Hepatoma-Derived Growth Factor in Carcinogenesis and Cancer Progression

Hideji      Nakamura; Hirayuki      Enomoto

Abstract

Hepatoma-derived growth factor (HDGF) has been purified and cloned from a human hepatocellular carcinoma (HCC) cell line. HDGF and five HDGF-related proteins form a new protein family with a significant homology in their amino terminus containing a PWWP domain. HDGF is a unique growth factor with nuclear localization signals, and dominantly located in the nucleus. HDGF translocates to the nucleus and displays a mitogenic activity. Exogenous HDGF also stimulates the cellular proliferation via a signal pathway through MAP kinase activation from cell membrane binding. HDGF is strongly expressed in cancer cells. HDGF over-expression in NIH3T3 cells induced tumorigenesis and that in HCC cells enhanced the growth of tumors in vivo. HDGF stimulated the migration, tubule formation and proliferation of human endothelial cells as well as the proliferation of smooth muscle cells, thus indicating that HDGF is an angiogenic factor. HDGF induced tumorigenesis in vivo through both its direct angiogenic activity and induction of VEGF. The down-regulation of endogenous HDGF in cancer cells suppressed their proliferation, invasive activity and anchorageindependent growth in soft agar in vitro. HDGF is involved in an anti-apoptotic pathway. The higher expression of HDGF shows a more malignant potential for cancer progression. Clinically, HDGF may be a useful prognostic factor for determining the disease-free and/or overall survivals in patients who have undergone a resection of several types of cancer by immunohistochemical studies. This review will describe the current knowledge of HDGF in carcinogenesis and cancer progression, and evaluate its possible clinical utility in cancer regulation.

Keywords: HDGF, carcinogenesis, cancer progression, tumor marker, prognostic factor, Esophageal Cancer, Gastrointestinal Stromal Tumor, Lung Cancer, HDGF,