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: Alpha Synuclein (α-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). α-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether α-Syn expression affects tumorigenesis of three types of tumors. Specifically, B16 melanoma, E0771 mammary gland adenocarcinoma and D122 Lewis lung carcinoma. For this aim, we utilized transgenic mice expression the human A53T α-Syn form. We found that the in vivo growth of B16 and E0771 but not D122 was enhanced in the A53T α-Syn mice. The effect on tumorigenesis was not detected in age-matched APP/PS1 mice, modeling Alzheimer's disease (AD), suggesting a specific effect for α-Syn-dependent neurodegeneration. Importantly, transgenic α-Syn expression was detected within the three tumor types. We further show uptake of exogenously added, purified α-Syn, by the cultured tumor cells. In accord, with the affected tumorigenesis in the young A53T α-Syn mice, over-expression of α-Syn in cultured B16 and E0771 cells enhanced proliferation, however, had no effect on the proliferation of D122 cells. Based on these results, we suggest that certain forms of α-Syn may selectively accelerate cellular mechanisms leading to cancer.PLoS ONE 01/2011; 6(5):e19622. · 3.53 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: Pancreatic Adenocarcinoma (PDAC), the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS) and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX). A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7) and Alpha Synuclein (aSyn), both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP) which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC.PLoS ONE 01/2011; 6(3):e17177. · 3.53 Impact Factor