SOX17 methylation inhibits its antagonism of Wnt signaling pathway in lung cancer

Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing 100853, China.
Discovery medicine (Impact Factor: 3.63). 07/2012; 14(74):33-40.
Source: PubMed


The purpose of this study was to explore epigenetic changes and functions of SOX17 in human lung cancer. Five lung cancer cell lines and 88 primary lung cancer samples were examined in this study. Methylation-specific polymerase chain reaction (MSP), semi-quantitative reverse-transcription PCR, immunohistochemistry, luciferase reporter assays, colony-formation assays, and western blotting were used to analyze methylation changes and functions of SOX17 in lung cancer. SOX17 methylation was found in 60.2% of primary human lung cancer samples, and promoter region methylation of SOX17 silenced its expression. SOX17 methylation was associated with female patients and lung cancer differentiation. Colony-formation assays revealed that SOX17 suppressed lung cancer cell proliferation. Re-expression of SOX17 inhibited Wnt signaling in H23 lung cancer cell line. SOX17 acts as a Wnt signaling inhibitor.

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    • "An activated Wnt/beta-catenin pathway, which in A540 cells up-regulates the stem marker OCT-4,30 predicts increased risk of tumor recurrence.31 SOX17, which acts as a Wnt signaling inhibitor and inhibits proliferating cells, is frequently downregultated in lung cancer cells.32 Hedgehog is also linked to lung cancer development33 and plays a role in the maintenance of lung cancer cells stemness. "
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    ABSTRACT: Lung cancer is a devastating disease that is responsible for around 160,000 deaths each year in United States. The discovery that lung cancer, like most other solid tumors, contains a subpopulation of cancer stem cells or cancer stem-like cells (CSCs/CS-LCs) that if eliminated could lead to a cure has brought new hope. However, the exact nature of the putative lung CSCs/CS-LCs is not known and therefore therapies to eliminate this subpopulation have been elusive. A limited knowledge and understanding of cancer stem cell properties and tumor biology may be responsible for the limited clinical success. In this review we discuss the stemness and plasticity properties of lung cancer cells that are critical aspects in terms of developing effective therapies. We suggest that the available experimental evidence obtained from lung cancer cell lines and patients' derived primary cultures does not support a tumor model consistent with the classical CSC model. Instead, all lung cancer cells may be extremely versatile and new models of cancer stem cells may be better working models.
    OncoTargets and Therapy 06/2014; 7:1129-34. DOI:10.2147/OTT.S62345 · 2.31 Impact Factor
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    • "This unique epigenome characteristic might put colon cancer farthest from breast cancer. Breast and lung cancer have many common prognostic signatures, such as hypermethylation of BRCA1 [35], SOX17 [36], [37], and TLX3. "
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    ABSTRACT: Aberrant methylation of specific CpG sites at the promoter is widely responsible for genesis and development of various cancer types. Even though the microarray-based methylome analyzing techniques have contributed to the elucidation of the methylation change at the genome-wide level, the identification of key methylation markers or top regulatory networks appearing common in highly incident cancers through comparison analysis is still limited. In this study, we in silico performed the genome-wide methylation analysis on each 10 sets of normal and cancer pairs of five tissues: breast, colon, liver, lung, and stomach. The methylation array covers 27,578 CpG sites, corresponding to 14,495 genes, and significantly hypermethylated or hypomethylated genes in the cancer were collected (FDR adjusted p-value <0.05; methylation difference >0.3). Analysis of the dataset confirmed the methylation of previously known methylation markers and further identified novel methylation markers, such as GPX2, CLDN15, and KL. Cluster analysis using the methylome dataset resulted in a diagram with a bipartite mode distinguishing cancer cells from normal cells regardless of tissue types. The analysis further revealed that breast cancer was closest with lung cancer, whereas it was farthest from colon cancer. Pathway analysis identified that either the "cancer" related network or the "cancer" related bio-function appeared as the highest confidence in all the five cancers, whereas each cancer type represents its tissue-specific gene sets. Our results contribute toward understanding the essential abnormal epigenetic pathways involved in carcinogenesis. Further, the novel methylation markers could be applied to establish markers for cancer prognosis.
    PLoS ONE 05/2014; 9(5):e97818. DOI:10.1371/journal.pone.0097818 · 3.23 Impact Factor
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    • "Of the 42 common Significant hypermethylated genes unique to Stages I and III, GALR1, NID2 have been identified as highly methylated in NSCLC [46,55], PAX7 has been identified in lung cancer but not reported with methylation [57], though PAX family genes have been previously reported being methylated in cancer [58]. Recent studies have reported SOX17 methylation in lung cancer [59], but not at the stage level. Additionally low expression of GAS7 has been reported in lung squamous cell carcinoma suggesting its importance as marker [60], but this gene has not been previously found to be methylated in LUAD but reported as methylated in colorectal cancer [61]. "
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    ABSTRACT: Epigenetics refers to the reversible functional modifications of the genome that do not correlate to changes in the DNA sequence. The aim of this study is to understand DNA methylation patterns across different stages of lung adenocarcinoma (LUAD). Our study identified 72, 93 and 170 significant DNA methylated genes in Stages I, II and III respectively. A set of common 34 significant DNA methylated genes located in the promoter section of the true CpG islands were found across stages, and these were: HOX genes, FOXG1, GRIK3, HAND2, PRKCB, etc. Of the total significant DNA methylated genes, 65 correlated with transcription function. The epigenetic analysis identified the following novel genes across all stages: PTGDR, TLX3, and POU4F2. The stage-wise analysis observed the appearance of NEUROG1 gene in Stage I and its re-appearance in Stage III. The analysis showed similar epigenetic pattern across Stage I and Stage III. Pathway analysis revealed important signaling and metabolic pathways of LUAD to correlate with epigenetics. Epigenetic subnetwork analysis identified a set of seven conserved genes across all stages: UBC, KRAS, PIK3CA, PIK3R3, RAF1, BRAF, and RAP1A. A detailed literature analysis elucidated epigenetic genes like FOXG1, HLA-G, and NKX6-2 to be known as prognostic targets. Integrating epigenetic information for genes with expression data can be useful for comprehending in-depth disease mechanism and for the ultimate goal of better target identification.
    BMC Systems Biology 12/2013; 7(1):141. DOI:10.1186/1752-0509-7-141 · 2.44 Impact Factor
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