OVA66 increases cell growth, invasion and survival via regulation of IGF-1R-MAPK signaling in human cancer cells.
Carcinogenesis
; 35(7): 1573-81, 2014 Jul.
Article
em En
| MEDLINE
| ID: mdl-24667688
ABSTRACT
Ovarian cancer-associated antigen 66 (OVA66), also known as CML66 (GenBank Accession No. AF283301), was first identified in an ovarian carcinoma complementary DNA (cDNA) expression library and was shown to play a role in tumorigenesis. Here, we find that OVA66 influences tumorigenesis by regulating the type I insulin-like growth factor receptor (IGF-1R) signaling pathway. Stable knockdown of OVA66 in cancer cells attenuated phosphorylation of IGF-1R and extracellular signal-regulated kinase 1/2 (ERK1/2)-Hsp27; similarly, a higher level of p-IGF-1R and ERK1/2-Hsp27 signaling was also detected after OVA66 overexpression in HO8910 cells. In vivo knockdown of OVA66 both reduced tumor burden in nude mice and decreased phosphorylation of IGF-1R, ERK1/2 and hsp27. We blocked IGF-1R function both by small interfering RNA (siRNA) and with the chemical inhibitor Linsitinib (OSI-906). By either method, tumorigenesis was inhibited regardless of OVA66 expression; thus, mechanistically, IGF-1R, probably, lies downstream of OVA66 in cancer cells. We also found that OVA66 regulates expression of murine double minute 2 (MDM2); this attenuates ubiquitination of IGF-1R in response to IGF-1 stimulation and promotes active ERK1/2 signaling. Thus, we propose that combined overexpression of OVA66 and MDM2 promotes oncogenesis by enhancing activation of the IGF-1R-ERK1/2 signaling pathway.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Regulação Neoplásica da Expressão Gênica
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Movimento Celular
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Receptor IGF Tipo 1
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Proteínas Quinases Ativadas por Mitógeno
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Proliferação de Células
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Antígenos de Neoplasias
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Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Carcinogenesis
Ano de publicação:
2014
Tipo de documento:
Article