Anaplastic Lymphoma Kinase Overexpression Is Associated with Aggressive Phenotypic Characteristics of Ovarian High-Grade Serous Carcinoma.

Toshihide Matsumoto, Yusuke Oda, Yoshinori Hasegawa, Miki Hashimura, Yasuko Oguri, Hisako Inoue, Ako Yokoi, Masataka Tochimoto, Mayu Nakagawa, Zesong Jiang, Makoto Saegusa

The American journal of pathology 2021 Oct

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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). The current study focused on the functional roles of ALK in HGSC. Cytoplasmic ALK immunoreactivity without chromosomal rearrangement and gene mutations was significantly higher in HGSC compared with non-HGSC-type ovarian carcinomas, and was significantly associated with several unfavorable clinicopathologic 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 cells. Expression of the nervous system-associated gene, ELAVL3, and the corresponding protein (commonly known as HuC) was significantly increased in cells overexpressing ALK. Expression of SRY-box transcription factor (Sox)2 and Sox3 (genes associated with the neural progenitor population) increased in ALK-overexpressing but not ALK-knockdown 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 attributed to increased expression of neuroendocrine markers, including synaptophysin, CD56, and B-cell lymphoma 2, in HGSC 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 the establishment and maintenance of the aggressive phenotypic characteristics of HGSC. Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Citation

Toshihide Matsumoto, Yusuke Oda, Yoshinori Hasegawa, Miki Hashimura, Yasuko Oguri, Hisako Inoue, Ako Yokoi, Masataka Tochimoto, Mayu Nakagawa, Zesong Jiang, Makoto Saegusa. Anaplastic Lymphoma Kinase Overexpression Is Associated with Aggressive Phenotypic Characteristics of Ovarian High-Grade Serous Carcinoma. The American journal of pathology. 2021 Oct;191(10):1837-1850