Loss of lung WWOX expression causes neutrophilic inflammation

Singla, Sunit; Chen, Jiwang; Sethuraman, Shruthi; Sysol, Justin R.; Gampa, Amulya; Zhao, Shuangping; Machado, Roberto F.

doi:10.1152/ajplung.00034.2017

Cited by 17 publications

(25 citation statements)

References 73 publications

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“…Unlike the previously reported observations in whole lung WWOX knockdown mice [20], there were no significant differences between untreated EC WWOX KO mice and controls. Increased vascular leak of cells and protein in LPS-treated EC WWOX KO mice was confirmed by histologic examination of H & E stained lung sections ( Figure 3D).…”

Section: Ec-specific Wwox Ko Mice Exhibit Greater Amounts Of Pulmonarcontrasting

confidence: 99%

“…Amongst both of these categories of CS-induced gene changes is the tumor suppressor, WWOX, which resides at the second most active chromosomal fragile site in the human genome [18,19]. Apart from its heightened susceptibility to loss of function mutations and methylation induced downregulation via environmental exposures including cigarette smoke, its potential role in the pathogenesis of lung disease was elucidated by gene knockdown studies in mice and cultured pulmonary epithelial cells [20]. Acute si-RNA mediated knockdown of lung WWOX expression in mice was observed to result in neutrophilic inflammation, a finding that may be relevant to the pathogenesis of chronic lung diseases such as COPD [20].…”

Section: Introductionmentioning

confidence: 99%

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Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS

Zeng

Chen

Moshensky

et al. 2020

Preprint

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RATIONALEA history of chronic cigarette smoking is known to increase risk for ARDS, but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures, and thus an interesting candidate gene for the study of exposure-related lung disease.METHODS AND RESULTSLungs harvested from current versus former/never smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle treated controls. In separate studies, endothelial (EC)-specific WWOX KO versus wild type mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31+CD45- cells. These were grown in culture, confirmed to be WWOX-deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing (ECIS) as well as a FITC dextran transwell assay for their barrier properties during MRSA or LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to wild type cells during either MRSA or LPS treatment as measured by both ECIS and the transwell assay.CONCLUSIONThe increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.

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Section: Ec-specific Wwox Ko Mice Exhibit Greater Amounts Of Pulmonarcontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS

Zeng

Chen

Moshensky

et al. 2020

Preprint

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“…35–37 More recently, loss of WWOX expression in mice lung was shown to cause neutrophilic inflammation. 38 Surprisingly, increase in cancer cases was never reported in either patients with biallelic WWOX germline pathogenic variants or their heterozygous parents. The severity of WOREE syndrome with a high frequency of premature death in the first years of life could explain the absence of any cancers.…”

Section: Discussionmentioning

confidence: 99%

The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

Piard

Hawkes

Milh

et al. 2019

Genetics in Medicine

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PurposeGermline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations.MethodsWe report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing.ResultsTwo copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes.ConclusionGermline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.

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“…33,34 WWOX gene alterations in cancer, metabolic disorders, and neural diseases Null mutations in the WWOX/Wwox gene lead to complete loss of protein expression. Loss of WWOX expression has been reported in breast, [35][36][37][38] esophageal, [39][40][41] lung, 42,43 ovarian, 44,45 colon, 46 prostate, 47,48 and gastric 49 carcinomas. Alternative transcripts of WWOX are found in breast cancer.…”

Section: Tumor Suppressor Ww-domain Containing Oxidoreductase Wwoxmentioning

confidence: 99%

Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events

Huang

Chang

2018

Exp Biol Med (Maywood)

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Abnormal differentiation and growth of hematopoietic stem cells cause the development of hematopoietic diseases and hematopoietic malignancies. However, the molecular events underlying leukemia development are not well understood. In our recent study, we have demonstrated that calcium ionophore and phorbol ester force the differentiation of T lymphoblastic leukemia. The event involves a newly identified IκBα/WWOX/ERK signaling, in which WWOX is Ser14 phosphorylated. Additional evidence also reveals that pS14-WWOX is involved in enhancing cancer progression and metastasis and facilitating neurodegeneration. In this mini-review, we update the current knowledge for the functional roles of WWOX under physiological and pathological settings, and provide new insights regarding pS14-WWOX in T leukemia cell maturation, and switching the anticancer pY33-WWOX to pS14-WWOX for cancer promotion and disease progression. Impact statement WWOX was originally designated as a tumor suppressor. However, human newborns deficient in WWOX do not spontaneously develop tumors. Activated WWOX with Tyr33 phosphorylation is present in normal tissues and organs. However, when pY33-WWOX is overly induced under stress conditions, it becomes apoptotic to eliminate damaged cells. Notably, WWOX with Ser14 phosphorylation is upregulated in the lesions of cancer, as well as in the brain hippocampus and cortex with Alzheimer's disease. Suppression of pS14-WWOX by Zfra reduces cancer growth and mitigates Alzheimer's disease progression, suggesting that pS14-WWOX facilitates disease progression. pS14-WWOX can be regarded as a marker of disease progression.

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Loss of lung WWOX expression causes neutrophilic inflammation

Cited by 17 publications

References 73 publications

Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS

Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS

The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events

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