Insight into the role and regulation of gap junction genes in lung cancer and identification of nuclear Cx43 as a putative biomarker of poor prognosis
Aasen, Trond (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sansano, Irene (Hospital Universitari Vall d'Hebron)
Montero, María Ángeles (Hospital Universitari Vall d'Hebron)
Romagosa, Cleofé (Hospital Universitari Vall d'Hebron)
Temprana-Salvador, Jordi (Hospital Universitari Vall d'Hebron)
Martinez-Marti, Alex (Hospital Universitari Vall d'Hebron)
Moliné, Teresa (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Hernández-Losa, Javier (Centro de Investigación Biomédica en Red de Cáncer)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Fecha:	2019
Resumen:	Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30. 3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 73 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival (p = 0. 014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p = 0. 002) but not in the squamous carcinoma subtype (p = 0. 578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.
Ayudas:	Instituto de Salud Carlos III CPII16-00042 Instituto de Salud Carlos III PI13-00763 Instituto de Salud Carlos III PI16-00772
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Connexins ; Cx43 ; Gap junctions ; Lung cancer ; Immunohistochemistry ; Prognosis ; Nuclear
Publicado en:	Cancers, Vol. 11 Núm. 3 (march 2019) , p. 320, ISSN 2072-6694

DOI: 10.3390/cancers11030320
PMID: 30845770

20 p, 5.5 MB

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