RESUMEN
Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development and progression of many cancers. Partial EMT (pEMT) could represent a critical step in tumor migration and dissemination. Sarcomatoid renal cell carcinoma (sRCC) is an aggressive form of renal cell carcinoma (RCC) composed of a carcinomatous (sRCC-Ca) and sarcomatous (sRCC-Sa) component. The role of (p)EMT in the progression of RCC to sRCC remains unclear. The aim of this study was to investigate the involvement of (p)EMT in RCC and sRCC. Tissue samples from 10 patients with clear cell RCC (ccRCC) and 10 patients with sRCC were selected. The expression of main EMT markers (miR-200 family, miR-205, SNAI1/2, TWIST1/2, ZEB1/2, CDH1/2, VIM) was analyzed by qPCR in ccRCC, sRCC-Ca, and sRCC-Sa and compared to non-neoplastic tissue and between both groups. Expression of E-cadherin, N-cadherin, vimentin and ZEB2 was analyzed using immunohistochemistry. miR-200c was downregulated in sRCC-Ca compared to ccRCC, while miR-200a was downregulated in sRCC-Sa compared to ccRCC. CDH1 was downregulated in sRCC-Sa when compared to any other group. ZEB2 was downregulated in ccRCC and sRCC compared to corresponding non-neoplastic kidney. A positive correlation was observed between CDH1 expression and miR-200a/b/c. Our results suggest that full EMT is not present in sRCC. Instead, discreet molecular differences exist between ccRCC, sRCC-Ca, and sRCC-Sa, possibly representing distinct intermediary states undergoing pEMT.
Asunto(s)
Biomarcadores de Tumor , Carcinoma de Células Renales , Transición Epitelial-Mesenquimal , Neoplasias Renales , MicroARNs , Vimentina , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Humanos , Transición Epitelial-Mesenquimal/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , MicroARNs/genética , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Femenino , Vimentina/metabolismo , Vimentina/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Anciano , Cadherinas/genética , Cadherinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Antígenos CD/genética , Antígenos CD/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/metabolismo , Adulto , Proteínas NuclearesRESUMEN
Ribosome biogenesis is a multi-step process, in which a network of trans-acting factors ensures the coordinated assembly of pre-ribosomal particles in order to generate functional ribosomes. Ribosome biogenesis is tightly coordinated with cell proliferation and its perturbation activates a p53-dependent cell-cycle checkpoint. How p53-independent signalling networks connect impaired ribosome biogenesis to the cell-cycle machinery has remained largely enigmatic. We demonstrate that inactivation of the nucleolar SUMO isopeptidases SENP3 and SENP5 disturbs distinct steps of 40S and 60S ribosomal subunit assembly pathways, thereby triggering the canonical p53-dependent impaired ribosome biogenesis checkpoint. However, inactivation of SENP3 or SENP5 also induces a p53-independent checkpoint that converges on the specific downregulation of the key cell-cycle regulator CDK6. We further reveal that impaired ribosome biogenesis generally triggers the downregulation of CDK6, independent of the cellular p53 status. Altogether, these data define the role of SUMO signalling in ribosome biogenesis and unveil a p53-independent checkpoint of impaired ribosome biogenesis.
Asunto(s)
Cisteína Endopeptidasas , Ribosomas , Proteína p53 Supresora de Tumor , Nucléolo Celular/metabolismo , Proliferación Celular , Proteínas Ribosómicas/metabolismo , Ribosomas/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Humanos , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismoRESUMEN
Epithelial-mesenchymal transition (EMT) is a fundamental physiologically relevant process that occurs during morphogenesis and organ development. In a pathological setting, the transition from epithelial toward mesenchymal cell phenotype is hijacked by cancer cells, allowing uncontrolled metastatic dissemination. The competing endogenous RNA (ceRNA) hypothesis proposes a competitive environment resembling a large-scale regulatory network of gene expression circuits where alterations in the expression of both protein-coding and non-coding genes can make relevant contributions to EMT progression in cancer. The complex regulatory diversity is exerted through an array of diverse epigenetic factors, reaching beyond the transcriptional control that was previously thought to single-handedly govern metastatic dissemination. The present review aims to unravel the competitive relationships between naturally occurring ceRNA transcripts for the shared pool of the miRNA-200 family, which play a pivotal role in EMT related to cancer dissemination. Upon acquiring more knowledge and clinical evidence on non-genetic factors affecting neoplasia, modulation of the expression levels of diverse ceRNAs may allow for the development of novel prognostic/diagnostic markers and reveal potential targets for the disruption of cancer-related EMT.
Asunto(s)
Transición Epitelial-Mesenquimal , MicroARNs/metabolismo , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Animales , Transición Epitelial-Mesenquimal/genética , Humanos , MicroARNs/genética , Fenotipo , ARN Circular/genética , ARN Circular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Aim: Identification of aberrant hypermethylation in promoter regions of candidate genes to discover potential biomarkers for colorectal cancer. Materials & Methods: Genes BMP2, IRF4, KCNA1, LRRC7, NRG3, SLC27A6 and UNC5D were pre-selected in a bioinformatics study for their hypermethylation status in colorectal cancer. Methylation analysis was performed on 202 cancer tissue specimens to validate candidate genes. Results: Genes KCNA1 and UNC5D displayed methylation in 95.3 and 99.7% of The Cancer Genome Atlas dataset samples and in 96 and 98% of our experimentally tested samples, respectively. Conclusion:KCNA1 and UNC5D promoter hypermethylation holds diagnostic biomarker potential in patients with early colorectal cancer.