RUMI is a novel negative prognostic marker and therapeutic target in non–small‐cell lung cancer
| Autor: | Agnes Malysa, Gerold Bepler, Rodrigo Fernandez-Valdivia, Carlos Redondo, Wei Chen, Hyejeong Jang, May Chammaa |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Cell Survival Physiology Clinical Biochemistry Notch signaling pathway Biology Article Transcriptome 03 medical and health sciences Downregulation and upregulation Cell Movement Carcinoma Non-Small-Cell Lung Biomarkers Tumor medicine Animals Gene silencing Neoplastic transformation Gene Silencing Molecular Targeted Therapy Lung cancer Bronchioles Cell Proliferation Receptors Notch Cell growth Epithelial Cells Cell Biology Cell cycle Prognosis medicine.disease respiratory tract diseases Gene Expression Regulation Neoplastic Mice Inbred C57BL Pulmonary Alveoli 030104 developmental biology Glucosyltransferases Cancer research Signal Transduction |
| Zdroj: | Journal of Cellular Physiology. 233:9548-9562 |
| ISSN: | 1097-4652 0021-9541 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text