Genome-wide detection of testis- and testicular cancer-specific alternative splicing

Abstract

Alternative pre-messenger RNA (mRNA) splicing is a key molecular event that allows for protein diversity and plays important roles in development and disease. Alternative pre-mRNA splicing regulations during spermatogenesis and alternative pre-mRNA splicing etiology in testicular tumorigenesis are yet to be characterized. By genome-wide analysis, here we describe alternative splicing features that distinguish distinctive patterns of alternative pre-mRNA splicing among human testis, testicular cancer and mouse testis. Through computationally subtractive analysis, we detected 80 testis-specific transcript candidates in human testis, 175 in human testicular cancer and 262 in mouse testis, which were integrated into a database. Reverse transcription-polymerase chain reaction confirmed that most of these transcript candidates from mouse testis were testis specific. Around 40% of the transcripts were from unknown/hypothetical genes, which were useful for further functional analysis. These transcripts were not overlapped, indicating lack of evolutionary conservation. Further chromosome mapping showed distinct chromosomal preference of alternative pre-mRNA splicing events. Comparison analysis indicated that alternative pre-mRNA splicing in human testicular tumor shared some characters/trends with those in mouse testis. Moreover, human testicular tumor tended to use rare splice sites and there were also distinct sequences adjacent dominant splice sites between normal testis and testicular tumor. These special features of alternative pre-mRNA splicing in human testicular tumor suggested that testicular tumorigenesis was involved in multiple steps/levels of alternative splicing events. Using alternative splicing as a potential source for new clinical diagnostic, prognostic and therapeutic strategies for treatment of testicular tumors seems to have a bright prospect.

Alternative splicing and breast cancer

“…Evidence for wide changes in alternative splicing in cancer is present in EST databases, where a large fraction of variants are actually tumor specific. [50][51][52][53] Interestingly, Ritchie and collaborators recently found that the number of different splicing variants produced from a single gene was higher in a cancer tumor than in its normal counterpart tissue. 52 In contrast, an EST-based study by Kim and collaborators indicated that, in general, alternative splicing was less prevalent in cancerous than normal tissues.…”

Desmosomal Cadherins in Basal Cell Carcinomas

“…AS is a common phenomenon and more than 90% human genes are alternatively spliced (Pan et al, 2008;Wang et al, 2008). It is known that AS is involved in numerous human diseases (Kim et al, 2007), thus accumulating evidence revealed that aberrant splicing contributes to human neoplasms (Miura et al, 2011;Xing, 2007;Kim et al, 2007;Venables, 2006;He et al, 2007;Srebrow & Kornblihtt, 2006). However, in only few cases it has been proved, e.g.…”

“…In light of this, oligonucleotide microarrays containing exon junction probes may be a powerful tool to investigate tissue-specific regulation of AS taking place in BCC (Nagao et al, 2005). Literature data may suggest that AS should be regarded as a potential source for new clinical diagnostic, prognostic and therapeutic strategies in cancer (He et al, 2007).…”

CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

“…3 Particularly, the splice variants differ between cancer and normal corresponding tissues. 4,5 Cancerspecific splice variants are thus of significant interest as they may be involved in pathogenesis and may further potentially be used as biomarkers and generate novel targets for therapy. Because immune recognition of antigenic epitopes is highly specific, alternative exon splicing could provide the structural basis for expression of novel amino-acid sequences not subject to self repertoire tolerance.…”