Identification of SomaticVHLGene Mutations in Sporadic Head and Neck Paragangliomas in Association With Activation of the HIF-1α/miR-210 Signaling Pathway
| Autor: | Miguel Arístegui, Inés Saenz de Santa-María, Sandra Bernaldo de Quirós, Carlos Suárez, María-Dolores Chiara, Bartolomé Scola, Ana S. Pitiot, Anna Merlo, Aurora Astudillo, Miquel Quer, Milagros Balbín |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Endocrinology Diabetes and Metabolism Clinical Biochemistry Context (language use) Biology medicine.disease_cause Biochemistry Paraganglioma Transcriptome Endocrinology microRNA medicine Humans Carcinoma Renal Cell Aged Regulation of gene expression Mutation Biochemistry (medical) Middle Aged Gene signature Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Kidney Neoplasms Gene Expression Regulation Neoplastic Gene expression profiling MicroRNAs Head and Neck Neoplasms Von Hippel-Lindau Tumor Suppressor Protein Cancer research Female Carcinogenesis Signal Transduction |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 98:E1661-E1666 |
| ISSN: | 1945-7197 0021-972X |
| Popis: | Head and neck paragangliomas (HNPGLs) arise from parasympathetic paraganglias and 35% to 45% are hereditary caused by mutations in succinate dehydrogenase (SDH) genes. The connection between SDH and tumor development is unclear. The most accepted hypothesis proposes a central role for the pseudohypoxic (pHx) pathway activated by hypoxia-inducible factor (HIF). Paradoxically, we showed that activation of HIF in HNPGLs is restricted to a subset of HNPGLs lacking SDH mutations. These tumors overexpress HIF-1α protein and target genes and the HIF-inducible microRNA miR-210 (pHx-HNPGLs).The present study aimed at unraveling the SDH-independent mechanisms involved in the activation of HIF in HNPGLs.The VHL gene was analyzed in 53 tumors by gene sequencing, multiplex-ligation-dependent probe amplification, and quantitative PCR. The miR-210, HIF-1α, and CA9 levels were used as markers of the pHx gene signature. Meta-analysis of the transcriptome of pHx-HNPGLs was performed using the Oncomine platform. Assays in cells lacking functional pVHL and HIF-1α were performed to analyze the role of pVHL/HIF-1α on miR-210 expression.We identified, for the first time, somatic VHL mutations in HNPGLs. These were found in 2 of 4 pHx-HNPGLs with concomitant loss of heterozygosity in one of them; but not in non-pHx-HNPGLs. Meta-analysis of the transcriptome of pHx-HNPGLs revealed that these tumors are highly related to clear cell renal cell carcinoma. Cell-based assays showed that loss of pVHL lead to upregulation of miR-210 mainly via HIF-1α activation.VHL, involved in tumorigenesis of PGLs and clear cell renal cell carcinomas, may be an important player in the pathogenesis of sporadic HNPGLs via activation of an HIF-1α/miR-210 pHx pathway. |
| Databáze: | OpenAIRE |
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