Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan.
Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
J Cell Physiol. 2018 Dec;233(12):9548-9562. doi: 10.1002/jcp.26858. Epub 2018 Jun 28.
Recent comprehensive next-generation genome and transcriptome analyses in lung cancer patients, several clinical observations, and compelling evidence from mouse models of lung cancer have uncovered a critical role for Notch signaling in the initiation and progression of non-small-cell lung cancer (NSCLC). Notably, Rumi is a "protein O-glucosyltransferase" that regulates Notch signaling through O-glucosylation of Notch receptors, and is the only enzymatic regulator whose activity is required for both ligand-dependent and ligand-independent activation of Notch. We have conducted a detailed study on RUMI's involvement in NSCLC development and progression, and have further explored the therapeutic potential of its targeting in NSCLC. We have determined that Rumi is highly expressed in the alveolar and bronchiolar epithelia, including club cells and alveolar type II cells. Remarkably, RUMI maps to the region of chromosome 3q that corresponds to the major signature of neoplastic transformation in NSCLC, and is markedly amplified and overexpressed in NSCLC tumors. Notably, RUMI expression levels are predictive of poor prognosis and survival in NSCLC patients. Our data indicates that RUMI modulates Notch activity in NSCLC cells, and that its silencing dramatically decreases cell proliferation, migration, and survival. RUMI downregulation causes severe cell cycle S-phase arrest, increases genome instability, and induces late apoptotic-nonapoptotic cell death. Our studies demonstrate that RUMI is a novel negative prognostic factor with significant therapeutic potential in NSCLC, which embodies particular relevance especially when considering that, while current Notch inhibitory strategies target only ligand-dependent Notch activation, a large number of NSCLCs are driven by ligand-independent Notch activity.
最近在肺癌患者中进行的全面下一代基因组和转录组分析、一些临床观察以及来自肺癌小鼠模型的有力证据揭示了 Notch 信号在非小细胞肺癌（NSCLC）的发生和进展中的关键作用。值得注意的是，Rumi 是一种“蛋白 O-葡糖基转移酶”，可通过 Notch 受体的 O-葡糖基化调节 Notch 信号，并且是唯一的酶调节因子，其活性对于配体依赖性和配体非依赖性的 Notch 激活都是必需的。我们已经对 RUMI 在 NSCLC 发生和进展中的作用进行了详细的研究，并进一步探讨了其在 NSCLC 中的靶向治疗潜力。我们已经确定 Rumi 在肺泡和细支气管上皮细胞中高度表达，包括 club 细胞和 II 型肺泡细胞。值得注意的是，RUMI 定位于染色体 3q 区域，该区域对应于 NSCLC 中肿瘤转化的主要特征，并且在 NSCLC 肿瘤中明显扩增和过表达。值得注意的是，RUMI 表达水平可预测 NSCLC 患者的预后不良和生存。我们的数据表明，Rumi 调节 NSCLC 细胞中的 Notch 活性，其沉默可显著降低细胞增殖、迁移和存活。RUMI 下调导致严重的细胞周期 S 期停滞，增加基因组不稳定性，并诱导晚期凋亡-非凋亡细胞死亡。我们的研究表明，RUMI 是 NSCLC 中一种新的负预后因素，具有显著的治疗潜力，特别是当考虑到当前的 Notch 抑制策略仅靶向配体依赖性 Notch 激活，而大量 NSCLC 则由配体非依赖性 Notch 活性驱动时，这一点尤为重要。
