DESCRIPTION (provided by applicant): Squamous cell oesophageat cancer (SCOC) occurs with a high frequency in South Africa (13.61/100 000), where it causes the most cancer-related deaths in Black males. A better understanding of the molecular events involved in the development of oesophageal cancer will allow early diagnosis, the development of better therapeutic strategies and the prevention of metastatic spread. The project aim is to determine the role of NDRG1 (N-Myc Downstream Regulated Gene 1) in the development of SCOC, since it was demonstrated that expression of this gene was reduced in poorly differentiated oesophageal tumors. The function of this protein is presently unknown, although there are reports implicating this gene in cell differentiation, cell proliferation and metastasis. The specific aims of the project are determine the role of specific transcriptional factors (c-Jun, HIF-la, N-Myc and c-myc) in regulating the expression of NDRG1 in cultured oesophageal cancer cells by generating stable transfectants, in which the level of these transcriptional factors are altered. NDRG1 expression levels will also be altered in oesophageal cancer cells by placing NDRG1 or anti-sense NDRG1 under the control of an inducible promoter. This system will be used to test the effect of NDRG1 on markers of tumorigenesis (differentiation, cell proliferation, cell migration and invasion, and metastasis). In addition, deletion mutants of NDRG1 will be constructed, and these will be expressed in oesophageal cancer cells. The effect of these deletions on the sub-cellular localization of NDRG1 and markers of tumorigenesis described above will be determined.
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