Loss of Epigenetic Control of Synuclein-γ Gene as a Molecular Indicator of Metastasis in a Wide Range of Human Cancers

Abstract

Metastasis is a major contributing factor to poor prognosis in cancer. Reliable and sensitive biomarkers that indicate the development of metastasis of primary tumors would be of great clinical use. In this study, we show that the neuronal protein synuclein-; (SNCG) is abnormally expressed in a high percentage (67.5%) of tumor tissues of diversified cancer types, including liver, esophagus, colon, gastric, lung, prostate, cervical, and breast cancer, but rarely expressed in tumormatched nonneoplastic adjacent tissues (0.6%). Expressions of SNCG protein in different cancer types all display stagespecific patterns of very low expression in stage I and high expression in stages II to IV. Importantly, we observe a strong association between SNCG protein expression in primary tumors with distant metastasis in patients regardless of the cancer type (60.6%, P < 0.001). By performing genomic sequencing and methylation-specific PCR assays, we identify an inclusive demethylation of CpG sites within the CpG island of SNCG gene in every tumor sample (100%) across all cancer types, illustrating a universal loss of the epigenetic control of SNCG gene expression in tumors and further demonstrating that the demethylation of SNCG CpG island is primarily responsible for the aberrant expression of SNCG protein in cancerous tissues. These new findings strongly suggest that reactivation of SNCG gene expression by DNA demethylation is a common critical contributing factor to malignant progression of many solid tumors and its expression in primary carcinomas is an effective molecular indicator of distant metastasis. Our studies also suggest that the methylation status of SNCG gene can be used as a sensitive molecular tool in early detections of tumorigenesis. (Cancer Res 2005; 65(17): 7635-43)

Cigarette smoke induces demethylation of prometastatic oncogene synuclein-γ in lung cancer cells by downregulation of DNMT3B

“…Repression of the endogenous SNCG expression by siRNA also inhibited invasion of the H292 cells. Our previous clinical study of 20 lung tumor samples detected SNCG expression in all seven tumor samples from patients with metastatic disease (7/7, 100%), whereas SNCG expression was considerably lower in lung tumors of patients without detectable metastasis (2/13, 15.3%) (Liu et al, 2005). These clinical observations and the results of this current study support the role for SNCG as a prometastatic oncogene.…”

“…SNCG expression has been detected in nine different types of human cancers including lung cancer. SNCG is highly expressed in tumor tissues but not expressed in tumor-matched nonneoplastic adjacent tissues of lung cancer patients (Liu et al, 2005). The SNCG expression in lung tumors shows a correlation with stage progression and metastasis.…”

“…DNA (2 mg) was modified by sodium bisulfite and purified (Palmisano et al, 2000). Genomic sequencing and MNMSP analysis of SNCG CpG island in control and CSE-treated cells were performed as described previously (Liu et al, 2005). An MNMSP approach was developed in this study to examine the changes in methylation status of the promoter regions of TSGs RASSF1A and MGMT, oncogene uPA, and the exon 1 region of SNCG.…”

“…The human synuclein-g (SNCG) gene has been identified as a prometastatic oncogene by our laboratory and other investigators (Li et al, 2004;Liu et al, 2005;Zhao et al, 2006). The normal expression of SNCG is restricted to the brain and periphery neuronal tissues (Lavedan et al, 1998) and its aberrant expression outside neuronal system is highly associated with human malignancies (Ji et al, 1997;Bruening et al, 2000;Wu et al, 2003;Yanagawa et al, 2004;Cao et al, 2005).…”

“…The exon 1 of SNCG gene contains a CpG island with 15 CpG dinucleotides (Lu et al, 2001). By performing genomic sequencing and methylation-specific polymerase chain reaction (MSP) assays, we have shown that the SNCG CpG island is completely unmethylated in lung tumor samples as well as in other types of tumors, which is in sharp contrast to the predominantly methylated CpG island of SNCG in the majority of normal tissues adjacent to tumors (Liu et al, 2005). These previous studies demonstrate that demethylation of the CpG island of SNCG gene is a primary determinant responsible for its aberrant expression in cancerous tissues.…”