RESUMO
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that mostly occurs in the elderly. Merkel cell polyomavirus (MCPyV) is detected in approximately 80% of MCCs and is associated with carcinogenesis. Hedgehog signaling pathway plays a role in human embryogenesis and organogenesis. In addition, reactivation of this pathway later in life can cause tumors. Twenty-nineMCPyV-positive and 21 MCPyV-negative MCCs were immunohistochemically stained with primary antibodies for hedgehog signaling (SHH, IHH, PTCH1, SMO, GLI1, GLI2, and GLI3) and evaluated using H-score. Polymerase chain reaction and sequence analysis for SHH and GLI1 exons were also performed. Expression of SHH was higher in MCPyV-positive MCCs than in MCPyV-negative MCCs (P<.001). Higher expression of GLI1, MCPyV infection, male sex, and Japanese ethnicity were associated with better overall survival (P=.034, P=.001, P=.042, and P=.036, respectively). Higher expression of SHH and MCPyV infection were associated with improved MCC-specific survival (P=.037 and P=.002, respectively). The mutation analysis of prognosis-related GLI1 and SHH genes in our study revealed a low frequency of mutations in the 10 exons examined, except GLI1 exon 5 (18/22 cases), all having the same silent mutation of c.576G>A. Only 2 mutations with amino acid changes were detected in MCPyV-negative MCCs only: 1 missense mutation in GLI1 exon 4 and 1 nonsense mutation in SHH-3B. Expression of SHH and GLI1 may be useful prognostic markers of MCC because increased expression was associated with better prognosis. The high rate of c.576G>A silent mutation in GLI1 exon 5 was a feature of MCC.
Assuntos
Carcinoma de Célula de Merkel/química , Carcinoma de Célula de Merkel/virologia , Proteínas Hedgehog/análise , Poliomavírus das Células de Merkel/isolamento & purificação , Transdução de Sinais , Neoplasias Cutâneas/química , Neoplasias Cutâneas/virologia , Proteína GLI1 em Dedos de Zinco/análise , Biomarcadores Tumorais/genética , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/patologia , Transformação Celular Viral , Análise Mutacional de DNA , Éxons , Feminino , Proteínas Hedgehog/genética , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Fatores de Risco , Mutação Silenciosa , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteína GLI1 em Dedos de Zinco/genéticaRESUMO
Although thousands of long noncoding RNAs (lncRNAs) are localized in the nucleus, only a few dozen have been functionally characterized. Here we show that nuclear enriched abundant transcript 1 (NEAT1), an essential lncRNA for the formation of nuclear body paraspeckles, is induced by influenza virus and herpes simplex virus infection as well as by Toll-like receptor3-p38 pathway-triggered poly I:C stimulation, resulting in excess formation of paraspeckles. We found that NEAT1 facilitates the expression of antiviral genes including cytokines such as interleukin-8 (IL8). We found that splicing factor proline/glutamine-rich (SFPQ), a NEAT1-binding paraspeckle protein, is a repressor of IL8 transcription, and that NEAT1 induction relocates SFPQ from the IL8 promoter to the paraspeckles, leading to transcriptional activation of IL8. Together, our data show that NEAT1 plays an important role in the innate immune response through the transcriptional regulation of antiviral genes by the stimulus-responsive cooperative action of NEAT1 and SFPQ.