UBC Theses and Dissertations
Identification of metastasis-associated genes in prostate cancer Lin, Dong
Metastasis is thought to be based on genetic and epigenetic alterations. The mechanisms underlying prostate cancer metastasis are not clear. Studies aimed at identifying genes with key roles in this process have been impeded by lack of clinically relevant models. The heterogeneity of primary prostate cancer specimens from patients, consisting of non-metastatic and metastatic subpopulations, hampers identification of metastasis-associated genes by direct comparison of primary and secondary cancers. To overcome such hurdles, metastatic and non-metastatic tumor sublines have been developed from one patient’s primary prostate cancer specimen using subrenal capsule grafting into NOD-SCID mice. Chromosomal alterations present in the metastatic subline, but not in non-metastatic counterparts, were identified in a small percentage of cells in the parental tissue, suggesting that metastatic potential of primary cancers can be associated with a small cancer cell subpopulation. Sublines with different metastatic potential derived from same patient’s multifocal primary cancer provide valuable materials for identifying metastasis-associated genes and predictive markers. To identify metastasis-associated genes, differential gene expression analysis of metastatic PCa1-met and non-metastatic PCa2 prostate cancer sublines was carried out. Among various differentially expressed genes identified, ASAP1, a gene not previously associated with prostate cancer, was upregulated in the metastatic subline as confirmed by qRT-PCR and immunohistochemical staining. In clinical specimens, ASAP1 protein staining was elevated in 80% of primary prostate cancers and substantially higher in metastatic lesions compared to benign prostate tissue. Extra ASAP1 gene copies were detected in 58% of primary prostate cancer specimens. Increased ASAP1 protein expression was correlated with prostate cancer metastasis and PSA recurrence. siRNA- and shRNA-induced reduction of levels of ASAP1 protein markedly suppressed in vitro PC-3 cell migration, matrigel invasion and metastasis in vivo. These results indicate that ASAP1 plays an important role in prostate cancer invasion and metastasis and suggest that it provides a potential predictive marker and therapeutic target for the disease. Furthermore, the approach used to identify metastasis-associated genes by comparison of gene profiles of paired metastatic and non-metastatic sublines was validated. The subrenal capsule xenograft system provides a valuable platform for studying various aspects of prostate cancer metastasis.
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