The possible modulation of p63 and other genes in prostate tumorigenesis

Su, Nguok Ngie (2007) The possible modulation of p63 and other genes in prostate tumorigenesis. Masters thesis, Universiti Malaysia Sarawak (UNIMAS).

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Abstract

Prostate cancer (PCa) affects males in Malaysia, where in Peninsular Malaysia prostate cancer was the sixth most frequent cancer in males and accounted for 6.4% of the total cancers in males for the year 2003. In Sarawak, prostate cancer ranked eighth among the most frequent cancer occurrence in males with a rate of 3.4% of the total cancers in males for the year 1996-2000. Mice knockout for p63 have exhibited developmental defects such as abnormal skin and absence of hair follicles, prostate, breast, teeth and mammary glands. Mutation of p63 in human resulted in the ectrodactyly, ectodermal dysplasia and facial clefts (EEC) syndrome. Mutational analyses have revealed heterozygous mutation of p63 in colon (DLD1) and ovarian (SKOV3) cancer cell lines. Studies have shown that the p63 gene was selectively expressed in basal cells of normal, benign prostatic hyperplasia (BPH), prostatic epithelial stem cells and preneoplastic prostatic tissue Although indirect evidences from literature have implicated possible role(s) of p63 in prostate cancer, its actual involvement in the carcinogenesis of this cancer has yet been established. Furthermore, few studies have been done so far to delineate the molecular and genetic mechanisms that pertain to the predisposition and progression of prostate cancer. In this study, mutation analysis of p63 on prostate cancer cell line (PC-3), PCa biopsy and BPH biopsies have been performed. However, no mutation was detected in PC-3, CaP and BPH biopsies. Expression studies on various isoforms of p63 were performed on normal human prostate tissue, PC-3, clinically local prostate cancer and benign prostatic hyperplasia using RT-PCR. In addition, we report new data on the identification of differentially expressed III genes using gene expression profile analysis of the PC-3 cell line. The gene expression analysis data revealed a total of 673 downregulated genes and 240 upregulated genes. Sixteen transcripts were chosen from the differentially expressed genes for RT-PCR verification assay. The respective genes were HAT1, GAGE4, RPL30, BMP6, VIM, LOX, GNAll, MYBPC2, CASP5, FHL20, KLK10, A20, ANXA2, MYBPC3, SCGB2A2 and TNNT3. The majority of them concurred with existing literature (RPL30, FHL20, ANXA2, KLK10, BMP6, VIM), whereas some the differentially expressed genes represented the novel findings (GAGE4, MYBPC2, CASP5, A20, GNAll). The microarray results obtained from this study were based on only one sample. Therefore this is a preliminary result of gene expression for prostate carcinogenesis. In future, this preliminary microarray result can be strengthened by performing more microarray tests on more samples or through RT-PCR assays. It would be of interest to identify the roles of more candidate genes in the prostate carcinogenesis pathways. It is also necessary in future studies to identify whether alterations of mRNA levels to these genes correspond to the changes in protein levels in prostate cancer.

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