Prostate cancer is the second leading cause of cancer deaths among American men. The loss of Y chromosome has been frequently observed in primary prostate cancer as well as other types of cancer. Earlier, we showed that introduction of the human Y chromosome suppresses the in vivo tumorigenicity of the prostate cancer cell line PC-3. To further characterize the Y chromosome, we have developed a high-density bacterial artificial chromosome (BAC) microarray containing 178 BAC clones from the human Y chromosome. BAC microarray was used for array comparative genomic hybridization on prostate cancer samples and cell lines. The most prominent observation on prostate cancer specimens was a deletion at Yp11.2 containing the TSPY tandem gene array. Out of 36 primary prostate tumors analyzed, 16 (44.4%) samples exhibited loss of TSPY gene copies. Notably, we observed association between the number of TSPY copies in the blood and the incidence of prostate cancer. Moreover, PC-3 hybrids with an intact Yp11.2 did not grow tumors in nude mice, whereas PC-3 hybrids with a deletion at Yp11.2 grew tumors in nude mice.
"Recent study of the different breeds of Bos taurus confirms gross variation in the copy number of this gene . Significantly, an increase in copy number of tspy in humans is linked with male infertility , while a decrease is associated with prostate cancer . The copy number of tspy ranges 20–60 in human males and 50–200 in bovid males , , which is consistent with our present study. "
[Show abstract][Hide abstract] ABSTRACT: Minisatellites are an integral part of eukaryotic genomes and show variation in the complexity of their organization. Besides their presence in non-coding regions, a small fraction of them are part of the transcriptome, possibly participating in gene regulation, expression and silencing. We studied the minisatellite (TGG)(n) tagged transcriptome in the water buffalo Bubalus bubalis across various tissues and the spermatozoa, and characterized the genes TSPY1 and COL6A1 discovered in the process.
Minisatellite associated sequence amplification (MASA) conducted using cDNA and oligonucleotide primer (TGG)(5) uncovered 38 different mRNA transcripts from somatic tissues and gonads and 15 from spermatozoa. These mRNA transcripts corresponded to several known and novel genes. The majority of the transcripts showed the highest level of expression either in the testes or spermatozoa with exception of a few showing higher expression levels in the lungs and liver. Transcript SR1, which is expressed in all the somatic tissues and gonads, was found to be similar to the Bos taurus collagen type VI alpha 1 gene (COL6A1). Similarly, SR29, a testis-specific transcript, was found to be similar to the Bos taurus testis-specific Y-encoded protein-1 representing cancer/testis antigen 78 (CT78). Subsequently, full length coding sequences (cds) of these two transcripts were obtained. Quantitative PCR (q-PCR) revealed 182-202 copies of the TSPY1 gene in water buffalo, which localized to the Y chromosome.
The MASA approach enabled us to identify several genes, including two of clinical significance, without screening an entire cDNA library. Genes identified with TGG repeats are not part of a specific family of proteins and instead are distributed randomly throughout the genome. Genes showing elevated expression in the testes and spermatozoa may prove to be potential candidates for in-depth characterization. Furthermore, their possible involvement in fertility or lack thereof would augment animal biotechnology.
PLoS ONE 09/2011; 6(9):e24958. DOI:10.1371/journal.pone.0024958 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The human TSPY (testis-specific protein, Y-linked) gene family (30-60 copies) is situated in the MSY (male-specific) region of the Y chromosome. Testis-specific expression indicates that the gene plays a role in spermatogenesis. Refined quantitative fluorescence PCR (polymerase chain reaction) was applied to evaluate the relative number of TSPY copies compared with AMELY/X (amelogenin gene, Y-linked) genes in 84 stratified infertile men and in 40 controls. A significantly higher number of TSPY copies was found in infertile men compared with the controls (P = 0.002). The diagnostic discrimination potential of the relative number of TSPY copies was evaluated by receiver operating characteristic curve analysis. TSPY/AMELY was unambiguously found to be powerful in the diagnostic separation of both the control samples and the infertile men, reaching a good level of specificity (0.642) and sensitivity (0.732) at a cut-off point of 0.46. The findings were supported by independently repeated studies of randomly selected positive samples and controls. Evaluation of the TSPY copy number offers a completely new diagnostic approach in relation to the genetic cause of male infertility. The possible effect of the copy number of TSPY genes on spermatogenesis may explain indiscrete pathological alterations of spermatid quality and quantity.
[Show abstract][Hide abstract] ABSTRACT: Genomic alterations of chromosome 18q have been observed in prostate cancer. This research focuses on analyzing the role of increased gene copy number at chromosome 18q22.1 in prostate cancer. We believe the key genes in this region are the type II cadherins. We are studying the role of overexpression of these genes, particularly cadherin 7 (CDH7), on the tumorigenicand invasive potential of prostate cancer cells. We have shown the minimal region of increased copy number contains CDH7. This increased copy number of CDH7 is specific to prostate cancer and is not found in II other common cancers. The increased copy number of CDH7 also results in increased levels of cadherin-7 mRNA in prostate tumors. We are purifying polyclonal antibodies against cadherin-7 to use in immunohistochemistry experiments to determine if increased CDH7 copies results in increased levels of protein. We performed knockdown experiments of the cadherin-7 mRNA in a prostate cancer cell line and are analyzingthe cadherin-7 protein levels in these cells. We will subsequently evaluate these cellswith reduced cadherin-7 expression for their invasive and tumorigenic potential.
Bereket Mochona, Elizabeth Mazzio, Madhavei Gangapurum, Nelly Mateeva, K K Redda
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