent growth in soft agar, and tumorigenicity in nude mice (P < 0.05).Conclusion: GEP is an important factor for HCC growth, invasion, and metastasis. GET has the potential to serve as a tumor marker and therapeutic target.