RESUMEN
BACKGROUND: We aimed to identify novel tumor-promoting drivers highly expressed in gastric cancer (GC) that contribute to worsened prognosis in affected patients. METHODS: Genes whose expression was increased and correlated with worse prognosis in GC were screened using datasets from the Cancer Genome Atlas and Gene Expression Omnibus. We examined Claudin-6 (CLDN6) immunoreactivity in GC tissues and the effect of CLDN6 on cellular functions in GC cell lines. The mechanisms underlying GC-promoting function of CLDN6 were also investigated. RESULTS: CLDN6 was identified as a gene overexpressed in GC tumors as compared with adjacent non-tumorous tissues and whose increased expression was positively correlated with worse overall survival of GC patients, particularly those with Lauren's intestinal type GC, in data from multiple publicly available datasets. Additionally, membranous CLDN6 immunoreactivity detected in intestinal type GC tumors was correlated with worse overall survival. In CLDN6-expressing GC cells, silencing of CLDN6 inhibited cell proliferation and migration/invasion abilities, possibly via suppressing transcription of YAP1 and its downstream transcriptional targets at least in part. CONCLUSIONS: This study identified CLDN6 as a GC-promoting gene, suggesting that CLDN6 to be a possible single prognostic marker and promising therapeutic target for a subset of GC patients.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Claudinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Intestinales/patología , Neoplasias Gástricas/patología , Anciano , Apoptosis , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Ciclo Celular , Proliferación Celular , Claudinas/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Intestinales/metabolismo , Neoplasias Intestinales/cirugía , Masculino , Pronóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirugía , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Rett syndrome (RTT) is a severe neurodevelopmental disorder typically affecting females. It is mainly caused by loss-of-function mutations that affect the coding sequence of exon 3 or 4 of methyl-CpG-binding protein 2 (MECP2). Severe neonatal encephalopathy resulting in death before the age of 2 years is the most common phenotype observed in males affected by a pathogenic MECP2 variant. Mutations in MECP2 exon 1 affecting the MeCP2_e1 isoform are relatively rare causes of RTT in females, and only one case of a male patient with MECP2-related severe neonatal encephalopathy caused by a mutation in MECP2 exon 1 has been reported. This is the first reported case of a male with classic RTT caused by a 5-bp duplication in the open-reading frame of MECP2 exon 1 (NM_001110792.1:c.23_27dup) that introduced a premature stop codon [p.(Ser10Argfs*36)] in the MeCP2_e1 isoform, which has been reported in one female patient with classic RTT. Therefore, both males and females displaying at least some type of MeCP2_e1 mutation may exhibit the classic RTT phenotype.
Asunto(s)
Exones , Proteína 2 de Unión a Metil-CpG/genética , Mutación , Fenotipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Empalme Alternativo , Secuencia de Bases , Encéfalo/anomalías , Preescolar , Análisis Mutacional de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC.
RESUMEN
Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by heterozygous POLD1 mutations. To date, 13 patients affected by POLD1 mutation-caused MDPL have been described. We report a clinically undiagnosed 11-year-old male who noted joint contractures at 6 years of age. Targeted exome sequencing identified a known POLD1 mutation [NM_002691.3:c.1812_1814del, p.(Ser605del)] that diagnosed him as the first Japanese/East Asian MDPL case.