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首页> 外文期刊>Journal of Cellular Physiology >RUMI is a novel negative prognostic marker and therapeutic target in non–small‐cell lung cancer
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RUMI is a novel negative prognostic marker and therapeutic target in non–small‐cell lung cancer

机译：鲁米是一种新型的消极和预后标志治疗目标在非小细胞肺癌

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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.
机译：最近下的一代基因组和全面转录组分析在肺癌患者中,几个临床观察,引人注目肺癌的小鼠模型的证据发现了Notch信号的关键作用的发生和发展的非小细胞肺癌(NSCLC)。O葡糖基转移酶,调节切口信号通过O glucosylation应承担的缺口受体,是唯一的酶的活动都需要吗激活。在非小细胞肺癌发展研究鲁米的参与和发展,进一步探讨了在非小细胞肺癌治疗的潜在目标。我们已经确定,鲁米高度表达在细支气管和肺泡上皮细胞,包括俱乐部细胞和肺泡II型细胞。值得注意的是,鲁米映射到该地区的染色体3 q相对应的主要特征在非小细胞肺癌肿瘤转化,明显放大,在NSCLC中肿瘤。预测的不良预后和生存非小细胞肺癌患者。在非小细胞肺癌细胞,调节切口活动它沉默大大降低细胞增殖、迁移和生存。downregulation导致严重的细胞周期的必经阶段逮捕、基因组不稳定性增加,诱发晚apoptotic-nonapoptotic细胞死亡。研究表明,鲁米是一种新型的负面的与重要的治疗预后因子非小细胞肺癌的潜力,体现特定的相关性尤其是考虑到当前等级抑制策略目标配体依赖的切口应承担的激活,大量非小细胞肺癌是由配体还是独立的缺口活动。

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