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Note | The possible involvement of gamma-synuclein in tumorigenesis first came to light when a gene named BCSG1 (breast cancer-specific gene 1) was shown to be overexpressed in advanced infiltrating carcinoma of the breast. In fact, BCSG1 and gamma-synuclein appear to be the same protein. SNCG protein is highly expressed in diversified cancer types, including the female hormone-sensitive cervical and breast cancers, male hormone-sensitive prostate cancer, four cancer types of the digestive system, and lung cancer. These cancers are currently the leading cause of mortality in both men and women. How SNCG induces disease progression in different cancer types remains elusive. Oncogenic activation of gamma-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs. Overexpression of gamma-synuclein leads to constitutive activation of extracellular signal-regulated protein kinases (ERK1/ERK2) and down-regulation of c-Jun N-terminal kinase 1(JNK1) in response to environmental stress signals. Gamma-synuclein is found in a wide variety of transformed cells and its overexpression leads to a significant increase in proliferation, motility, invasiveness and metastasis. Cells expressing gamma-synuclein are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. Activation of JNK1 and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma-synuclein-expressing cells, indicating that the apoptosis pathway activated by vinblastine or paclitaxel is blocked by gamma-synuclein. In breast cancer cells, SNCG has been shown to act as a chaperon for estrogen receptor and stimulate estrogen receptor-a signaling pathway that leads to cell proliferation. On the other hand, the inhibitory effects of SNCG on mitotic checkpoint function are mediated through the mitotic checkpoint kinase BubR1 and are independent of the expression status of estrogen receptor-alpha. The inhibitory effects of SNCG on mitotic checkpoint can be overthrown by enforced overexpression of BubR1 in SNCG-expressing cells. SNCG intracellularly associates with BubR1 together. This observation suggests that SNCG expression compromises the mitotic checkpoint control by inhibition of the normal function of BubR1, thereby promoting genetic instability, a recognized and important contributing factor in tumorigenesis. Because all synucleins have chaperone-like activities, they may interact with different proteins in different cellular background. Identifications of specific cellular targets of SNCG in different tumor types will provide insight to delineate its oncogenic functions in human malignancies. |
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Entity | Breast cancer |
Note | Patients whose tumors expressed SNCG had a significantly shorter disease-free survival and overall survival. They also had a high probability of death when compared with those whose tumors did not express SNCG. Multivariate analysis demonstrated that SNCG is an independent predictive marker for recurrence and metastasis in breast cancer progression. SNCG is expected to be a useful marker for breast cancer progression and a potential target for breast cancer treatment. In one study it has been show that responses of 12 breast cancer cell lines to paclitaxel-induced mitotic arrest and cytotoxicity highly correlated with SNCG expression status. SNCG-positive cells exhibited a significantly higher resistance to paclitaxel-induced mitotic arrest than SNCG-negative cells. Down-regulation of SNCG expression directly increased the effectiveness of anti-microtubule drug-induced cytotoxicity in breast cancer cells without altering cell responses to doxorubicin. These new findings suggest that SNCG expression in breast carcinomas is probably a causal factor contributing to the poor patient response to paclitaxel treatment. |
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Entity | Ovarian cancer |
Note | Several studies indicated that SNCG expression was not detectable in normal ovarian epithelium but was highly expressed in the vast majority of advanced staged ovarian carcinomas. Eighty-seven percent of ovarian carcinomas were found to express at least 1 type of synuclein, and 42% expressed all 3 synucleins (alpha, beta, and gamma) simultaneously. Highly punctate gamma synuclein expression was also observed in 20% of preneoplastic lesions of the ovary, including epithelial inclusion cysts, hyperplastic epithelium, and papillary structures, suggesting that synuclein gamma up-regulation may occur early in the development of some ovarian tumors. Demethylation is an important event in abnormal synuclein-gamma expression. The methylation pattern in ovarian cancer cells is different from that in breast cancer cells. In one of the studies that examined SNCG-nonexpressing ovarian cancer cells, all of the CpG sites were completely methylated instead of selective methylation at certain sites shown in breast cancer cells, thereby suggesting a tissue-specific methylation pattern. Recent studies indicated that the detection of SNCG mRNA in tumor-positive tumors was strongly associated with demethylation or hypometylation of SNCG gene. Methylation status was not correlated with FIGO stage or histological type of tumor. Tumor grading was strongly associated with methylation status but due to relatively small group of studied samples (43 cases) this observation requires further confirmation. Another interesting observation was that in 21% of samples both products of amplification were present and all these cases were SNCG mRNA-positive. This observation could suggested that partial methylation of SNCG probably does not influence on synuclein expression in ovarian cancer tissue. Comparison of the methylation status of SNCG and the expression of synuclein-gamma in breast and ovarian cancer cells lines in another study indicated a strong correlation between hypomethylation of the CpG island and SNCG expression in cancer cell lines. The methylation pattern in ovarian cancer cells was different from that in breast cancer cells. The analyzed CpG sites in ovarian cancer cells were all methylated in contrary to a selective methylation at certain sites shown in breast cancer cells, thereby suggesting a tissue-specific methylation pattern. Moreover, when exon 1 was partially and heterogeneously methylated, then SNCG expression in breast cancer cells was not detected. |
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Entity | Lung cancer |
Note | SNCG is not expressed in normal lung tissues, but it is highly expressed in lung tumors. It has been demonstrated that cigarette smoke extract (CSE) has strong inducing effects on SNCG gene expression in lung cancer cells through demethylation of SNCG CpG island. CSE treatment also augments the invasive capacity of cells in an SNCG-dependent manner. These new findings demonstrate that tobacco exposure induces the abnormal expression of SNCG in lung cancer cells through downregulation of expression levels of DNA methyltransferases. |
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Entity | Gastric cancer |
Note | For the gastric cancer cell lines, SNCG mRNA expression strongly correlated with demethylation of SNCG exon 1 CpG islands. Whereas SNCG was not expressed in non-neoplastic gastric mucosal tissues obtained at autopsy, partial demethylation was present in these tissues. Demethylation occurs before malignant transformation and that only partial demethylation does not result in up-regulated SNCG mRNA expression. Thus, it appears that partial SNCG demethylation can occur in normal gastric mucosa, which then extends in some cases to become to fully demethylated, resulting in up-regulated SNCG mRNA expression. |
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Entity | Esophageal cancer |
Note | The examination of the serum γ-synuclein levels of patients with gastrointestinal and esophageal squamous cell carcinomas, benign disease and healthy controls by a sandwich ELISA demonstrated a positive correlation between serum γ-synuclein and the development of these types of cancer. From this study a conclusions was put forward that serum γ-synuclein is a promising diagnostic biomarker for early detection of gastrointestinal and esophageal cancer. Serum γ-synuclein SNCG may play an important role in invasion, infiltration and apoptosis of esophageal cancer and serve as target spots in the targeted therapy of esophageal cancer. However, the analysis of expression pattern of SNCG in another study including 27 cases of esophageal cancer (ESC) demonstrated that it is downregulated in 16 out of 27 cases of ESC. Overexpression of SNCG in ESC 9706 cell line has shown that the ectopic expression of SNCG in ESC cell line inhibits cell growth in dish and colony formation in soft agar. Therefore, unlike breast and ovarian cancers, a reversed correlation between SNCG expression and ESC development was found, which led to a hypothesis that SNCG may play a role of a tumor suppressor in the development of human ESC. |
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Entity | Prostate cancer |
Note | A strong association between SNCG expression and prostate cancer development is found. By performing genomic sequencing and methylation-specific PCR assays, an inclusive demethylation of CpG sites within the CpG island of SNCG gene in prostate cancer samples was established. These results suggest a loss of the epigenetic control of SNCG gene expression in tumors and demonstrate that the demethylation of SNCG CpG island is primarily responsible for the aberrant expression of SNCG in prostate cancerous tissues. A conclusion is drawn that that reactivation of SNCG gene expression by DNA demethylation is a common critical contributing factor to malignant progression of tumors and its expression in primary carcinomas is an effective molecular indicator of distant metastasis. Therefore, the methylation status of SNCG gene can be used as a sensitive molecular tool in early detections of tumorigenesis. Silencing SNCG by siRNA in LNCaP cells contributes to the inhibition of cellular proliferation, the induction of cell-cycle arrest at the G1 phase, the suppression of cellular migration and invasion in vitro, as well as the decrease of tumor growth in vivo with the notable exception of castrated mice. SNCG is a novel androgen receptor (AR) coactivator. It interacts with AR and promotes prostate cancer cellular growth and proliferation by activating AR transcription in an androgen-dependent manner. |
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Entity | Endometrial cancer |
Note | SNCG expression is associated with poor outcome in endometrial adenocarcinoma. There is a positive association between SNCG expression and tumor grade, tumor stage, type II carcinomas, deep myometrial invasion and lymphovascular invasion. A correlation between SNCG and adverse outcomes, such as shorter overall survival and disease free survival is found. The expression level of SNCG in endometrioid endometrial carcinoma is closely associated with International Federation of Gynecology and Obstetrics (IFGO) stages, the depth of myometrial invasion and lymph nodes metastases (p<0.05). SNCG is considered a useful marker for endometrioid endometrial carcinoma invasion, metastasis and prognosis in endometrioid endometrial carcinoma. |
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Entity | Gallbladder cancer |
Note | SNCG is highly expressed in human gallbladder cancer, and its abnormal expression is associated with tumor aggressiveness. SNCG gene silencing in NOZ cells inhibited cell growth, colony formation, and invasion. In addition, it directly increased the effectiveness of paclitaxel in inducing G2/M cell-cycle arrest and cell apoptosis. A decrease in tumor growth and weight was found in mice injected with SNCG-silenced NOZ cells. Together, these findings suggest that SNCG plays an important role in the progression of human gallbladder cancer. |
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Entity | Colon cancer |
Note | Abnormal expression of SNCG protein has been demonstrated in colon cancer. SNCG predicts poor clinical outcome in colon cancer with normal levels of carcinoembryonic antigen (CEA). SNCG levels in colon adenocarcinoma were closely associated with intravascular embolus and tumor recurrence but independent of preoperative serum CEA levels. SNCG expression was an independent prognostic factor of a shorter disease-free survival and overall survival (P < 0.0001). SNCG is a new independent predicator for poor prognosis in patients with colon adenocarcinoma, including those with normal CEA levels. Combination of CEA with SNCG improves prognostic evaluation for patients with colon adenocarcinoma. |
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