The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada.
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Sci Rep. 2022 Feb 22;12(1):3011. doi: 10.1038/s41598-022-06796-2.
High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy often diagnosed at an advanced stage. Although most HGSOC patients respond initially to debulking surgery combined with cytotoxic chemotherapy, many ultimately relapse with platinum-resistant disease. Thus, improving outcomes requires new ways of limiting metastasis and eradicating residual disease. We identified previously that Liver kinase B1 (LKB1) and its substrate NUAK1 are implicated in EOC spheroid cell viability and are required for efficient metastasis in orthotopic mouse models. Here, we sought to identify additional signalling pathways altered in EOC cells due to LKB1 or NUAK1 loss-of-function. Transcriptome analysis revealed that inflammatory signalling mediated by NF-κB transcription factors is hyperactive due to LKB1-NUAK1 loss in HGSOC cells and spheroids. Upregulated NF-κB signalling due to NUAK1 loss suppresses reactive oxygen species (ROS) production and sustains cell survival in spheroids. NF-κB signalling is also activated in HGSOC precursor fallopian tube secretory epithelial cell spheroids, and is further enhanced by NUAK1 loss. Finally, immunohistochemical analysis of OVCAR8 xenograft tumors lacking NUAK1 displayed increased RelB expression and nuclear staining. Our results support the idea that NUAK1 and NF-κB signalling pathways together regulate ROS and inflammatory signalling, supporting cell survival during each step of HGSOC pathogenesis. We propose that their combined inhibition may be efficacious as a novel therapeutic strategy for advanced HGSOC.
高级别浆液性卵巢癌（HGSOC）是一种侵袭性恶性肿瘤，通常在晚期诊断。尽管大多数 HGSOC 患者最初对减瘤手术联合细胞毒性化疗有反应，但许多患者最终会因铂类耐药疾病而复发。因此，改善预后需要新的方法来限制转移和根除残留疾病。我们之前发现，肝激酶 B1（LKB1）及其底物 NUAK1 参与 EOC 球体细胞活力，并且是在原位小鼠模型中有效转移所必需的。在这里，我们试图确定由于 LKB1 或 NUAK1 功能丧失而在 EOC 细胞中改变的其他信号通路。转录组分析显示，由于 LKB1-NUAK1 缺失，EOC 细胞和球体中的 NF-κB 转录因子介导的炎症信号通路过度活跃。由于 NUAK1 缺失导致 NF-κB 信号通路下调，抑制活性氧（ROS）的产生并维持球体中的细胞存活。NF-κB 信号通路也在 HGSOC 前体输卵管分泌上皮细胞球体中被激活，并且由于 NUAK1 的缺失而进一步增强。最后，对缺乏 NUAK1 的 OVCAR8 异种移植肿瘤进行免疫组织化学分析显示，RelB 表达和核染色增加。我们的结果支持这样一种观点，即 NUAK1 和 NF-κB 信号通路共同调节 ROS 和炎症信号，在 HGSOC 发病机制的每一步中支持细胞存活。我们提出，它们的联合抑制可能是一种有效的治疗晚期 HGSOC 的新策略。
