Molecular Biology of the WWOX Gene That Spans Chromosomal Fragile Site FRA16D

Lee, Cheng Shoou; Choo, Amanda; Dayan, Sonia; Richards, Robert I.; O’Keefe, Louise V.

doi:10.3390/cells10071637

Cited by 6 publications

(8 citation statements)

References 61 publications

(116 reference statements)

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“…ROS can lead to DNA damage and can cause DNA mutations. These DNA mutations lead to the activation of tumor-suppressor genes, inhibiting tumorigenesis by decreasing tumor cell proliferation, migration, and resistance to apoptosis [ 18 ]. Because fragile site gene expression is absent in most cancers [ 19 ], most cancers have lost this important ROS modulator, allowing the inappropriate survival and growth of cancers.…”

Section: Discussionmentioning

confidence: 99%

WWOX Modulates ROS-Dependent Senescence in Bladder Cancer

Liu

Chen

et al. 2022

Molecules

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The tumor-suppressor gene, WW domain-containing oxidoreductase (WWOX), has been found to be lost in various types of cancers. ROS result as a tightly regulated signaling process for the induction of cell senescence. The aim of this study was to investigate the role of WWOX in the regulation of ROS and cell senescence, which is intriguing in terms of the possible mechanism of WWOX contributing to bladder cancer. In this study, we used the AY-27 rat bladder tumor cell line and F344 orthotopic bladder tumor models to reveal the pro-senescence effects of WWOX and the corresponding underlying mechanism in bladder cancer. WWOX-overexpressing lentivirus (LV-WWOX) remarkably stimulated cellular senescence, including increased senescence-associated secretory phenotype (SASP) formation, enlarged cellular morphology, and induced SA-β-Gal-positive staining. A further mechanism study revealed that the pro-senescence effect of LV-WWOX was dependent on increased intercellular reactive oxygen species (ROS) generation, which subsequently triggered p21/p27. Moreover, LV-WWOX significantly inhibited the tumor size by 30.49% in the F344/AY-27 rat orthotopic model (p < 0.05) by activating cellular senescence. The expression of p21 was significantly enhanced in the orthotopic bladder tumors under WWOX treatment. The orthotopic bladder tumors in the groups of rats verified the effect in vivo. Our study suggests that WWOX, an ROS-dependent senescence-induced gene, could be further studied for its therapeutic implications in bladder cancer.

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Section: Discussionmentioning

confidence: 99%

WWOX Modulates ROS-Dependent Senescence in Bladder Cancer

Liu

Chen

et al. 2022

Molecules

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“…The genotype distribution of WWOX polymorphisms showed no significant difference between wild type and mutant EGFR in lung adenocarcinoma patients. The FRA16D fragile region, which contains the WWOX gene, is a hot spot for genomic instability, prone to chromosomal breakage and copy number variations [ 9 , 10 ]. The use of sequencing analysis has found high levels of SNPs in the WWOX gene and several missense polymorphisms in cancer cell lines and tumor tissues [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…The WW domain-containing oxidoreductase ( WWOX) gene is mapped to human chromosome 16q23.3–24.1, which spans approximately 1.1 megabases and consists of nine exons and eight introns [ 6 , 7 ]. The WWOX gene encompasses the FRA16D fragile region, which frequently undergoes chromosomal breaks and rearrangements in cancers [ 8 , 9 , 10 ]. The WWOX gene mainly encodes a protein of 414 amino acids (46 kDa).…”

Section: Introductionmentioning

confidence: 99%

Effect of WW Domain-Containing Oxidoreductase Gene Polymorphism on Clinicopathological Characteristics of Patients with EGFR Mutant Lung Adenocarcinoma in Taiwan

Chang

et al. 2021

IJERPH

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Lung adenocarcinoma is the most common histological type of non-small cell lung cancer, which accounts for the majority of lung cancers. Previous studies have showed that dysregulation of WW domain-containing oxidoreductase (WWOX) participates in the generation of several cancer types, including lung cancer. However, whether these WWOX polymorphisms are related to the clinical risk of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is worthy of investigation. The present study examined the relationship between the WWOX single-nucleotide polymorphisms (SNPs; rs11545028, rs12918952, rs3764340, rs73569323, and rs383362) and the clinicopathological factors in lung adenocarcinoma patients with or without EGFR mutations. We found that there was no significant difference in the genotype distribution of WWOX polymorphism between EGFR wild-type and EGFR mutant in patients with lung adenocarcinoma. Our results demonstrated that the presence of at least one G genotype (CG and GG) allele on WWOX rs3764340 was associated with a significantly higher risk of nearby lymph node involvement in those patients harboring EGFR mutations (odds ratio (OR) = 3.881, p = 0.010) compared with the CC genotype. Furthermore, in the subgroup of lung adenocarcinoma patients with the EGFR-L858R mutation, both WWOX rs3764340 C/G (OR = 5.209, p = 0.023) and rs73569323 C/T polymorphisms (OR = 3.886, p = 0.039) exhibited significant associations with the size of primary tumors and the invasion of adjacent tissues. In conclusion, these data indicate that WWOX SNPs may help predict tumor growth and invasion in patients with EGFR mutant lung adenocarcinoma, especially those with the EGFR-L858R mutant in Taiwan.

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“…A repeat expansion in the dog Nhlrc1 gene, the cause of its Lafora disease ( Lohi et al, 2005 ), does not appear to be present in humans, albeit non-repeat mutations in the same gene cause the same Lafora disease in humans ( Chan et al, 2003 ). Human fragile sites have also been conserved within animal species, such as FRA16D, a common AT-rich repeat fragile site mapped to the gene WWOX ( Lee et al, 2021 ). In the mouse, the Wwox gene and fragile site are highly conserved in the mouse genome, appearing as mouse fragile site Fra8E1 ( Krummel et al, 2002 ).…”

Section: Characteristics Of Fragile Sitesmentioning

confidence: 99%

Fragile sites, chromosomal lesions, tandem repeats, and disease

Mirceta

Shum²,

Schmidt³

et al. 2022

Front. Genet.

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Expanded tandem repeat DNAs are associated with various unusual chromosomal lesions, despiralizations, multi-branched inter-chromosomal associations, and fragile sites. Fragile sites cytogenetically manifest as localized gaps or discontinuities in chromosome structure and are an important genetic, biological, and health-related phenomena. Common fragile sites (∼230), present in most individuals, are induced by aphidicolin and can be associated with cancer; of the 27 molecularly-mapped common sites, none are associated with a particular DNA sequence motif. Rare fragile sites (≳ 40 known), ≤ 5% of the population (may be as few as a single individual), can be associated with neurodevelopmental disease. All 10 molecularly-mapped folate-sensitive fragile sites, the largest category of rare fragile sites, are caused by gene-specific CGG/CCG tandem repeat expansions that are aberrantly CpG methylated and include FRAXA, FRAXE, FRAXF, FRA2A, FRA7A, FRA10A, FRA11A, FRA11B, FRA12A, and FRA16A. The minisatellite-associated rare fragile sites, FRA10B, FRA16B, can be induced by AT-rich DNA-ligands or nucleotide analogs. Despiralized lesions and multi-branched inter-chromosomal associations at the heterochromatic satellite repeats of chromosomes 1, 9, 16 are inducible by de-methylating agents like 5-azadeoxycytidine and can spontaneously arise in patients with ICF syndrome (Immunodeficiency Centromeric instability and Facial anomalies) with mutations in genes regulating DNA methylation. ICF individuals have hypomethylated satellites I-III, alpha-satellites, and subtelomeric repeats. Ribosomal repeats and subtelomeric D4Z4 megasatellites/macrosatellites, are associated with chromosome location, fragility, and disease. Telomere repeats can also assume fragile sites. Dietary deficiencies of folate or vitamin B12, or drug insults are associated with megaloblastic and/or pernicious anemia, that display chromosomes with fragile sites. The recent discovery of many new tandem repeat expansion loci, with varied repeat motifs, where motif lengths can range from mono-nucleotides to megabase units, could be the molecular cause of new fragile sites, or other chromosomal lesions. This review focuses on repeat-associated fragility, covering their induction, cytogenetics, epigenetics, cell type specificity, genetic instability (repeat instability, micronuclei, deletions/rearrangements, and sister chromatid exchange), unusual heritability, disease association, and penetrance. Understanding tandem repeat-associated chromosomal fragile sites provides insight to chromosome structure, genome packaging, genetic instability, and disease.

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Molecular Biology of the WWOX Gene That Spans Chromosomal Fragile Site FRA16D

Cited by 6 publications

References 61 publications

WWOX Modulates ROS-Dependent Senescence in Bladder Cancer

WWOX Modulates ROS-Dependent Senescence in Bladder Cancer

Effect of WW Domain-Containing Oxidoreductase Gene Polymorphism on Clinicopathological Characteristics of Patients with EGFR Mutant Lung Adenocarcinoma in Taiwan

Fragile sites, chromosomal lesions, tandem repeats, and disease

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