RESUMO
BACKGROUND: The recently described navigator proteins have a multifaceted role in cytoskeletal dynamics. We report here on the relevance of one of them, navigator 3 (NAV3), in colorectal cancer (CRC). METHODS: We analysed changes in chromosome 12 and NAV3 copy number in CRC/adenoma samples of 59 patients and in 6 CRC cell lines, using fluorescence in situ hybridisation, loss of heterozygosity, and array-CGH. NAV3 target genes were identified by siRNA depletion, expression arrays, and immunohistochemistry. RESULTS: NAV3 deletion and chromosome 12 polysomy were detected in 30 and 70% of microsatellite stability (MSS) carcinomas, in 23 and 30% of adenomas and in four of six CRC cell lines. NAV3 amplification was found in 25% of MSS samples. NAV3 alterations correlated with lymph node metastasis. In normal colon cells, NAV3 silencing induced upregulation of interleukin 23 receptor (IL23R) and gonadotropin releasing hormone receptor. In MSS and microsatellite instability tumours, IL23R immunoreactivity correlated with Dukes' staging and lymph node metastases, whereas nuclear beta-catenin correlated with lymph node metastases only. CONCLUSION: NAV3 copy number changes are frequent in CRC and in adenomas, and upregulation of IL23R, following NAV3 silencing, strongly correlates with Dukes' staging and lymph node metastases. This suggests that NAV3 has a role in linking tissue inflammation to cancer development in the colon.
Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Adenoma/metabolismo , Adenoma/patologia , Linhagem Celular Tumoral , Cromossomos Humanos Par 12/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Repetições de Microssatélites , Estadiamento de Neoplasias , RNA Interferente Pequeno/análise , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores LHRH/genética , Receptores LHRH/metabolismo , Regulação para Cima/genéticaRESUMO
Here, we describe 2 patients with de novo genomic imbalances of 19p13.3. Using high-resolution microarray analysis, we detected a 1.25-Mb deletion in one patient and a 0.81- Mb duplication in another. The resulting phenotypes are quite different; one is a 2-year-old boy with macrocephaly and normal growth, while the other is a 9-year-old boy with microcephaly and growth retardation since birth. Both have dysmorphic features and psychomotor developmental delay. This report gives evidence of the effect of small aberrations of chromosome 19 and describes the phenotypes arising from a duplication and deletion of the same location at 19p13.3.
