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- Title
Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma.
- Authors
Gavine, Paul R.; Mei Wang; Dehua Yu; Eva Hu; Chunlei Huang; Jenny Xia; Xinying Su; Joan Fan; Tianwei Zhang; Qingqing Ye; Li Zheng; Guanshan Zhu; Ziliang Qian; Qingquan Luo; Ying Yong Hou; Qunsheng Ji
- Abstract
Background: MAPK7/ERK5 (extracellular-signal-regulated kinase 5) functions within a canonical three-tiered MAPK (mitogen activated protein kinase) signaling cascade comprising MEK (MAPK/ERK kinase) 5, MEKK(MEK kinase) 2/3 and ERK5 itself. Despite being the least well studied of the MAPK-modules, evidence supports a role for MAPK7-signaling in the pathology of several cancer types. Methods and Results: Fluorescence in situ hybridization (FISH) analysis identified MAPK7 gene amplification in 4 % (3/74) of non-small cell lung cancers (NSCLC) (enriched to 6 % (3/49) in squamous cell carcinoma) and 2 % (2/95) of squamous esophageal cancers (sqEC). Immunohistochemical (IHC) analysis revealed a good correlation between MAPK7 gene amplification and protein expression. MAPK7 was validated as a proliferative oncogenic driver by performing in vitro siRNA knockdown of MAPK7 in tumor cell lines. Finally, a novel MEK5/MAPK7 co-transfected HEK293 cell line was developed and used for routine cell-based pharmacodynamic screening. Phosphorylation antibody microarray analysis also identified novel downstream pharmacodynamic (PD) biomarkers of MAPK7 kinase inhibition in tumor cells (pMEF2A and pMEF2D). Conclusions: Together, these data highlight a broader role for dysregulated MAPK7 in driving tumorigenesis within niche populations of highly prevalent tumor types, and describe current efforts in establishing a robust drug discovery screening cascade.
- Subjects
MITOGEN-activated protein kinases; SQUAMOUS cell carcinoma; ESOPHAGEAL cancer; LUNG cancer; GENE expression; FLUORESCENCE in situ hybridization
- Publication
BMC Cancer, 2015, Vol 15, Issue 1, p1
- ISSN
1471-2407
- Publication type
Article
- DOI
10.1186/s12885-015-1455-y