RESUMO
Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HGSOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here, we show that the IGF2 mRNA-binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HGSOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in an RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signalling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation, only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rationale for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HGSOC.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Quinases da Família src/metabolismo , Junções Aderentes/genética , Junções Aderentes/metabolismo , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Domínios de Homologia de src , Quinases da Família src/antagonistas & inibidoresRESUMO
An ischemic stroke during sexual intercourse is very rare. A basilar artery thrombosis during sexual intercourse has not been described previously. We report a young woman with a life-threatening basilar artery thrombosis during sexual intercourse, with a resulting locked-in syndrome. The positive high intensity transient signals (HITS) diagnosis showed a right-to-left shunt and is in line with paradoxic embolism. The molecular genetics revealed a homozygosity 4G/4G in the region PAI1, -675 (promoter polymorphism) as a risk factor for ischemic stroke. Sexual intercourse is a possible, albeit unusual stroke cause, especially in young people.
