RESUMEN
Li-Fraumeni syndrome is a rare hereditary cancer predisposition syndrome associated with germline pathogenic variants in TP53 gene. The phenotype may vary from classical to variant forms, known as Li-Fraumeni-like phenotypes. We searched for pathogenic variants in TP53 in a 14 year-old female diagnosed with fibrolamellar hepatocellular carcinoma, a rare subtype of hepatocellular carcinoma. The proband is a heterozygote carrier of the TP53 c.467G>A (p.Arg156His) in exon 5, and her mother is an asymptomatic carrier. Analysis of tumor DNA disclosed an additional somatic mutation in TP53, c.461G>A; p.Gly154Asp. The TP53 germline and somatic pathogenic variants may have acted as possible driver mutations, resulting in genomic instability and tumor development. The fibrolamellar subtype of hepatocellular carcinoma may be part of the broad spectrum of tumors associated with Li-Fraumeni phenotype.
Asunto(s)
Carcinoma Hepatocelular/genética , Síndrome de Li-Fraumeni/genética , Neoplasias Hepáticas/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Hígado/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , LinajeAsunto(s)
Neoplasias de la Vaina del Nervio/patología , Proteína p53 Supresora de Tumor/análisis , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Brasil/epidemiología , Métodos Epidemiológicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Vaina del Nervio/metabolismo , Neoplasias de la Vaina del Nervio/mortalidadRESUMEN
BACKGROUND: Alternative splicing of the osteopontin (opn, spp1) gene generates three protein splicing isoforms (OPN-SI), designated as OPNa, OPNb, and OPNc, which have demonstrated specific roles in different tumor models. This work aims to investigate the roles of each OPN-SI in prostate cancer (PCa) progression by using in vivo and in vitro functional assays. METHODS: The expression levels of OPN-SI in prostate cell lines were analyzed by qRT-PCR. PC-3 was stably transfected with expression vectors containing OPNa, OPNb, and OPNc, as well as empty vector controls. PC-3 cells overexpressing each construct were analyzed for in vivo tumor growth and in relation to different aspects mimicking tumor progression, such as cell proliferation, migration, invasion, and soft agar colony formation. RESULTS: OPN-SI are overexpressed in PCa as compared to non-tumoral prostate cell lines. OPNc and OPNb overexpressing cells significantly activated enhanced xenograft tumor growth and PC-3 proliferation, migration, invasion, and soft agar colony formation, as well as the expression of MMP-2, MMP-9, and VEGF. These isoforms also support sustained proliferative survival. We found that both OPNc and OPNb pro-tumorigenic roles are mainly mediated through PI3K signaling. Inhibition of this pathway by using LY294002 specifically inhibited tumor progression features evoked by OPNc and OPNb overexpression. CONCLUSIONS: Our data provide evidence that both OPNc and OPNb splicing isoforms promote distinct aspects of PCa progression by inducing PI3K signaling. These data give support to strategies aiming to downregulate OPNc and OPNb expression as an approach to inhibit PCa progression.
