Expression of alpha-, beta- and gamma-synuclein in colorectal cancer, and potential clinical significance in progression of the disease.
ABSTRACT The synucleins (alpha-, beta- and gamma-synuclein) are a small, soluble, highly conserved group of neuronal proteins that attracted considerable attention due to their involvement in both neurodegenerative diseases and cancer. In this study, we examined the synuclein exprsssion in colorectal cancer (CRC) tissues, tumor-matched non-neoplastic adjacent tissues (NNAT), and CRC cell lines, and then investigated clinical significance of synucleins. By using semi-quantitative RT-PCR, synuclein mRNA expression was detected in eight CRC cell lines. It was much higher in CRC samples than in NNAT samples (P<0.05). The results of western blotting showed that the levels of synucleins protein expression in CRC cells approximately corresponded to the levels of synuclein mRNA expression. Immunohistochemical staining revealed that gamma-synuclein protein expression was up-regulated in CRC samples compared to NNAT samples (P=0.022), and was significantly correlated with clinical stage and lymph node involvement of CRC (P<0.05). Although, there was no significant difference in either alpha- or beta-synuclein protein expression between tumor and normal samples (P>0.05), often more than one form of synuclein was expressed in a tumor sample. More ratios of later stage and lymph node-positive tumors expressed a least one type of synuclein protein, and more ratios showed positive for either alpha or gamma-synuclein expression, as well as positive either for beta or gamma-synuclein in more ratios of lymph node-positive tumors. These results show that alpha-, beta- and gamma-synuclein are expressed in a high percentage of CRC. gamma-synuclein protein is valuable for evaluation of progression of CRC, and it is more sensitive to predict advanced stage and lymph node invasion by detection of gamma-synuclein protein combined with either alpha- or beta-synuclein protein or both than by detection of gamma-synuclein only.
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ABSTRACT: BACKGROUND Docetaxel-resistance limits successful treatment of castration resistant prostate cancer. We previously demonstrated that extracellular vesicles (exosomes) may play a role in regulating docetaxel resistance. Here, we investigated intracellular and extracellular (exosomal) miRNAs related to docetaxel resistance.METHODS Following global miRNA profiling of cell line models of docetaxel-resistance and their corresponding exosomes, we investigated the clinical relevance of four selected miRNAs (miR-598, miR-34a, miR-146a, miR-148a) in four publically available clinical cohorts representing both primary and advanced disease in tissue and urine specimens. One of these miRNAs, miR-34a was selected for functional evaluation by miRNA inhibition and over-expression in vitro. We further assessed the panel of miRNAs for their combined clinical relevance as a biomarker signature by examining their common predicted targets.RESULTSA strong correlation was found between the detection of miRNAs in exosomes and their corresponding cells of origin. Of the miRNAs chosen for further validation and clinical assessment, decreased miR-34a levels showed substantial clinical relevance and so was chosen for further analysis. Manipulating miR-34a in prostate cancer cells confirms that this miRNA regulates BCL-2 and may, in part, regulate response to docetaxel. When combined, these miRNAs are predicted to regulate a range of common mRNA targets, two of which (e.g., SNCA, SCL7A5) demonstrate a strong relationship with prostate cancer progression and poor prognosis.CONCLUSIONS This study supports the extracellular environment as an important source of minimally invasive predictive biomarkers representing their cellular origin. Using miR-34a as example, we showed that biomarkers identified in this manner may also hold functional relevance. Prostate © 2014 The Authors. The Prostate, published by Wiley Periodicals, Inc.The Prostate 07/2014; · 3.84 Impact Factor
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ABSTRACT: Approximately 75 % of extraskeletal myxoid chondrosarcoma tumors (EMC) harbor a t(9;22) chromosome translocation generating an EWS/NR4A3 fusion protein that is thought to be instrumental in the tumoral process. Current evidence suggests that one function of the fusion protein is to overexpress target genes. We have generated an in vitro human cellular model in which the fusion protein is expressed in mesenchymal bone marrow stem cells. We have performed microarray analyses of these cells and identified several genes overexpressed in the presence of EWS/NR4A3 which are also overexpressed in EMC tumors. These genes and their products represent potential therapeutic targets for EMC tumors.Tumor Biology 05/2012; 33(5):1599-605. · 2.52 Impact Factor
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ABSTRACT: The relatively high co-occurrence of Parkinson's disease (PD) and melanoma has been established by a large number of epidemiological studies. However, a clear biological explanation for this finding is still lacking. Ultra-violet radiation (UVR)-induced skin melanin synthesis is a defense mechanism against UVR-induced damage relevant to the initiation of melanoma, whereas, increased neuromelanin (NM), the melanin synthesized in dopaminergic neurons, may enhance the susceptibility to oxidative stress-induced neuronal injury relevant to PD. SNCA is a PD-causing gene coding for alpha-Synuclein (α-Syn) that expresses not only in brain, but also in skin as well as in tumors, such as melanoma. The findings that α-Syn can interact with tyrosinase (TYR) and inhibit tyrosine hydroxylase (TH), both of which are enzymes involved in the biosynthesis of melanin and dopamine (DA), led us to propose that α-Syn may participate in the regulation of melanin synthesis. In this study, by applying ultraviolet B (UVB) light, a physiologically relevant stimulus of melanogenesis, we detected melanin synthesis in A375 and SK-MEL-28 melanoma cells and in SH-SY5Y and PC12 dopaminergic neuronal cells and determined effects of α-Syn on melanin synthesis. Our results showed that UVB light exposure increased melanin synthesis in all 4 cell lines. However, we found that α-Syn expression reduced UVB light-induced increase of melanin synthesis and that melanin content was lower when melanoma cells were expressed with α-Syn, indicating that α-Syn may have inhibitory effects on melanin synthesis in melanoma cells. Different from melanoma cells, the melanin content was higher in α-Syn-over-expressed dopaminergic neuronal SH-SY5Y and PC12 cells, cellular models of PD, than that in non-α-Syn-expressed control cells. We concluded that α-Syn could be one of the points responsible for the positive association between PD and melanoma via its differential roles in melanin synthesis in melanoma cells and in dopaminergic neuronal cells.PLoS ONE 01/2012; 7(9):e45183. · 3.73 Impact Factor