Research Institute in Oncology & Hematology, Winnipeg, Manitoba, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R3E 0V9, Canada.
Research Institute in Oncology & Hematology, Winnipeg, Manitoba, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R3E 0V9, Canada; Department of Obstetrics, Gynecology & Reproductive Sciences, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Cancer Lett. 2021 Mar 1;500:194-207. doi: 10.1016/j.canlet.2020.11.051. Epub 2020 Dec 5.
Despite high-grade serous ovarian cancer (HGSOC) being the most common and lethal gynecological cancer in women, the early etiological events driving disease development remain largely unknown. Emerging evidence now suggests that chromosome instability (CIN; ongoing changes in chromosome numbers) may play a central role in the development and progression of HGSOC. Importantly, genomic amplification of the Cyclin E1 gene (CCNE1) contributes to HGSOC pathogenesis in ~20% of patients, while Cyclin E1 overexpression induces CIN in model systems. Cyclin E1 levels are normally regulated by the SCF (SKP1-CUL1-FBOX) complex, an E3 ubiquitin ligase that includes RBX1 as a core component. Interestingly, RBX1 is heterozygously lost in ~80% of HGSOC cases and reduced expression corresponds with worse outcomes, suggesting it may be a pathogenic event. Using both short (siRNA) and long (CRISPR/Cas9) term approaches, we show that reduced RBX1 expression corresponds with significant increases in CIN phenotypes in fallopian tube secretory epithelial cells, a cellular precursor of HGSOC. Moreover, reduced RBX1 expression corresponds with increased Cyclin E1 levels and anchorage-independent growth. Collectively, these data identify RBX1 as a novel CIN gene with pathogenic implications for HGSOC.
尽管高级别浆液性卵巢癌（HGSOC）是女性中最常见和最致命的妇科癌症，但导致疾病发展的早期病因事件在很大程度上仍不清楚。现在有新的证据表明，染色体不稳定性（CIN；染色体数量的持续变化）可能在 HGSOC 的发展和进展中起核心作用。重要的是，细胞周期蛋白 E1 基因（CCNE1）的基因组扩增导致约 20%的患者发生 HGSOC 发病机制，而细胞周期蛋白 E1 的过表达在模型系统中诱导 CIN。细胞周期蛋白 E1 的水平通常受 SCF（SKP1-CUL1-FBOX）复合物调节，该复合物是一种 E3 泛素连接酶，其核心成分包括 RBX1。有趣的是，RBX1 在约 80%的 HGSOC 病例中存在杂合性缺失，表达减少与预后不良相对应，表明其可能是一种致病事件。我们使用短期（siRNA）和长期（CRISPR/Cas9）方法表明，RBX1 表达减少与输卵管分泌上皮细胞（HGSOC 的细胞前体）中 CIN 表型的显著增加相对应。此外，RBX1 表达减少与 Cyclin E1 水平升高和锚定非依赖性生长相对应。总的来说，这些数据表明 RBX1 是一种新的 CIN 基因，对 HGSOC 具有致病意义。
