RESUMEN
Our study aimed to investigate the expression, functional significance, and related mechanism of long noncoding RNA CRNDE (colorectal neoplasia differentially expressed) in hepatocellular carcinoma (HCC) pathogenesis. The resulted revealed that CRNDE was significantly overexpressed in HCC tissues and cell lines, and was statistically correlated with poor clinical outcome. CRNDE knockdown markedly decreased HCC cell proliferation, migration, and chemoresistance. In addition, in vivo experiments confirmed the suppressive effect of CRNDE knockdown on HCC progression. Mechanically, CRNDE directly bound to EZH2 (enhancer of zeste homolog), SUZ12 (suppressor of zeste 12), SUV39H1, and mediated their inhibition of tumor suppressor genes, including CUGBP Elav-like family member 2 (CELF2) and large tumor suppressor 2 (LATS2). CELF2 exerted tumor suppressive effect in HCC and was involved in CRNDE-mediated oncogenic effect. In addition, the oncogenic effects of CRNDE on HCC proliferation, migration and tumorigenesis, as well as its inhibition of Hippo pathway were abolished by LATS2 overexpression. Together, our work demonstrated the importance of CRNDE in HCC progression and elucidated the underlying molecular mechanisms. These findings provided new insights into HCC pathogenesis and chemoresistance mediated by CRNDE.
Asunto(s)
Carcinoma Hepatocelular/genética , ARN Largo no Codificante/genética , Proteínas CELF/metabolismo , Carcinogénesis/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , China , Neoplasias Colorrectales/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Epigénesis Genética/genética , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroARNs/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Largo no Codificante/metabolismo , Transducción de Señal/genética , Transcriptoma/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
AIM: To analyze the frequency of hereditary non-polyposis colorectal cancer (HNPCC) in Chinese colorectal cancer (CRC) patients, and to discuss the value of microsatellite instability (MSI) and/or immunohistochemistry (IHC) for MSH2/MLH1 protein analysis as pre-screening tests in China. METHODS: The Amsterdam criteria I and II (clinical diagnosis) and/or germline hMLH1/hMSH2 mutations (genetic diagnosis) were used to classify HNPCC families. Genetic tests, including microsatellite instability, immunohistochemistry for MSH2/MLH1 proteins and hMSH2/hMLH1 genes, were performed in each proband. RESULTS: From July 2000 to June 2004, 1988 patients with colorectal cancer were analysed and 114 CRC patients (5.7%) from 48 families were categorized as having HNPCC, including 76 from 26 families diagnosed clinically and 38 from the other 22 families diagnosed genetically. The sensitivity and specificity of high MSI and IHC for predicting mutations were 100% and 54%, and 79% and 77%, respectively. CONCLUSION: The frequency of HNPCC is approximately 10% among all Chinese CRC cases. The MSI and IHC detections for hMSH2/hMLH1 proteins are reliable pre-screening tests for hMLH1/hMSH2 germline mutations in families suspected of having HNPCC.