Frequent Loss of Heterozygocity (LOH) in specific chromosomal regions of tumors indicates the residence of at least one tumor suppressor gene (TSG) in the corresponding chromosomal region. Chromosome 8p22 is described as LOH hotspot in several epithelial tumors. However, the related genes of this chromosomal band are still very poorly described. The aim of this study was the identification and characterization of potential tumor suppressor genes on chromosome 8p22 in ovarian cancer. Two out of

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... 2 genes of 8p22 – hVps37A and TUSC3 – turned out to be promising tumor suppressor candidates and were characterized in more detail. It could be shown that hVps37 expression is significantly reduced in primary ovarian tumors relative to normal ovarian epithelias. Furthermore, survival rates of the patients were directly correlated with the hVps37A expression of the corresponding tumors. In-vitro characterization of hVps37A in two ovarian cancer cell lines resulted in an explanatory model of the clinical observations. As part of the ESCRT-I complex hVps37A is involved in the degradation process of activated receptor tyrosine kinases (RTKs) including the well described oncogenes EGFR and HER2. Consequently, hVps37A knockdown led to a hyperactivation of the MAPK (Mitogen Activated Protein Kinase) pathway secondary to accumulating amounts of the activated EGFR (pEGFR) in the cytoplasm. Furthermore, the hVps37-silenced cell lines developed a resistance against the growth inhibitory effect of Cetuximab. In contrast to hVps37A, 29.7% of the tumors analyzed were methylated at the TUSC3 promoter, acompanied with reduced mRNA expression and unfavourable survival rate of the patients. Therefore, promoter methylation turned out to be an independent prognostic factor for ovarian cancer. In-vitro, it could be shown that TUSCS3 resides in the endoplasmatic reticulum and is involved in the N-glycosilation process of integrin-ß1 and potentially further proteins. Moreover, reconstitution of TUSC3 in ovarian cancer cell lines decreased cellul [...]