Yokoi Ako, Yoshimori Daigo, Oguri Yasuko, Hashimura Miki, Saegusa Makoto
Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Mol Carcinog. 2025 May 19;64(8):1281-6. doi: 10.1002/mc.23928.
The current study aims to delineate the role of a novel anaplastic lymphoma kinase (ALK) transcript, ALK, in ovarian high-grade serous carcinoma (HGSC). Overexpressed ALK exhibited both cytoplasmic and nuclear localization in HGSC cells, whereas full-length ALK was predominantly cytoplasmic. ALK interacts with the DNA repair protein, poly (ADP ribose) polymer 1 (PARP1), and cells stably overexpressing ALK (OE- ALK) were more sensitive to cisplatin-induced apoptosis. Consistent with this, cleaved PARP1 levels were higher in HGSC tissue samples in areas with nuclear ALK immunoreactivity. The ratio of antiapoptotic BCL2 relative to proapoptotic BAX was significantly increased in OE-ALK cells, despite the increase in apoptosis, suggesting that ALK-mediated apoptosis is independent of mitochondrion-driven cell death. OE-ALK decreased epithelial-mesenchymal transition/cancer stem cell properties but did not alter proliferation rates, and nuclear ALK immunopositivity was not associated with clinicopathological factors or prognosis in HGSC. Together, our observations suggest that ALK sensitizes HGSC cells to apoptosis (probably though an association with PARP1) but this may have a relatively minor impact on tumor progression.
本研究旨在阐明一种新型间变性淋巴瘤激酶（ALK）转录本ALK在卵巢高级别浆液性癌（HGSC）中的作用。过表达的ALK在HGSC细胞中表现出胞质和核定位，而全长ALK主要定位于胞质。ALK与DNA修复蛋白聚（ADP核糖）聚合酶1（PARP1）相互作用，稳定过表达ALK（OE-ALK）的细胞对顺铂诱导的凋亡更敏感。与此一致的是，在具有核ALK免疫反应性的HGSC组织样本区域中，裂解的PARP1水平更高。尽管凋亡增加，但在OE-ALK细胞中抗凋亡BCL2与促凋亡BAX的比率显著增加，这表明ALK介导的凋亡独立于线粒体驱动的细胞死亡。OE-ALK降低了上皮-间质转化/癌症干细胞特性，但未改变增殖率，并且核ALK免疫阳性与HGSC的临床病理因素或预后无关。总之，我们的观察结果表明，ALK使HGSC细胞对凋亡敏感（可能通过与PARP1相关），但这可能对肿瘤进展的影响相对较小。
