Pan-cancer methylation and expression profiling of adenocarcinomas revealed epigenetic silencing in the WNT signaling pathway

Li, J; Huang, Kenan; Zhang, T; Li, H; Zhao, Jiaxun; Wang, H

doi:10.4149/205_150601n306

Cited by 10 publications

(11 citation statements)

References 19 publications

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“…However, in the current study, higher methylation level of PRKCB promoter was observed in tumor tissues than adjacent normal tissues. Our findings were consistent with the pan-cancer study of Li et al [23]. They identified PRKCB promoter hypermethylation in LUAD, colon cancer and rectal cancer, showing PRKCB as an epigenetically-silenced gene in Wnt pathway.…”

Section: Discussionsupporting

confidence: 93%

“…Aberrant epigenetic regulation of Wnt pathway genes has been identified to be a common signature in adenocarcinoma [23]. Wnt antagonist or inhibitors are known as tumor suppressors, implying that hypermethylation-induced silencing of these tumor suppressor genes may participate in the pathogenesis or progression of human malignancies [24–26].…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 93%

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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“…Finally, 2 lncRNAs were selected for further investigation: SOX2-OT and NCBP2-AS2. These lncRNAs were selected since SOX2-OT was the most upregulated lncRNA and NCBP2-AS2 potentially regulates the cancer-associated Wnt signaling pathway ( Table II ) ( 40 ). To explore SOX2-OT and NCBP2-AS2 expression in NSCLC cells, RT-qPCR was used to determine SOX2-OT levels in normal lung cell line NL-20 and cancer cell lines A549, L78, H226 and H520.…”

Section: Resultsmentioning

confidence: 99%

Microarray data re-annotation reveals specific lncRNAs and their potential functions in non-small cell lung cancer subtypes

Zhou

Xie

et al. 2017

Molecular Medicine Reports

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Non-small-cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide. The most common subtypes of NSCLC are adenocarcinoma (AC) and squamous cell carcinoma (SCC). However, the pathophysiological mechanisms contributing to AC and SCC are still largely unknown, especially the roles of long non-coding RNAs (lncRNAs). The present study identified differentially expressed lncRNAs between lung AC and SCC by re-annotation of NSCLC microarray data analysis profiling. The potential functions of lncRNAs were predicted by using coding-non-coding gene co-expressing network. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to investigate lncRNA expression levels in AC cell lines (A549 and L78), SCC cell lines (H226 and H520) and normal cells (NL-20). Western blotting analysis was used to investigate the protein expression levels in these cell lines. A total of 65 lncRNAs were differentially expressed between AC and SCC including 28 lncRNAs that were downregulated in SCC subtypes compared with those in AC ones, and 37 upregulated lncRNAs in SCC subtypes compared with AC subtypes. Three lncRNAs, sex determining region Y-box 2 overlapping transcript (SOX2-OT), NCBP2 antisense RNA 2 (NCBP2-AS2) and ubiquitin like with PHD and ring finger domains 1 (UHRF1), were predicted to be associated with lung cancer; RT-qPCR confirmed that SOX2-OT and NCBP2-AS2 were associated with lung cancer. Finally, western blot assays demonstrated that there was no difference in β-catenin and glycogen synthase kinase 3β (GSK-3β) expression in cancer cells compared with NL-20, but increased phosphorylated (p-)β-catenin and p-GSK-3β was detected in lung cancer cell lines compared with NL-20, particularly in A549 cells. Although these results require further experimental verification, the analysis of lncRNA signatures between AC and SCC has provided insights into the regulatory mechanism of NSCLC development.

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“…sFRP genes inhibit both canonical and non-canonical signaling pathways [21]. The Wnt signaling pathway plays a key role in the development of lung adenocarcinoma [22,23]. In our study, expression levels of APC1, APC2, Dkk-1, Dkk-3, sFRP-2, sFRP-4, sFRP-5 genes involved in the Wnt signaling pathway were evaluated in para n-embedded lung adenocarcinoma and adjacent normal lung tissue.…”

Section: Discussionmentioning

confidence: 97%

Reverse Regulation Between sFRP 5 and Dkk 1 Gene in Early Stage Lung Adenocancer

Zeybek

Öz

Kalemci³

et al. 2021

Preprint

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Purpose: We aimed to examine the expression levels of the genes of APC (Adenomatous Polyposis Coli) 1, APC 2, Dkk (Dickkopf related protein) 1, Dkk -3, sFRP (Secreted frizzled-related protein) -2, sFRP-4, and sFRP-5 genes which play a role in the Wnt signaling pathway in lung adenocarcinoma and adjacent normal lung tissues, and to evaluate their relationship with clinical-pathological factors.Materials and methods: Between 2011 and 2018, the expression levels of the relevant genes in formalin-fixed paraffin-embedded tumor and adjacent intact lung tissue samples of 57 patients who were operated for lung adenocarcinoma were determined by Real-time PCR analysis. Results: The expression levels of the Dkk-1 gene in the tumor tissue, especially in stage I-II, were statistically significantly suppressed compared to normal tissue (p <0.025 ). Although Dkk-1 gene expression was suppressed in the tumor tissue of patients with early-stage lung adenocarcinoma, the level of expression of the sFRP-5 gene was found to be statistically significantly higher (p<0.039). Conclusion: In our study, between the sFRP-5 and Dkk-1 genes, known as the extracellular antagonist of the Wnt signaling pathway was found the reverse regulation. sFRP-5 gene was found as having an oncogenic role in adenocarcinoma development. Reverse regulation between these genes in early-stage lung adenocarcinoma may shed light on the mechanisms associated with the development of carcinogenesis. For that reason, clinically, this relationship needs to research in a larger series of pure adenocarcinoma and normal human lung tissues, separated by its stage, for potential therapeutic target or prognostic its significance.

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Pan-cancer methylation and expression profiling of adenocarcinomas revealed epigenetic silencing in the WNT signaling pathway

Cited by 10 publications

References 19 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

Microarray data re-annotation reveals specific lncRNAs and their potential functions in non-small cell lung cancer subtypes

Reverse Regulation Between sFRP 5 and Dkk 1 Gene in Early Stage Lung Adenocancer

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