ROLES OF HEPATOCYTE GROWTH FACTOR IN TUMORIGENESIS

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The hepatocyte growth factor (HGF) is a newly identified factor which works as a most potent mitogen for primary culture of the liver. A recent cloning and sequencing analysis of the gene revealed that HGF is identical to the scatter factor which has the ability to disperse (scatter) cohesive epithelial cell colonies and stimulates cell motility. This factor is also known to stimulate invasion through collagen or basement membrane matrices in a variety of carcinoma cell types. Because of these characteristics, HGF has been strongly implicated in tumor progression and metastasis. HGF and its receptor c-met genes are indeed found to be over- expressed in a variety of types of tumors. Our long-term goal is to elucidate mechanisms of (i) how the HGF gene is up-regulated in cancer patients and (ii) how the HGF molecule exerts significantly different biological activities in the same and/or different cells and affects tumor progressions. Our preliminary results suggest that a defect in the retinoblastoma (Rb) or TGF-beta gene augments the expression of HGF, which in turn activates c-fos and collagenase genes and hence stimulates tumor progression and metastasis. In this project, we will (1) characterize regulatory elements in the 5'-flanking region of the HGF gene, (2) identify and characterize the responsive sequences in the 5'-upstream region of c-fos and collagenase IV genes that are positively regulated by HGF and (3) identify and characterize primary responding genes to HGF in different tissues. The results should significantly contribute to the understanding of the molecular mechanisms of HGF functions in tumor progression and metastasis, which may lead to identification of the therapeutic targets of HGF-related tumors.