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Granulin–Epithelin Precursor Overexpression Promotes Growth and Invasion of Hepatocellular Carcinoma

¹ Centre for the Study of Liver Disease and Departments of ² Surgery and ³ Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China; ⁴ Department of Biopharmaceutical Sciences, University of California-San Francisco, San Francisco, California; and ⁵ Department of Surgery, Asian Liver Center, Stanford University School of Medicine, Stanford, California

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 prolifera-tion 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. GEP has the potential to serve as a tumor marker and therapeutic target.

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