IntroductionProstate carcinoma (PRAD) is one of the most frequently diagnosed malignancies amongst men worldwide. It is well-known that androgen receptor (AR) plays a pivotal role in a vast majority of prostate tumors. However, recent evidence emerged stating that estrogen receptors (ERs) may also contribute to prostate tumor development. Moreover, progression and aggressiveness of prostate cancer may be associated with differential expression genes of epithelial-to-mesenchymal transition (EMT). Therefore we aimed to assess the significance of receptors status as well as EMT marker genes expression among PRAD patients in accordance to their age and Gleason score.Materials and methodsWe analyzed TCGA gene expression profiles of 497 prostate tumor samples according to 43 genes involved in EMT and 3 hormone receptor genes (AR, ESR1, ESR2) as well as clinical characteristic of cancer patients. Then patients were divided into four groups according to their age and 5 groups according to Gleason score. Next, we evaluated PRAD samples according to relationship between the set of variables in different combinations and compared differential expression in subsequent groups of patients. The analysis was applied using R packages: FactoMineR, gplots, RColorBrewer and NMF.ResultsMFA analysis resulted in distinct grouping of PRAD patients into four age categories according to expression level of AR, ESR1 and ESR2 with the most distinct group of age less than 50 years old. Further investigations indicated opposite expression profiles of EMT markers between different age groups as well as strong association of EMT gene expression with Gleason score. We found that depending on age of prostate cancer patients and Gleason score EMT genes with distinctly altered expression are: KRT18, KRT19, MUC1 and COL4A1, CTNNB1, SNAI2, ZEB1 and MMP3.ConclusionsOur major observation is that prostate cancer from patients under 50 years old compared to older ones has entirely different EMT gene expression profiles showing potentially more aggressive invasive phenotype, despite Gleason score classification.
Introduction Prostate cancer (PC) is the first cause of fatality related to the reproductive system in men. One out of seven men encounter this pathology once in their lifetime. Prostate Specific Antigen along with digital rectal exam are the first line of screening for prostate pathologies but numerous studies showed that these techniques lack specificity and in sometimes validity for screening. From this notion comes the need to find new biomarkers and molecular players that help get an early detection and effective treatment of PC. Casein Kinase 1 Alpha (CSNK1A1) is an enzyme involved in multiple cellular processes such as the regulation of the oncogenic Wnt/beta-catenin signalling pathway. Its implication in carcinogenesis and cancer progression is still unclear. In this study, we aim to establish a CSNK1A1 expression profile in BPH and in differently advanced PC grades and to investigate the localization of the enzyme compared to beta catenin in the different samples. Material and methods Formalin-fixed paraffin-embedded human prostatic tissues were collected as follows: 85 BPH, 64 PC and 3 controls. Gene expression was assessed by quantitative RT-PCR of cellular transcripts. Protein localization was monitored by tissue immunostaining for CSNK1A1 and Beta-Catenin. Further in-vitro validation of the results is to be made on normal prostate epithelial cell line and PC cell lines using RT-PCR and western blotting. Results and discussions We were able to identify a continuous increase in the CSNK1A1 expression between controls, BPH and PC. These results are being validated in vitro. Preliminary immunostaining results showed membranous beta catenin in BPH and that seemed to be more heterogeneous in PC sections. A correlation with CSNK1A1 localization and amount is still to be achieved. Our results suggest a role of CSNK1A1 in the pathogenesis of BPH and PC by working on the proliferation induction axis, and malignant behaviour of cells. Our staining results suggest a minor role of beta catenin and Wnt pathway in these axes from which emerges the need to deeply investigate the pathways in which CSNK1A1 is implicated in BPH and PC initiation and progression. Conclusion Our results suggest an increase in CSNK1A1 in BPH and PC, which flags this protein as a potential marker in the progression of PC. More investigation is needed to verify whether this protein is involved in cancer initiation or in the direct inhibition of the oncogenic Wnt/beta-catenin signalling pathway and other pathways.
IntroductionCancer initiation and progression mechanisms contingent upon tobacco use are not yet comprehensively understood. In lung adenocarcinoma (LUAD) increased overall mutation rate was attributed to smoking, whereas in bladder cancer (BLCA) reduced suppression of oncogenes in smokers, might have been a distinguishing factor between cancers caused in smokers and never smokers (NS).It is well established that cigarette smoking is a risk factor for BLCA. However it is also found that the risk of BLCA as well as LUAD, might be higher in women than in men when both subjects have smoked comparable amounts of cigarettes, whilst confirmed that smoking cessation reduces the risk of BLCA.Smoking is usually associated with lung cancer however, almost 25% of all lung cancer cases worldwide have been found in NS. Environmental tobacco is a relatively weak carcinogen thus it is a controversial thought to assume that LUAD in NS is due to passive exposure.Material and methodsIn our analyses we used mRNASeq expression and clinical data downloaded from The Cancer Genome Atlas (TCGA), and to perform differential gene expression analysis we used Gene Set Enrichment Analysis (GSEA). We focused on signalling pathways to investigate the molecular biology of the association of TGF-β, Wnt and Notch to explain their contribution to the inter-individual variations associated with smoking status. We will investigate how these three pathways crosstalk and respond to signals from the microenvironment to regulate the expression and function of epithelial mesenchymal transition (EMT) inducing transcription factors in the development and physiology of both cancers.Results and discussionsOf interest our analysis in nonsmokers have showed JAG1 to be underexpressed in LUAD and overexpressed in BLCA contrary to the expression of NOTCH2. Whereas in current smokers ADAM17 as well as PSEN2 have showed underexpression in LUAD but overexpression in BLCA with NOTCH1 presenting a reverse effect.ConclusionOur approach to a pathway specific gene association analysis will help detect the accumulative effect of group of functionally related genes aiding in revealing the transcriptional program accounting for the variability in the phenotype, since cancers arise from the aberrations in multiple genes, several of which have moderate or even less than moderate effects, making them difficult to detect by individual gene analysis.This work was supported by the Medical University of Lodz grant number 503/0-078-02/503-01-004. Authors declare.
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