Splice variant PRKC-ζ-PrC is a novel biomarker of human prostate cancer

Abstract

Background:Previously, using gene-knockdown techniques together with genome expression array analysis, we showed the gene protein Kinase C (PKC)-zeta (PRKCZ) to mediate the malignant phenotype of human prostate cancer. However, according to NCBI, the gene has undergone several major iterations. Therefore, to understand the relationship between its structure and biological activities, we have analysed its expressed sequence in prostate cancer cell lines and tissues.Methods:Transcriptome-walking and targeted PCR were used to sequence the mRNA transcribed from PRKCZ. Hydropathy analysis was employed to analyse the hypothetical protein sequence subsequently translated and to identify an appropriate epitope to generate a specific monoclonal antibody.Results:A novel sequence was identified within the 3′-terminal domain of human PRKCZ that, in prostate cancer cell lines and tissues, is expressed during transcription and thereafter translated into protein (designated PKC-ζ-PrC) independent of conventional PKC-ζ-a. The monoclonal antibody detected expression of this 96 kD protein only within malignant prostatic epithelium.Interpretation:Transcription and translation of this gene sequence, including previous intronic sequences, generates a novel specific biomarker of human prostate cancer. The presence of catalytic domains characteristic of classic PKC-β and atypical PKC-ι within PKC-ζ-PrC provides a potential mechanism for this PRKCZ variant to modulate the malignant prostatic phenotype out-with normal cell-regulatory control.

Altered Endosome Biogenesis in Prostate Cancer Has Biomarker Potential

“…The prostate specific antigen is still commonly used to detect prostate cancer, but has significant problems in terms of miss-diagnosis and prognostic prediction (see for example: 26). Some promising adjunct tests have recently been developed including prostate cancer antigen 3 (PCA3) (27), the analysis of cholesterol sulphate (28) and a novel sequence of the gene protein kinase C-zeta ( PRKCZ ), which is translated to the protein PRKC-ζ- PrC (29). However, these biomarkers do not provide early and accurate detection of prostate cancer, which is needed to enable the selection of the most appropriate therapeutic intervention and to avoid potential overtreatment (2).…”

Transcriptome sequencing of human breast cancer reveals aberrant intronic transcription in amplicons and dysregulation of alternative splicing with major therapeutic implications

“…Intronic L1s, Alus and other retroelements (enigmatic dark matter) affect transcription and gene expression via exon skipping and exonisation using cryptic splice sites, forcing exonisation and cryptic polyadenylation so genes acquire new exons from intronic or intergenic sequences thereby generating novel alternatively spliced variants (41,48). Recently, we described intronic exonisation in human prostate cancer, suggesting that this phenomenon is likely to be common to many different malignancies (49). In normal somatic cells, this sequence compartment is attenuated by epigenetic silencing mechanisms involving dNA methylation and chromatin-mediated repression to maintain genomic integrity (45,50,51).…”

“…Since such tumour-specific sequences encompass transcripts not included in RefSeq exons or revealed by exome analysis, studies should be extended beyond the limits of individual exomes if the full extent of cancer transcription and exploitation of intronic and intergenic sequences is to be uncovered. Such previously unrecognised transcription and translation from amplified or disrupted oncogenes will generate RNA transcripts and proteins with altered size structures, functions and subcellular localisations similar to those detected in prostate cancer (49). drug development has been predicated on targeting normal full-length RefSeq proteins with domains such as external, transmembrane and TK domains in RTKs.…”

Towards improved genome-scale metabolic network reconstructions: unification, transcript specificity and beyond

“…Furthermore, switch-like effects, where variants lose their dominant position in favour of other variants, were observed for hundreds of genes during differentiation [68, 69], demonstrating the plasticity of a tightly regulated process. Alterations of the latter are implicated in numerous pathologies, especially in cancer, and several splice variants are even considered as biomarkers, like PRKC- ζ -PrC for prostate cancer, Nek2C for breast cancer and CD-44 splice variants for colon cancer [70–72]. …”