The Reciprocal Regulation of γ-Synuclein and IGF-I Receptor Expression Creates a Circuit That Modulates IGF-I Signaling

Li, Minjing; Yin, Yancun; Hua, Hui; Sun, Xiangming; Luo, Ting; Wang, Jiao; Jiang, Yangfu

doi:10.1074/jbc.m110.131698

Cited by 31 publications

(19 citation statements)

References 44 publications

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“…3). These results are in agreement with studies that demonstrated decreased DNA methylation and increased expression of certain proteins in 5-aza-dC-treated cells, [23][24][25][26][27][28] and they indicate that ALDH1L1 promoter methylation is the mechanism silencing this gene in tumors.…”

Section: Methylation Status Of the Aldh1l1 Cpg Island In Normal Humansupporting

confidence: 82%

Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers

Oleinik

Krupenko

2011

Genes & Cancer

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FDH (10-formyltetrahydrofolate dehydrogenase, the product of the ALDH1L1 gene), a major folate-metabolizing enzyme in the cytosol, is involved in the regulation of cellular proliferation. We have previously demonstrated that FDH is strongly and ubiquitously down-regulated in malignant human tumors and cancer cell lines. Here, we report that promoter methylation is a major mechanism controlling FDH levels in human cancers. A computational analysis has identified an extensive CpG island in the ALDH1L1 promoter region. It contains 96 CpG pairs and covers the region between −525 and +918 bp of the ALDH1L1 gene including the promoter, the entire exon 1, and a part of intron 1 immediately downstream of the exon. Bisulfite sequencing analysis revealed extensive methylation of the island (76%-95% of CpGs) in cancer cell lines. In agreement with these findings, treatment of FDHdeficient A549 cells with the methyltransferase inhibitor 5-aza-2′-deoxycytidine restored FDH expression. Analysis of the samples from patients with lung adenocarcinomas demonstrated methylation of the ALDH1L1 CpG island in tumor samples and a total lack of methylation in respective normal tissues. The same phenomenon was observed in liver tissues: the CpG island was methylation free in DNA extracted from normal hepatocytes but was extensively methylated in a hepatocellular carcinoma. Levels of ALDH1L1 mRNA and protein correlated with the methylation status of the island, with tumor samples demonstrating down-regulation of expression or even complete silencing of the gene. Our studies have also revealed that exon 1 significantly increases transcriptional activity of ALDH1L1 promoter in a luciferase reporter assay. Interestingly, the exon is extensively methylated in samples with a strongly down-regulated or silenced ALDH1L1 gene. Keywords ALDH1L1, CpG island methylation, folate metabolism, lung adenocarcinomaOriginal Article

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Section: Methylation Status Of the Aldh1l1 Cpg Island In Normal Humansupporting

confidence: 82%

Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers

Oleinik

Krupenko

2011

Genes & Cancer

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“…SNCG is a small soluble protein that interferes with the normal mitotic checkpoint and forms a positive feedback loop with insulin-like growth factor signaling (58). SNCG promotes tumor invasion, metastasis, and resistance to antineoplastic-induced apoptosis (58)(59)(60). SNCG expression is upregulated in several common human cancers (e.g., lung, breast, prostate, colon) and is correlated with metastasis risk (61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

“…STC1 is a secreted glycoprotein that modulates angiogenesis and promotes tumorigenesis and metastasis in various cancers, including breast (55), lung (56), and colorectal cancer (57). SNCG is a small soluble protein that interferes with the normal mitotic checkpoint and forms a positive feedback loop with insulin-like growth factor signaling (58). SNCG promotes tumor invasion, metastasis, and resistance to antineoplastic-induced apoptosis (58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

Metastasis regulation by PPARD expression in cancer cells

Zuo¹,

Xu²,

Xu³

et al. 2017

JCI Insight

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“…SNCG is overexpressed in various tumor tissues and predict adverse outcomes in breast [12, 13], colon [14, 15], and pancreatic [16] cancer patients. SNCG decreases rigidity of microtubule bundles caused by paclitaxel [17], stimulates membrane-initiated estrogen signaling by chaperoning estrogen receptor (ER)-alpha36 [18], activates mTOR signaling [19], insulin-like growth factor I (IGF-I)/IGF-IR signaling [20], and mitogen-activated protein kinases (MAPK) signaling pathways [21]. SNCG secreted from tumor cells by unconventional secretion pathway [22] and elevated serum levels of SNCG are found in pancreatic [23], gastrointestinal, esophageal, and colorectal [24, 25] cancers.…”

Section: Introductionmentioning

confidence: 99%

Urine gamma-synuclein as a biomarker for the diagnosis of bladder cancer

Liu

Shi

Hao³

et al. 2016

Oncotarget

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Gamma-synuclein (SNCG) is secreted from tumor cells and elevated in the urine of bladder cancer (BCa) patients, however, the diagnostic and prognostic values of urine SNCG for BCa remain unknown. Here, we used enzyme immunoassay and western blotting to measure urine SNCG levels. Patients with BCa or other urological diseases and healthy controls were enrolled at four Chinese hospitals from April 2010 to November 2014. Diagnostic performance was evaluated by analyzing the area under receiver operating characteristic curves (AUROCs). The AUROC was 0.903 ± 0.019 (95% confidence interval [CI], 0.867 - 0.940) for the test and 0.929 ± 0.015 (95% CI, 0.901 - 0.958) for the validation cohort. The optimal cutoff value yielded sensitivities of 68.4%, 62.4% and specificities of 97.4%, 97.8% for the test and validation cohort, respectively. Urine SNCG levels were decreased after tumor resection, but were higher in BCa patients with recurrence than those without (P = 0.001). The urine SNCG levels in patients with urological benign diseases were significantly lower than BCa patients (all P < 0.05) but higher than healthy controls (all P < 0.05). Hematuria did not interfere with the SNCG detection by spiking urine specimens with whole blood. Compared with a nuclear-matrix-protein-22 assay in an additional cohort excluding hematuria, SNCG showed a similar sensitivity and higher specificity. In summary, our results demonstrated that urine SNCG can discriminate BCa from urinary diseases, and is a useful prognosticator of postsurgical recurrence.

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The Reciprocal Regulation of γ-Synuclein and IGF-I Receptor Expression Creates a Circuit That Modulates IGF-I Signaling

Cited by 31 publications

References 44 publications

Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers

Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers

Metastasis regulation by PPARD expression in cancer cells

Urine gamma-synuclein as a biomarker for the diagnosis of bladder cancer

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