Synuclein-γ (SNCG) expression in ovarian cancer is associated with high-risk clinicopathologic disease

Strohl, Anna E.; Mori, Kristina M.; Akers, Stacey N.; Bshara, Wiam; Buttin, Barbara M.; Frederick, Peter J.; Helenowski, Irene; Morrison, Carl; Odunsi, Kunle; Schink, Julian C.; Scholtens, Denise M.; Wei, Jian Jun; Kim, Julie

doi:10.1186/s13048-016-0281-4

Cited by 14 publications

(16 citation statements)

References 20 publications

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“…This could explain why members of the synuclein family are found in non-neural cells, where they are not involved in synaptic transmission. For instance, synuclein family members are upregulated in certain cancers: alpha-synuclein in melanoma 67 ; and gamma-synuclein in breast 68,69 , prostate 70 , bladder 71 , uterine 72 and ovarian 73 cancer. Since we postulate that alpha-synuclein’s normal nuclear DNA binding and DDR functions may be conserved amongst the other family members, it will be important to test whether the synucleins could also be participating in the DDR in these forms of cancer.…”

Section: Discussionmentioning

confidence: 99%

Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders

Schaser

Osterberg

Dent

et al. 2019

Sci Rep

192

207

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Alpha-synuclein is a presynaptic protein that forms abnormal cytoplasmic aggregates in Lewy body disorders. Although nuclear alpha-synuclein localization has been described, its function in the nucleus is not well understood. We demonstrate that alpha-synuclein modulates DNA repair. First, alpha-synuclein colocalizes with DNA damage response components within discrete foci in human cells and mouse brain. Removal of alpha-synuclein in human cells leads to increased DNA double-strand break (DSB) levels after bleomycin treatment and a reduced ability to repair these DSBs. Similarly, alpha-synuclein knock-out mice show increased neuronal DSBs that can be rescued by transgenic reintroduction of human alpha-synuclein. Alpha-synuclein binds double-stranded DNA and helps to facilitate the non-homologous end-joining reaction. Using a new, in vivo imaging approach that we developed, we find that serine-129-phosphorylated alpha-synuclein is rapidly recruited to DNA damage sites in living mouse cortex. We find that Lewy inclusion-containing neurons in both mouse model and human-derived patient tissue demonstrate increased DSB levels. Based on these data, we propose a model whereby cytoplasmic aggregation of alpha-synuclein reduces its nuclear levels, increases DSBs, and may contribute to programmed cell death via nuclear loss-of-function. This model could inform development of new treatments for Lewy body disorders by targeting alpha-synuclein-mediated DNA repair mechanisms.

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Section: Discussionmentioning

confidence: 99%

Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders

Schaser

Osterberg

Dent

et al. 2019

Sci Rep

192

207

View full text Add to dashboard Cite

show abstract

“…Recently, a growing number of reports have described the function of SNCG in tumors. Strohl et al have shown that high expression of SNCG is bound up with invasion and development in ovarian cancer 8 . In MCF7 breast cancer cells, SNCG is also overexpressed, activating extracellular signal‐regulated kinase pathways and disrupting intercellular connections, which leads to cell migration, so it may also be a predictive marker for breast cancer 24 .…”

Section: Discussionmentioning

confidence: 99%

“…The synuclein protein family is a small, soluble proteome composed of synuclein‐α, synuclein‐β and synuclein‐γ (SNCG), originally found in brain tissue, peripheral nerve tissue, and retina, which is involved in neurodegenerative diseases and cancers 6 . In recent years, researchers have found that SNCG is highly expressed in breast cancer, 7 ovarian cancer, 8 and bladder cancer 9 . The role of SNCG in cancer progression has been extensively studied.…”

Section: Introductionmentioning

confidence: 99%

Assessment of serum synuclein‐γ and squamous cell carcinoma antigen as diagnostic biomarkers in patients with oral squamous cell carcinoma and oral potentially malignant disorders

Chen

Luo

Yang

et al. 2020

J Oral Pathology Medicine

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Background Clinical diagnosis and monitoring are crucial to reduce the mortality from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). It has been demonstrated that synuclein‐γ (SNCG) and squamous cell carcinoma antigen (SCCAg) are highly expressed in patients with OSCC and perhaps participate in OSCC progression. This study analyzed the levels of serum SNCG and SCCAg in OSCC, OPMD, and control patients, and evaluated the diagnostic and clinical value of single and combined detection of serum SNCG and SCCAg in OSCC and OPMDs. Patients and methods Serum samples were collected from 197 patients including 87 patients with OSCC, 30 patients with OPMDs, and 80 healthy volunteers as controls. Enzyme‐linked immunosorbent assay and statistical analysis were utilized to determine SNCG and SCCAg levels in serum. Results The levels of SNCG and SCCAg in serum were significantly higher in OSCC compared with OPMDs and controls. There was a correlation between SNCG level and ethnicity, and SCCAg was correlated with differentiation. Furthermore, the area under the curves, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of combined detection of SNCG and SCCAg were better than any single detection. Conclusion The combined detection of SNCG and SCCAg in serum could become a new standard method to distinguish between OSCC and OPMDs and improve diagnostic performance for OSCC.

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“…Synuclein family members (α, β and γ) have been extensively studied since their discovery thirty years ago due to their involvement in human pathology, mainly Parkinson's disease and cancer [ 26 , 27 ]. Thus, synuclein-γ (SNCG) abnormal expression has been described in a wide range of human cancer such as endometrial [ 28 ], bladder [ 29 ], prostate [ 30 ], ovarian [ 31 ], gastric [ 32 ], liver [ 33 ], lung [ 34 ], colon [ 35 ], and breast [ 5 , 6 ]. In ovarian and breast carcinoma, hypomethylation of SNCG gene CpG island is responsible for aberrant SNCG expression.…”

Section: Discussionmentioning

confidence: 99%

Synuclein gamma expression enhances radiation resistance of breast cancer cells

et al. 2018

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Resistance to therapy is a major obstacle for the effective treatment of cancer. Expression of synuclein-gamma (SNCG) has been associated with poor prognosis and resistance to therapy. While reports on SNCG overexpression contributing to chemoresistance exist, limited information is available on the relationship between SNCG and radioresistance of cancer cells. Here we investigated the role of SNCG in radiation resistance in breast cancer cells. siRNA mediated knockdown of SNCG (siSNCG) markedly reduced SNCG protein level compared to scrambled siRNA (siScr) treatment. Furthermore, siSNCG treatment sensitized Estrogen Receptor-positive breast cancer cells (MCF7 and T47D) to ionizing radiation at 4 to 12 Gy as evidenced by the significant increase of apoptotic or senescent cells and reduction in clonogenic cell survival in siSNCG treated cells compared to siScr treated cells. On the other hand, we established an in vitro model of SNCG ectopic expression by using a triple-negative breast cancer cell line (SUM159PT) to further investigate the radioprotective effect of SNCG. We showed that ectopic expression of SNCG significantly decreased apoptosis of SUM159PT cells and enhanced clonogenic cell survival after radiation treatment. At the molecular level, after irradiation, the p53 pathway was less activated when SNCG was present. Conversely, p21Waf1/Cip1 expression was upregulated in SNCG-expressing cells. When p21 was down-regulated by siRNA, radiosensitivity of SNCG-expressing SUM159PT cells was dramatically increased. This suggested a possible connection between p21 and SNCG in radioresistance in these cells. In conclusion, our data provide for the first time experimental evidence for the role of SNCG in the radioresistance of breast cancer cells.

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Synuclein-γ (SNCG) expression in ovarian cancer is associated with high-risk clinicopathologic disease

Cited by 14 publications

References 20 publications

Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders

Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders

Assessment of serum synuclein‐γ and squamous cell carcinoma antigen as diagnostic biomarkers in patients with oral squamous cell carcinoma and oral potentially malignant disorders

Synuclein gamma expression enhances radiation resistance of breast cancer cells

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