|M.Sc Student||Fink-Barkai Dorit|
|Subject||Human Sef, an Inhibitor of Growth Factor Signaling, is Down|
Regulated in Cancer
|Department||Department of Biology||Supervisor||Professor Dina Ron|
RTKs play an important role in the integration and interpretation of diverse extracellular stimuli to internal signal transduction pathways. As such, RTKs control the most fundamental cellular processes. Inappropriate signaling by RTKs is implicated in the onset and progression of a variety of human diseases including cancer. This implies that that the strength and the duration of signaling mediated by RTKs must be tightly controlled. Negative feedback is one of the mechanisms that provide an effective means of controlling the response to growth factors and their RTKs. Sef has recently been identified as a specific antagonist of fibroblast growth factor (FGF) signaling in Zebrafish and subsequently in mouse and human. Further studies indicated that mammalian Sef is likely a general inhibitor of RTK signaling. Studies performed in our laboratory revealed several isoforms of the hSef gene. Among them, hSef-a and hSef-b were found to inhibit FGF-induced cell proliferation through the Ras/MAPK pathway and prevent therefore the activation of this pathway.
In the present study we demonstrate, dramatic down-regulation in hSef transcript expression, by mRNA in-situ hybridization, in a variety of human cancers including breast, prostate, ovary and thyroid, when compared to corresponding healthy tissues. A total of 155 primary carcinomas were examined in order to evaluate the hSef transcript expression levels. hSef expression was down-regulated in all examined cancerous tissues and in all tumor types. In 65% of all the examined primary tumors hSef expression was lost. Moreover, down-regulation of hSef expression was observed even in pre-malignant stages. Additionally, when hSef was re-expressed in cancerous breast cell lines we could clearly see its cell-growth suppressing effect.
Our finding that hSef is down-regulated in a variety of carcinomas correlated well with its inhibitory role on cell proliferation. Down-regulation of hSef may therefore lead to excessive signaling by various RTKs, and can contribute to tumor progression via enhanced proliferation. Our results may imply that hSef may function as a tumor suppressor-like gene. Moreover, the cytotoxic effect of hSef when over expressed in the breast cancer cell line MDA-MB-435 points to the potential benefit of hSef for cancer therapy. Additional studies are required to further investigate these possibilities.