The contribution of specific genes on the Y chromosome in the etiology of prostate cancer has been undefined. Genetic mapping studies have identified a gonadoblastoma locus on the human Y chromosome (GBY) that predisposes the dysgenetic gonads of XY sex-reversed patients to tumorigenesis. Recently a candidate gene, the testis-specific protein Y-encoded (TSPY) that resides on the GBY critical region, has been demonstrated to express preferentially in tumor cells in gonadoblastoma and testicular germ cell tumors. TSPY shares high homology to a family of cyclin B binding proteins and has been considered to possibly play a role in cell cycle regulation or cell division. To address the possible involvement of the TSPY gene in prostate cancer, both in situ mRNA hybridization and immunohistochemistry techniques were used to study the expression of this putative GBY gene in prostate specimens. Our results demonstrated that TSPY was expressed at low levels in normal epithelial cells and benign prostatic hyperplasia (BPH), but at elevated levels in tumor cells of prostate cancers at various degrees of malignancy. Sequence analysis of RT-PCR products obtained from both prostatic and testicular tissues using specific primers flanking the open reading frame of the TSPY mRNA revealed a complex pattern of RNA processing of the TSPY transcripts involving cryptic intron splicing and/or intron skipping. The variant transcripts encode a variety of polymorphic isoforms or shortened versions of the TSPY protein, some of which might possess different biochemical and/or functional properties. The abbreviated transcripts were more abundant in prostatic cancer tissues than the testicular ones. Although the exact nature of such variant TSPY transcripts and proteins is still unclear, their differential expression suggests that the TSPY gene may also be involved in the multi-step prostatic oncogenesis besides its putative role in gonadoblastoma and testicular seminoma.
The gonadoblastoma locus on the Y chromosome (GBY) predisposes the dysgenetic gonads of XY females to develop in situ tumors. It has been mapped to a critical interval on the short arm and adjacent centromeric region on the Y chromosome. Currently there are five functional genes identified on the GBY critical region, thereby providing likely candidates for this cancer predisposition locus. To evaluate the candidacy of one of these five genes, testis-specific protein Y-encoded (TSPY), as the gene for GBY, expression patterns of TSPY in four gonadoblastoma from three patients were analyzed by immunohistochemistry using a TSPY specific antibody. Results from this study showed that TSPY was preferentially expressed in tumor germ cells of all gonadoblastoma specimens. Additional study on two cases of testicular seminoma demonstrated that TSPY was also abundantly expressed in all stages of these germ cell tumors. The present observations suggest that TSPY may either be involved in the oncogenesis of or be a useful marker for both types of germ cell tumors.
The regulation of MUC2, a major goblet cell mucin gene, was examined by constructing transgenic mice containing bases −2864 to +17 of the human MUC25′-flanking region fused into the 5′-untranslated region of a human growth hormone (hGH) reporter gene. Four of eight transgenic lines expressed reporter. hGH message expression was highest in the distal small intestine, with only one line expressing comparable levels in the colon. This contrasts with endogenous MUC2 expression, which is expressed at its highest levels in the colon. Immunohistochemical analysis indicated that goblet cell-specific expression of reporter begins deep in the crypts, as does endogenous MUC2 gene expression. These results indicate that the MUC2 5′-flanking sequence contains elements sufficient for the appropriate expression of MUC2 in small intestinal goblet cells. Conversely, elements located outside this region appear necessary for efficient colonic expression, implying that the two tissues utilize different regulatory elements. Thus many, but not all, of the elements necessary for MUC2 gene regulation reside between bases −2864 and +17 of the 5′-flanking region.
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