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1.
Cell ; 153(1): 101-11, 2013 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-23540693

RESUMEN

LINE-1 (L1) retrotransposons are mobile genetic elements comprising ~17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic ß-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2(-/-) mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Análisis Mutacional de ADN , Genes Supresores de Tumor , Neoplasias Hepáticas/genética , Elementos de Nucleótido Esparcido Largo , Mutagénesis Insercional , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/genética , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
2.
PLoS Genet ; 14(5): e1007380, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29734330

RESUMEN

Chronic inflammation promotes oncogenic transformation and tumor progression. Many inflammatory agents also generate a toxic microenvironment, implying that adaptive mechanisms must be deployed for cells to survive and undergo transformation in such unfavorable contexts. A paradigmatic case is represented by cancers occurring in pediatric patients with genetic defects of hepatocyte phosphatidylcholine transporters and in the corresponding mouse model (Mdr2-/- mice), in which impaired bile salt emulsification leads to chronic hepatocyte damage and inflammation, eventually resulting in oncogenic transformation. By combining genomics and metabolomics, we found that the transition from inflammation to cancer in Mdr2-/- mice was linked to the sustained transcriptional activation of metabolic detoxification systems and transporters by the Constitutive Androstane Receptor (CAR), a hepatocyte-specific nuclear receptor. Activation of CAR-dependent gene expression programs coincided with reduced content of toxic bile acids in cancer nodules relative to inflamed livers. Treatment of Mdr2-/- mice with a CAR inhibitor blocked cancer progression and caused a partial regression of existing tumors. These results indicate that the acquisition of resistance to endo- or xeno-biotic toxicity is critical for cancers that develop in toxic microenvironments.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Transformación Celular Neoplásica/genética , Inactivación Metabólica/genética , Hígado/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Androstanoles/farmacología , Animales , Transformación Celular Neoplásica/metabolismo , Receptor de Androstano Constitutivo , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Hepatitis/genética , Hepatitis/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Ratones Noqueados , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/genética , Transducción de Señal/genética , Activación Transcripcional/efectos de los fármacos , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
3.
Genome Res ; 25(12): 1812-24, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26510915

RESUMEN

An increasing number of noncoding RNAs (ncRNAs) have been implicated in various human diseases including cancer; however, the ncRNA transcriptome of hepatocellular carcinoma (HCC) is largely unexplored. We used CAGE to map transcription start sites across various types of human and mouse HCCs with emphasis on ncRNAs distant from protein-coding genes. Here, we report that retroviral LTR promoters, expressed in healthy tissues such as testis and placenta but not liver, are widely activated in liver tumors. Despite HCC heterogeneity, a subset of LTR-derived ncRNAs were more than 10-fold up-regulated in the vast majority of samples. HCCs with a high LTR activity mostly had a viral etiology, were less differentiated, and showed higher risk of recurrence. ChIP-seq data show that MYC and MAX are associated with ncRNA deregulation. Globally, CAGE enabled us to build a mammalian promoter map for HCC, which uncovers a new layer of complexity in HCC genomics.


Asunto(s)
Carcinoma Hepatocelular/etiología , Perfilación de la Expresión Génica , Neoplasias Hepáticas/etiología , Regiones Promotoras Genéticas , ARN no Traducido/genética , Secuencias Repetidas Terminales , Sitio de Iniciación de la Transcripción , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Viral , Biología Computacional/métodos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , Ratones , Ratones Noqueados , Unión Proteica , Factores de Transcripción/metabolismo , Transcriptoma , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
4.
Hepatology ; 65(5): 1708-1719, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-27859418

RESUMEN

The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus far. Here, we demonstrate that ST18 is critical for tumor progression and maintenance in a mouse model of liver cancer, based on oncogenic transformation and adoptive transfer of primary precursor cells (hepatoblasts). ST18 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after subcutaneous engraftment and tumor growth. ST18 expression in liver cells was induced by inflammatory cues, including acute or chronic inflammation in vivo, as well as coculture with macrophages in vitro. Knocking down the ST18 mRNA in transplanted hepatoblasts delayed tumor progression. Induction of ST18 knockdown in pre-established tumors caused rapid tumor involution associated with pervasive morphological changes, proliferative arrest, and apoptosis in tumor cells, as well as depletion of tumor-associated macrophages, vascular ectasia, and hemorrhage. Reciprocally, systemic depletion of macrophages in recipient animals had very similar phenotypic consequences, impairing either tumor development or maintenance, and suppressing ST18 expression in hepatoblasts. Finally, RNA sequencing of ST18-depleted tumors before involution revealed down-regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B-dependent transcription. CONCLUSION: ST18 expression in epithelial cells is induced by tumor-associated macrophages, contributing to the reciprocal feed-forward loop between both cell types in liver tumorigenesis. Our findings warrant the exploration of means to interfere with ST18-dependent epithelium-macrophage interactions in a therapeutic setting. (Hepatology 2017;65:1708-1719).


Asunto(s)
Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas Experimentales/etiología , Factores de Transcripción/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Ratones Endogámicos C57BL
5.
Nat Commun ; 5: 3850, 2014 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-24819516

RESUMEN

Hepatocellular carcinoma (HCC) is almost invariably associated with an underlying inflammatory state, whose direct contribution to the acquisition of critical genomic changes is unclear. Here we map acquired genomic alterations in human and mouse HCCs induced by defects in hepatocyte biliary transporters, which expose hepatocytes to bile salts and cause chronic inflammation that develops into cancer. In both human and mouse cancer genomes, we find few somatic point mutations with no impairment of cancer genes, but massive gene amplification and rearrangements. This genomic landscape differs from that of virus- and alcohol-associated liver cancer. Copy-number gains preferentially occur at late stages of cancer development and frequently target the MAPK signalling pathway, and in particular direct regulators of JNK. The pharmacological inhibition of JNK retards cancer progression in the mouse. Our study demonstrates that intrahepatic cholestasis leading to hepatocyte exposure to bile acids and inflammation promotes cancer through genomic modifications that can be distinguished from those determined by other aetiological factors.


Asunto(s)
Carcinoma Hepatocelular/genética , Colestasis Intrahepática/genética , Variaciones en el Número de Copia de ADN/genética , Amplificación de Genes , Hepatocitos/metabolismo , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas/genética , Sistema de Señalización de MAP Quinasas/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/deficiencia , Transportadoras de Casetes de Unión a ATP/genética , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Ratones , Ratones Noqueados , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
6.
Mol Cell Biol ; 31(11): 2210-26, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21482671

RESUMEN

ΔNp73α, a dominant-negative inhibitor of p53 and p73, exhibits antiapoptotic and transforming activity in in vitro models and is often found to be upregulated in human cancers. The mechanisms involved in the regulation of ΔNp73α protein levels in normal and cancer cells are poorly characterized. Here, we show that that IκB kinase beta (IKKß) increases ΔNp73α protein stability independently of its ability to activate NF-κB. IKKß associates with and phosphorylates ΔNp73α at serine 422 (S422), leading to its accumulation in the nucleus, where it binds and represses several p53-regulated genes. S422A mutation in ΔNp73α abolished IKKß-mediated stabilization and inhibition of p53-regulated gene expression. Inhibition of IKKß activity by chemical inhibitors, overexpression of dominant-negative mutants, or gene silencing by siRNA also resulted in ΔNp73α destabilization, which under these conditions was rapidly translocated into the cytoplasm and degraded by a calpain-mediated mechanism. We also present evidence for the IKKß and ΔNp73α cross talk in cancer-derived cell lines and primary cancers. Our data unveil a new mechanism involved in the regulation of the p73 and p53 network.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Quinasa I-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Células Cultivadas , Proteínas de Unión al ADN/genética , Expresión Génica , Células HEK293 , Humanos , Immunoblotting , Inmunoprecipitación , Ratones , Mutación , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Fosforilación , Estabilidad Proteica , Interferencia de ARN , ARN Interferente Pequeño , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serina/metabolismo , Transcripción Genética , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética
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