Synuclein-γ Is Closely Involved in Perineural Invasion and Distant Metastasis in Mouse Models and Is a Novel Prognostic Factor in Pancreatic Cancer

Abstract

Purpose: Perineural invasion is associated with the high incidence of local recurrence and a dismal prognosis in pancreatic cancer. We previously reported a novel perineural invasion model and distinguished high^and low^perineural invasion groups in pancreatic cancer cell lines. This study aimed to elucidate the molecular mechanism of perineural invasion. Experimental Design: To identify key biological markers involved in perineural invasion, differentially expressed molecules were investigated by proteomics and transcriptomics. Synuclein-g emerged as the only up-regulated molecule in high^perineural invasion group by both analyses. The clinical significance and the biological property of synuclein-g were examined in 62 resected cases of pancreatic cancer and mouse models. Results: Synuclein-g overexpression was observed in 38 (61%) cases and correlated with major invasive parameters, including perineural invasion and lymph node metastasis (P < 0.05).Multivariate analyses revealed synuclein-g overexpression as the only independent predictor of diminished overall survival [hazard ratio, 3.4 (95% confidence interval, 1.51-7.51)] and the strongest negative indicator of disease-free survival [2.8 (1.26-6.02)]. In mouse perineural invasion and orthotopic transplantation models, stable synuclein-g suppression by short hairpin RNA significantly reduced the incidence of perineural invasion (P = 0.009) and liver/lymph node metastasis (P = 0.019 and P = 0.020, respectively) compared with the control. Conclusions: This is the first study to provide in vivo evidence that synuclein-g is closely involved in perineural invasion/distant metastasis and is a significant prognostic factor in pancreatic cancer. Synuclein-g may serve as a promising molecular target of early diagnosis and anticancer therapy.

Synuclein γ Compromises Spindle Assembly Checkpoint and Renders Resistance to Antimicrotubule Drugs

“…These studies suggest that SNCG can be used as biomarker for docetaxel resistance. Interestingly, although the SNCG gene does not have a signal peptide, suggesting it is not a secreted protein, a secreted form of SNCG can be detected in sera of pancreatic (22) and colon (20) cancer and urine samples of bladder cancer (23). In these studies, SNCG protein is abnormally detected in a high percentage in sera (20,22) or urine samples (23) of patients with cancer but rarely expressed in healthy controls.…”

“…Interestingly, although the SNCG gene does not have a signal peptide, suggesting it is not a secreted protein, a secreted form of SNCG can be detected in sera of pancreatic (22) and colon (20) cancer and urine samples of bladder cancer (23). In these studies, SNCG protein is abnormally detected in a high percentage in sera (20,22) or urine samples (23) of patients with cancer but rarely expressed in healthy controls. Identification of cellular factors, particularly a soluble serum factor, that are associated with the sensitivity to docetaxel-based treatment and development of a predictive/prognostic marker to identify responders and nonresponders would have great clinical implications.…”

“…Although synucleins are highly expressed in neuronal cells and have been specifically implicated in neurodegenerative diseases (14,15), SNCG is not clearly involved in neurodegenerative diseases but is primarily involved in neoplastic diseases. So far, the abnormal expression of SNCG protein has been demonstrated in many different malignant diseases, including breast (12,16,17), liver (18,19), esophagus (18), colon (18,20,21), gastric (18), lung (18), prostate (18), pancreas (22), bladder (23), cervical cancers (18), ovarian cancer (24), and glial tumors (25). In these studies, SNCG protein is abnormally expressed in a high percentage of tumor tissues but rarely expressed in tumor-matched nonneoplastic adjacent tissues.…”

A Novel Serum Metabolomics-Based Diagnostic Approach to Pancreatic Cancer

“…Screening tests for the general population have to be accurate, safe, and convenient, as well as capable of high throughput. Many researchers have devoted considerable effort to discovering biomarkers of pancreatic cancer (8)(9)(10), and CA242 (11), M2-pyruvate kinase (12), PBF-4 (13), MIC-1 (14), PNA-binding glycoprotein (15), hTert (16), MMP-2 (17), and synuclein-g (18) have been reported as candidate biomarkers, but they were not clinically superior to CA19-9 or other clinical examinations.…”

Novel Biomarkers in Pancreatic Cancer

“…Increased expression of aSyn has been also identified in melanoma , while its isoform gamma-synuclein (cSyn) has been shown to be elevated in tumors of breast, uterine, colorectal and pancreas (Ye et al, 2009;Hibi et al, 2009;Ahmad et al, 2007;Li et al, 2004;Gupta et al, 2003;Jia et al, 1999;Morgan et al, 2009). Moreover, due to the structural omology between cSyn and aSyn, these factors potentiate invasion in these tumors.…”