Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer

Xie, Junran; Zhang, Yaping; Hu, Xuming; Lv, Ruihua; Xiao, Dongju; Jiang, Li; Bao, Qi

doi:10.1007/s12032-015-0592-0

Cited by 30 publications

(16 citation statements)

References 39 publications

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“…SFRP2 hypermethylation has also been shown in several cancers including acute myeloblastic leukemia [47], mesothelioma [48], bladder cancer [49], liver cancer [50], as well as lung cancer [51]. SFRP2 hypermethylation was previously detected in women and nonsmoking NSCLC patients [52], indicating a gender-specific effect of DNA methylation on gene expression.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer

Liu

Chen

et al. 2017

Oncotarget

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Wnt signal pathway genes are known to be involved with cancer development. Here we tested the hypothesis whether DNA methylation of genes part of the Wnt signaling pathway could help the diagnosis of non-small cell lung cancer (NSCLC). The methylation levels of SFRP1, SFRP2, WIF1 and PRKCB in 111 NSCLC patients were evaluated by quantitative methylation-specific PCR (qMSP). Promoter methylation levels of four candidate genes were significantly higher in tumor tissues compared with the adjacent tissues. SFRP1, SFRP2 and PRKCB genes were all shown to be good predictors of NSCLC risk (SFRP1: AUC = 0.711; SFRP2: AUC = 0.631; PRKCB: AUC = 0.650). The combined analysis showed that the methylation status of the four genes had a sensitivity of 70.3% and a specificity of 73.9% in the prediction of NSCLC risk for study cohort. A higher diagnostic value with an AUC of 0.945 (95% CI: 0.923–0.967, sensitivity: 90.6%, specificity: 93.0%) was found in TCGA cohort. In addition, SFRP1 and SFRP2 hypermethylation events were specific to male patients. Further TCGA data mining analysis suggested that SFRP1_cg15839448, SFRP2_cg05774801, and WIF1_cg21383810 were inversely associated with the host gene expression. Moreover, GEO database analysis showed that 5′-Aza-deoxycytidine was able to upregulate gene expression in several lung cancer cell lines. Subsequent dual-luciferase reporter assay showed a crucial regulatory function of PRKCB promoter. In summary, our study showed that a panel of Wnt signal pathway genes (SFRP1, SFRP2, WIF1 and PRKCB) had the potential as methylation biomarkers in the diagnosis of NSCLC.

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Section: Discussionmentioning

confidence: 99%

Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer

Liu

Chen

et al. 2017

Oncotarget

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“…The anti-cancer activity of NCTD relies on its ability in activation of the caspase signaling pathway that leads to apoptosis [7] accompanied with a decreased ratio of Bcl-2/Bax [8, 9], the changes in the expression of cell cycle-related proteins are co-related with cell cycle arrest [10], the interruption of DNA synthesis [11], inhibition of tumor invasion and metastasis [12, 13], MAPK activation, and protein kinase C pathway activation [14]. …”

Section: Introductionmentioning

confidence: 99%

Norcantharidin Inhibits cell growth by suppressing the expression and phosphorylation of both EGFR and c-Met in human colon cancer cells

et al. 2017

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BackgroundNorcantharidin (NCTD) is a Chinese FDA approved, chemically synthesized drug for cancer treatment. The effect of NCTD on signaling proteins of EGFR and c-Met was systematically elucidated in current study.MethodsTwo human colon cancer cell lines, HCT116 and HT29, were used as model systems to investigate the anti-cancer molecular mechanism of NCTD. Cell cycle arrest and early/late apoptosis were analyzed by flow cytometry. The levels of EGFR, phospho-EGFR, c-Met, phospho-c-Met and other related proteins were quantified by western blot analysis.ResultsNCTD induced cell cycle arrest at G2/M phase in both cell lines. The early and late apoptosis was also observed. Further investigation indicated that NCTD suppressed not only the expression of the total EGFR and the phosphorylated EGFR but also the expression of the total c-Met and the phosphorylated c-Met in colon cancer cells. Moreover, EGFR expression could be mostly restored by co-treatment with MG132, a proteasome inhibitor. In addition, NCTD-induced cell death was comparable to that of the anti-cancer drug gefitinib, a tyrosine kinase inhibitor for EGFR, based on the immunoblot analysis of the expressed proteins after the drug treatment.ConclusionsNCTD might be a useful and inexpensive drug candidate to substitute for gefitinib to serve the treatment needs of cancer patients.

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“…Recent work has provided preclinical evidence that isoliquiritigenin treatment can prevent breast cancer initiation and progression through WIF1 demethylation 51 . In human non-small cell lung cancer, norcantharidin treatment was found to inhibit tumor cell proliferation and invasion by promoting WIF1 demethylation 52 . This is attractive as it may expand the activity of these agents in clinic.…”

Section: Discussionmentioning

confidence: 96%

Wnt inhibitory factor 1 (WIF1) methylation and its association with clinical prognosis in patients with chondrosarcoma

Liu

Shen

Hornicek

et al. 2017

Sci Rep

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Chondrosarcoma (CS) is a rare cancer, but it is the second most common primary malignant bone tumor and highly resistant to conventional chemotherapy and radiotherapy. Aberrant DNA methylation in the promoter CpG island of Wnt inhibitory factor 1 (WIF1) has been observed in different cancers. However, no studies have shown the relationship between WIF1 methylation and CS. In this study, we found promoter methylated WIF1 in both CS cell lines (CS-1 and SW1353) and tumor tissues. Western blot analysis confirmed loss WIF1 expression and activation of Wnt pathway proteins (Wnt5a/b, LRP6, and Dvl2). We subsequently examined the correlation between levels of WIF1 methylation and overall survival (OS) and progression-free survival (PFS) in CS patient samples with a follow-up spanning 234 months (mean: 57.6 months). Kaplan-Meier survival curves and log-rank tests revealed that high levels of WIF1 methylation were associated with lower OS and PFS rates (p < 0.05). Multivariate Cox hazard analysis suggested that detection of high level methylation of WIF1 could be an independent prognostic factor in OS and PFS. In conclusion, we found that WIF1 is epigenetically silenced via promoter DNA methylation in CS and propose that WIF1 methylation may serve as a potential prognostic marker for patients with CS.Chondrosarcoma (CS) is a heterogeneous subtype of malignant cartilage forming tumor. It is a rare cancer in humans and is diagnosed in approximately 600 patients per year in the United States. CS is the second most common primary bone cancer after osteosarcoma 1, 2 . CS accounts for more than 20% of all primary bone malignancies and affects people at any age with a predilection for proximal femur and pelvic sites 3-5 . Pathological identification and radiographic imaging remain important diagnostic tools in the clinical management of patients with CS. However, the reliability of diagnosis by the current subjective imaging and histological criteria has been controversial 6 . CS, especially conventional CS, is notoriously resistant to both chemotherapy and radiation treatment 7 . Thus, surgical resection remains the primary treatment for localized lesions and radiotherapy is limited to the definitive treatment of inoperable micro-lesions and in the palliation of local symptoms 6 . The outcome of patients with CS is relatively poor largely due to the potent capacity for local invasion and distant metastasis 8,9 . Five-year survival rates of patients with dedifferentiated CS are less than 20% as a result of early disseminated metastases 6, 10-12 . Therefore, there is an urgent need to develop novel strategies for diagnosis, treatment, and prognosis of CS to improve outcomes for patients.Recently, aberrant DNA methylation and epigenetic changes have been found to play a pivotal role in the pathogenesis of human malignancies. Hypermethylation mostly presents at the promoter CpG island of tumor suppressor genes and inactivates gene expression, while hypomethylation commonly affects repetitive DNA sequences and/or gene regulatory re...

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Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer

Cited by 30 publications

References 39 publications

Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer

Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer

Norcantharidin Inhibits cell growth by suppressing the expression and phosphorylation of both EGFR and c-Met in human colon cancer cells

Wnt inhibitory factor 1 (WIF1) methylation and its association with clinical prognosis in patients with chondrosarcoma

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