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Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8.

ABSTRACT: Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (ZNF83). ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation, p.E293V, in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated nuclear factor κB (NF-κB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established a foundation for using the ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors.

SUBMITTER: Lyu ZJ

PROVIDER: S-EPMC7791007 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8.

Lyu Zhao J ZJ Wang Ying Y Huang Jin L JL Chen Miao M Wu Sha Y SY Yan Qian Q Zhang Yu Y Tang Ying Y Jiang Chen C Li Lei L Jia Yi Z YZ Liu Yu C YC Mei Hong B HB Wang Feng F Li Ren H RH Chen Ya C YC Lin Xiang X Cai Zhi M ZM Guan Xin Y XY

Molecular therapy : the journal of the American Society of Gene Therapy 20200905 1

Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger ...[more]

PMID: 33002420

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Project description:BackgroundBladder Cancer (BCa) is a severe genitourinary tract disease with an uncertain pathology. Increasing evidence indicates that the tumor microenvironment plays a decisive role with respect to cancer progression, and that this is driven by tumor cell interactions with stromal components. Tenascin-C (TN-C) is an important extracellular matrix (ECM) component, which has been reported to be involved in other types of cancer, such as breast cancer. The expression of TN-C in BCa tissue has been reported to be positively associated with the BCa pathological grade, yet the presence of urine TN-C is considered as an independent risk factor for BCa. However, the role of TN-C in BCa progression is still unknow. Thus, the object of the present investigation is to determine the role of TN-C in BCa progression and the involved mechanism.MethodsIn this study, expression of TN-C in BCa tissue of Chinese local people was determined by IHC. Patients corresponding to tumor specimens were flowed up by telephone call to get their prognostic data and analyzed by using SPSS 19.0 statistic package. In vitro mechanistic investigation was demonstrated by QT-qPCR, Western Blot, Plasmid transfection to establishment of high/low TN-C-expression stable cell line, Boyden Chamber Assay, BrdU incorporation, Wound Healing, laser scanning confocal microscopy (LSCM) and ELISA.ResultsTN-C expression in BCa tissue increases with tumor grade and is an independent risk factor for BCa patient. The in vitro investigation suggested that TN-C enhances BCa cell migration, invasion, proliferation and contributes to the elevated expression of EMT-related markers by activating NF-κB signaling, the mechanism of which involving in syndecan-4.ConclusionsExpression of TN-C in BCa tissues of Chinese local people is increased according to tumor grade and is an independent risk factor. TN-C mediates BCa cell malignant behavior via syndecan-4 and NF-κB signaling. Although the mechanisms through which syndecan-4 is associated with the activation of NF-κB signaling are unclear, the data presented herein provide a foundation for future investigations into the role of TN-C in BCa progression.

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Dataset Information

Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8.

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Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8.

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