THESIS
2004
xvii, 144 leaves : ill. (some col.) ; 30 cm
Abstract
The key genes involved in esophageal squamous cell carcinoma (ESCC) development remain to be elucidated. Previous findings from cytogenetic and molecular allelotyping approaches implicate chromosome 9 and chromosome 18 as harboring possible tumor suppressor genes (TSGs) associated with esophagus carcinogenesis. One of the most common approaches to identifying a TSG in sporadic cancer is the positional cloning of the common region of loss of heterozygosity (LOH) from primary tumors. Another approach, microcell-mediated chromosome transfer (MMCT), provides functional evidence for tumor suppressive activities in cancer cells....[
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The key genes involved in esophageal squamous cell carcinoma (ESCC) development remain to be elucidated. Previous findings from cytogenetic and molecular allelotyping approaches implicate chromosome 9 and chromosome 18 as harboring possible tumor suppressor genes (TSGs) associated with esophagus carcinogenesis. One of the most common approaches to identifying a TSG in sporadic cancer is the positional cloning of the common region of loss of heterozygosity (LOH) from primary tumors. Another approach, microcell-mediated chromosome transfer (MMCT), provides functional evidence for tumor suppressive activities in cancer cells.
We investigated the tumor suppressive role of chromosomes 9 and 18. For chromosome 9, we determined the frequency of allelic loss in ESCC tissues. It ranged between 42.9% to 80%, showing extensive genetic losses are suffered on this chromosome. Three commonly deleted regions were observed on chromosome 9 at 9p23-p22, 9q13-q22.3, and 9q34. Functional evidence via MMCT was utilized to evaluate the tumor suppressive activities of chromosomes 9 and 18 in ESCC with the SLMT-1S1 ESCC cell line. While a 9p21 microdeleted chromosome 9 suppressed ESCC tumorigenicity in a nude mice model, in contrast chromosome 18 did not. With more detailed studies of the chromosome 9 microcell hybrids and their tumor segregants (TSs), one critical region (CR) associated with ESCC tumorigenicity was mapped to a 2.4 Mb region mapped to 9q32-q34 between markers D9S1798 and D9S61. Interestingly, a high prevalence of allelic loss in this CR is also observed in primary ESCC tumors by microsatellite typing. Allelic loss is found in 30/34 (88%) tumors and the LOH frequency ranges from 67% to 86%. Absent to low expression of a 9q32 candidate TSG, DEC1, is detected in four Asian ESCC cell lines. Stably expressing DEC1 transfectants provide functional evidence for inhibition of tumor growth in nude mice, DEC1 expression was decreased in TSs arising after selection in the mice. There is 74% LOH in the DEC1 region of 34 ESCC primary tumors. These findings provide the first functional evidence for the presence of multiple critical tumor suppressive regions on 9q and for DEC1 being one of the candidate TSGs involved in ESCC development.
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