MOLECULAR ANALYSIS OF HEPATOMA CELL MIGRATION FACTOR

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Cell locomotion is essential for tumor cells to invade into surrounding tissues and achieve metastasis. Soluble factors that enhance cellular motility have been implicated in the process. We have found an activity in conditioned media of human fibroblasts that stimulates the motility of hepatoma cells. The long-term objective of this proposal is to characterize this novel factor, tentatively termed "hepatoma cell migration factor" (HMF). HMF disperses tightly packed colonies of well-differentiated hepatoma cells into single cells and promotes the migration of the cells out of colonies. The dispersed cells spread extensively and assume a fibroblastic, dedifferentiated morphology. These phenotypical changes are induced with less than 1 ng/ml of partially purified HMF. The estimated molecular weight (60 kDa), the narrow range of target cell specificity toward hepatocytes/hepatoma cells, and other biological and biochemical data suggest that HMF is distinct from other motility factors and cytokines known to affect cell morphology and motility. Thus, our working hypothesis is that HMF is a novel cytokine-type molecule which regulates the migration and differentiation of hepatocytes/hepatoma cells and possibly the invasion and metastasis of hepatoma in vivo. To examine the biological roles of HMF, we will 1) purify HMF and obtain its amino acid sequences; 2) molecularly clone and sequence HMF cDNA; 3) investigate the tissue distribution of HMF by immunohistochemical staining with specific antibody probes; and 4) characterize the biological effects of HMF on the differentiation, migration and invasion of hepatocytes/hepatoma cells by using exogenously added HMF and by gene transfer of HMF cDNA into cells. These studies will contribute to our understanding of the molecular mechanisms of the invasion and metastasis of hepatoma in vivo and define a role for HMF in these processes.