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RUMI is a novel negative prognostic marker and therapeutic target in non-small-cell lung cancer.
- Source :
-
Journal of cellular physiology [J Cell Physiol] 2018 Dec; Vol. 233 (12), pp. 9548-9562. Date of Electronic Publication: 2018 Jun 28. - Publication Year :
- 2018
-
Abstract
- 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.<br /> (© 2018 Wiley Periodicals, Inc.)
- Subjects :
- Animals
Bronchioles metabolism
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung pathology
Cell Movement
Cell Proliferation
Cell Survival
Epithelial Cells metabolism
Epithelial Cells pathology
Gene Expression Regulation, Neoplastic
Gene Silencing
Lung Neoplasms genetics
Lung Neoplasms pathology
Mice, Inbred C57BL
Prognosis
Pulmonary Alveoli metabolism
Pulmonary Alveoli pathology
Receptors, Notch metabolism
Signal Transduction
Biomarkers, Tumor metabolism
Carcinoma, Non-Small-Cell Lung metabolism
Glucosyltransferases metabolism
Lung Neoplasms metabolism
Molecular Targeted Therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4652
- Volume :
- 233
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of cellular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 29953591
- Full Text :
- https://doi.org/10.1002/jcp.26858