Anaplastic Lymphoma Kinase Overexpression Is Associated with Aggressive Phenotypic Characteristics of Ovarian High-Grade Serous Carcinoma
Anaplastic Lymphoma Kinase Overexpression Is Associated with Aggressive Phenotypic Characteristics of Ovarian High-Grade Serous Carcinoma
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DOI：
10.1016/j.ajpath.2021.06.009
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发表时间：
2021-09-21
影响因子：
6
通讯作者：
Saegusa, Makoto
中科院分区：
文献类型：
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作者：
Matsumoto, Toshihide;Oda, Yusuke;Saegusa, Makoto
在一些原发性实体瘤中发现了全长间变性淋巴瘤激酶（ALK）过度表达，但对其在卵巢高级别浆液性癌（HGSC）中的作用知之甚少。目前的研究重点是ALK在HGSC中的功能作用。与非HGSC型卵巢癌相比，HGSC中无染色体重排和基因突变的细胞质ALK免疫反应性显著较高，并且与几个不利的临床病理因素和不良预后显著相关。稳定过表达ALK的HGSC细胞系表现出细胞增殖增加、癌症干细胞特征增强和细胞迁移加速，而这些表型在ALK敲低细胞中被废除。神经系统相关基因ELAVL 3和相应蛋白（通常称为HuC）的表达在过表达ALK的细胞中显著增加。SRY盒转录因子（Sox）2和Sox 3（与神经祖细胞群相关的基因）的表达在ALK过表达细胞中增加，但在ALK敲低细胞中没有增加。此外，Sox 2或Sox 3的过表达增强了ALK和ELAVL 3启动子的活性，表明存在ALK/Sox/HuC信号环。最后，ALK过表达归因于HGSC组织中神经内分泌标志物（包括突触素、CD 56和B细胞淋巴瘤2）的表达增加。这些结果表明，全长ALK的过表达可能通过与ELAVL 3和Sox因子的协同作用影响HGSC的生物学行为，导致HGSC的侵袭性表型特征的建立和维持。
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.