RESUMO
The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach.
Assuntos
Ataxia , Neoplasias Encefálicas , Calcinose , Cistos do Sistema Nervoso Central , Regulação da Expressão Gênica/efeitos dos fármacos , Leucoencefalopatias , Espasticidade Muscular , Mutação , Doenças Retinianas , Convulsões , Proteínas de Ligação a Telômeros , Telômero , Talidomida/administração & dosagem , Animais , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/metabolismo , Ataxia/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Calcinose/tratamento farmacológico , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Cistos do Sistema Nervoso Central/tratamento farmacológico , Cistos do Sistema Nervoso Central/genética , Cistos do Sistema Nervoso Central/metabolismo , Cistos do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Feminino , Humanos , Leucoencefalopatias/tratamento farmacológico , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Masculino , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/genética , Espasticidade Muscular/metabolismo , Espasticidade Muscular/patologia , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/genética , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/metabolismo , Convulsões/patologia , Telômero/genética , Telômero/metabolismo , Telômero/patologia , Proteínas de Ligação a Telômeros/biossíntese , Proteínas de Ligação a Telômeros/genética , Talidomida/efeitos adversos , Peixe-ZebraRESUMO
The WWOX gene encodes a tumor suppressor spanning the second most common human fragile site, FRA16D. Targeted deletion of the Wwox gene in mice led to an increased incidence of spontaneous and ethyl nitrosourea-induced tumors. In humans, loss of heterozygosity and reduced or loss of WWOX expression has been reported in esophageal squamous cell cancers (SCC). In the present study, we examined whether inactivation of the Wwox gene might lead to enhanced esophageal/forestomach tumorigenesis induced by N-nitrosomethylbenzylamine. Wwox+/- and Wwox+/+ mice were treated with six intragastric doses of N-nitrosomethylbenzylamine and observed for 15 subsequent weeks. Ninety-six percent (25 of 26) of Wwox+/- mice versus 29% (10 of 34) of Wwox+/+ mice developed forestomach tumors (P = 1.3 x 10(-7)). The number of tumors per forestomach was significantly greater in Wwox+/- than in Wwox+/+ mice (3.2 +/- 0.34 versus 0.47 +/- 0.17; P < 0.0001). In addition, 27% of Wwox+/- mice had invasive SCC in the forestomach, as compared with 0% of wild-type controls (P = 0.002). Intriguingly, forestomachs from Wwox+/- mice displayed moderately strong Wwox protein staining in the near-normal epithelium, but weak and diffuse staining in SCC in the same tissue section, a result suggesting that Wwox was haploinsufficient for the initiation of tumor development. Our findings provide the first in vivo evidence of the tumor suppressor function of WWOX in forestomach/esophageal carcinogenesis and suggest that inactivation of one allele of WWOX accelerates the predisposition of normal cells to malignant transformation.
