Anaplastic lymphoma kinase (ALK) overexpression is associated with aggressive phenotypic characteristics of ovarian high-grade serous carcinoma
Menée à l'aide de lignées cellulaires de carcinome séreux ovarien de haut grade, d'échantillons tumoraux et de données du projet "The cancer Genome Atlas", cette étude met en évidence une association entre la surexpression de la kinase du lymphome anaplasique ALK et le caractère agressif de la tumeur
Résumé en anglais
Deregulated full-length anaplastic lymphoma kinase (ALK) overexpression has been found in some primary solid tumors, but little is known about its role in ovarian high-grade serous carcinoma (HGSC). Here we focused on the functional roles of ALK in HGSC. Cytoplasmic ALK immunoreactivity without chromosomal rearrangement and gene mutations was significantly higher in HGSC as compared to non-HGSC type ovarian carcinomas, and was significantly associated with several unfavorable clinicopathological factors and poor prognosis. HGSC cell lines stably overexpressing ALK exhibited increased cell proliferation, enhanced cancer stem cell features, and accelerated cell mobility, whereas these phenotypes were abrogated in ALK-knockdown (KD) cells. Expression of the nervous system-associated gene, ELAVL3, and the corresponding protein (commonly known as HuC) was significantly increased in cells overexpressing ALK. There was increased expression of Sox2 and Sox3 (genes associated with the neural progenitor population) in ALK-overexpressing but not ALK-KD cells. Furthermore, overexpression of Sox2 or Sox3 enhanced both ALK and ELAVL3 promoter activities, suggesting the existence of ALK/Sox/HuC signaling loops. Finally, ALK overexpression was due to increased expression of neuroendocrine markers including synaptophysin, CD56, and BCL2 in HGCS tissues. These findings suggest that overexpression of full-length ALK may influence the biological behavior of HGSC through cooperation with ELAVL3 and Sox factors, leading to establishment and maintenance of the aggressive phenotypic characteristics of HGSC.
