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C?Jun suppresses the expression of WNT inhibitory factor 1 through transcriptional regulation and interaction with DNA methyltransferase 1 in gallbladder cancer.

ABSTRACT: WNT inhibitory factor 1 (WIF?1) is involved in the tumorigenicity and progression of several types of tumor, which has been attributed to aberrant hypermethylation of its promoter. However, the role of WIF?1 in the pathogenesis of gallbladder cancer (GBC) remains to be fully elucidated, and the data available are insufficient to identify the upstream molecular mechanisms involved. In the present study, the methylation status of the WIF?1 promoter was investigated using methylation?specific polymerase chain reaction (PCR) and bisulfate sequencing PCR in GBC cells. Immunohistochemistry, reverse transcription?quantitative PCR and western blotting were used to analyze the expression of WIF?1 and c?Jun. In addition, a co?immunoprecipitation assay was designed to determine the DNA methyltransferase that was implicated in WIF?1 methylation. The results revealed that the expression of WIF?1 was low in GBC, and that this was caused by aberrant DNA hypermethylation. However, there were no significant correlations between the expression of WIF?1 and certain key clinicopathological characteristics of GCB. Subsequently, a negative correlation was found between the protein expression of c?Jun and WIF?1 in 50 GBC specimens using immunohistochemistry. The demethylation and re?expression of WIF?1 was observed when the expression of c?Jun was silenced. Finally, it was found that the knockdown of c?Jun downregulated the expression of DNA methyltransferase 1 (DNMT1) and that c?Jun interacted with DNMT1. Taken together, the present study suggested that c?Jun suppressed the expression of WIF?1 through transcriptional regulation and interaction with DNMT1 in GBC. These findings provide an alternative pathogenesis of GBC, which may be promising as a novel reference for early diagnosis or future treatment.

SUBMITTER: Lin B

PROVIDER: S-EPMC5983991 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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c‑Jun suppresses the expression of WNT inhibitory factor 1 through transcriptional regulation and interaction with DNA methyltransferase 1 in gallbladder cancer.

Lin Bin B Hong Haijie H Jiang Xiaojie X Li Chengzong C Zhu Siyuan S Tang Nanhong N Wang Xiaoqian X She Feifei F Chen Yanling Y

Molecular medicine reports 20180416 6

WNT inhibitory factor 1 (WIF‑1) is involved in the tumorigenicity and progression of several types of tumor, which has been attributed to aberrant hypermethylation of its promoter. However, the role of WIF‑1 in the pathogenesis of gallbladder cancer (GBC) remains to be fully elucidated, and the data available are insufficient to identify the upstream molecular mechanisms involved. In the present study, the methylation status of the WIF‑1 promoter was investigated using methylation‑specific polym ...[more]

PMID: 29693707

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Project description:Hyperactivation of the Wingless-type (Wnt)/β-catenin pathway promotes tumor initiation, tumor growth and metastasis in various tissues. Although there is evidence for the involvement of Wnt/β-catenin pathway activation in salivary gland tumors, the precise mechanisms are unknown. Here we report for the first time that downregulation of the Wnt inhibitory factor 1 (WIF1) is a widespread event in salivary gland carcinoma ex-pleomorphic adenoma (CaExPA). We also show that WIF1 downregulation occurs in the CaExPA precursor lesion pleomorphic adenoma (PA) and indicates a higher risk of progression from benign to malignant tumor. Our results demonstrate that diverse mechanisms including WIF1 promoter hypermethylation and loss of heterozygosity contribute to WIF1 downregulation in human salivary gland tumors. In accordance with a crucial role in suppressing salivary gland tumor progression, WIF1 re-expression in salivary gland tumor cells inhibited cell proliferation, induced more differentiated phenotype and promoted cellular senescence, possibly through upregulation of tumor-suppressor genes, such as p53 and p21. Most importantly, WIF1 significantly diminished the number of salivary gland cancer stem cells and the anchorage-independent cell growth. Consistent with this observation, WIF1 caused a reduction in the expression of pluripotency and stemness markers (OCT4 and c-MYC), as well as adult stem cell self-renewal and multi-lineage differentiation markers, such as WNT3A, TCF4, c-KIT and MYB. Furthermore, WIF1 significantly increased the expression of microRNAs pri-let-7a and pri-miR-200c, negative regulators of stemness and cancer progression. In addition, we show that WIF1 functions as a positive regulator of miR-200c, leading to downregulation of BMI1, ZEB1 and ZEB2, with a consequent increase in downstream targets such as E-cadherin. Our study emphasizes the prognostic and therapeutic potential of WIF1 in human salivary gland CaExPA. Moreover, our findings demonstrate a novel mechanism by which WIF1 regulates cancer stemness and senescence, which might have major implications in the field of cancer biology.

Dataset Information

C?Jun suppresses the expression of WNT inhibitory factor 1 through transcriptional regulation and interaction with DNA methyltransferase 1 in gallbladder cancer.

Publications

c‑Jun suppresses the expression of WNT inhibitory factor 1 through transcriptional regulation and interaction with DNA methyltransferase 1 in gallbladder cancer.

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