Alternative splicing enhances proteome diversity and modulates cancer-associated proteins. To identify tissueand tumor-specific alternative splicing, we used the GeneChip Human Exon 1.0 ST Array to measure wholegenome exon expression in 102 normal and cancer tissue samples of different stages from colon, urinary bladder, and prostate. We identified 2069 candidate alternative splicing events between normal tissue samples from colon, bladder, and prostate and selected 15 splicing events for RT-PCR validation, 10 of which were successfully validated by RT-PCR and sequencing. Furthermore 23, 19, and 18 candidate tumor-specific splicing alterations in colon, bladder, and prostate, respectively, were selected for RT-PCR validation on an independent set of 81 normal and tumor tissue samples. In total, seven genes with tumor-specific splice variants were identified (ACTN1, CALD1, COL6A3, LRRFIP2, PIK4CB, TPM1, and VCL). The validated tumor-specific splicing alterations were highly consistent, enabling clear separation of normal and cancer samples and in some cases even of different tumor stages. A subset of the tumor-specific splicing alterations (ACTN1, CALD1, and VCL) was found in all three organs and may represent general cancer-related splicing events. In silico protein predictions suggest that the identified cancerspecific splice variants encode proteins with potentially altered functions, indicating that they may be involved in pathogenesis and hence represent novel therapeutic targets. In conclusion, we identified and validated alternative splicing between normal tissue samples from colon, bladder, and prostate in addition to cancerspecific splicing events in colon, bladder, and prostate Alternative splicing is a key component in expanding a relatively limited number of genes into very complex proteomes. It has been estimated that about three-quarters of all human genes undergo alternative splicing (1-3), which may affect function, localization, binding properties, and stability of the encoded proteins (4). The recent results from the ENCODE (Encyclopedia of DNA Elements) consortium (5) extend and confirm the ubiquity of alternative splicing (6). Several splice variants with antagonistic functions have been described, e.g. BCL-X has an antiapoptotic long isoform and a proapoptotic short isoform (7,8). Alternative splicing can also lead to degradation of the transcript, thereby abrogating protein expression; examples include certain Serine/Arginine-rich (SR) protein splicing factors for which the inclusion of a particular exon causes mRNA degradation by nonsense-mediated decay (9, 10).Single nucleotide polymorphisms and somatic splice site mutations leading to aberrant splicing patterns have been described for a number of tumor suppressor genes, including APC, TP53, and BRCA1 (11). Deregulation of trans-acting proteins, such as splicing factors and heterogeneous nuclear ribonucleoproteins, may cause a more general change in RNA splicing in cancer cells. The SFRS1 gene, encoding the splicing factor 2/alternate spli...
K E Y W O R D S: ConclusionThe performance of first-trimester biochemical screening for trisomy 21 is best at 9-10 weeks rather than at 7-8 or 11-14 weeks.
Objective To estimate the difference between levels of the two biochemical markers pregnancy-associated plasma protein-A (PAPP-A
Purpose:Through cDNA array analyses and immunohistochemistry on tissue microarrays, trefoil factor 3 (TFF3) was recently shown to be overexpressed in prostate cancer. The purpose of this study was to test the feasibility of using the levels of trefoil factors as a plasma marker for prostate cancer. Experimental Design: In 79 patients with prostate cancer, 23 patients with benign prostatic hyperplasia, and 44 healthy individuals plasmaTFF1,TFF2, andTFF3 were determined with ELISAs and compared with clinical stage and prostate-specific antigen (PSA) values. Plasma levels of TFF were compared with the immunohistochemical expression of TFF and chromogranin A in 30 prostate cancer tissue samples. Results: Patients with advanced prostate cancer had significantly higher plasma concentrations of TFF1, TFF2, and TFF3 (P < 0.01) compared with patients with localized disease. Using a cutoff of 200 pmol/L, the sensitivity and specificity of plasma TFF3 in differentiating between patients with localized and advanced disease was 74% (59-85%) and 81% (66-91%). Plasma levels of TFF3 were highest in patients with bone metastases (P = 0.008). Patients with serum PSA >10 Ag/L had significantly higher plasma TFF3 values than patients with serum PSA <10 Ag/L (P = 0.03) and TFF3 levels were higher in patients with Gleason sums of z7 (P = 0.02).Expression ofTFF1andTFF3 determined by immunohistochemistry was increased in patients with prostate cancer but did not correlate with plasma trefoil factor values. Conclusions: Plasma levels of trefoil factors are increased in patients with advanced prostate cancer. Prospective studies are needed to confirm the predictive utility of trefoil factors in prostate cancer.
Trefoil factors, mucin-associated peptides, are overexpressed in prostate cancer (PC). We hypothesized that promoter methylation contributes to the regulation of trefoil factors (TFF1, TFF2 and TFF3) in human prostate cells. Here we show hypomethylation of promoter regions of TFF1 and TFF3 in PC cell lines with significant TFF expression as compared to benign immortalized prostate cell lines and PC cell lines not expressing trefoil factor. The most striking difference was observed for CpG sites located close to the AUG start codon overlapping several putative binding sites for cellular transcription factors. TFF2 was hypermethylated and had no or very low expression in all prostate cell lines investigated. Treatment of methylated cell lines with 5-aza-2 0 -deoxycytidine restored TFF expression in cell lines not expressing TFF and increased expression significantly in low-expressing cell lines. In clinical samples, methylation of the promoter/enhancer regions of TFF1 and TFF3 was significantly lower in PC compared to benign prostatic hyperplasia. The present study shows an inverse relation between promoter methylation and expression of trefoil factors. Preliminary analysis on clinical samples suggests that this regulatory mechanism is responsible for the increased levels of TFF1 and TFF3 observed in PC. The overexpression and promoter hypomethylation of trefoil factors may serve as biomarkers in PC.
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