Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma.

Paul R Gavine,Joan Fan,Qunsheng Ji,Dehua Yu,Jenny Xia,Qingquan Luo,Ziliang Qian,Xinying Su,Ying Yong Hou,Li Zheng,Qingqing Ye,Tianwei Zhang,Mei Wang,Guanshan Zhu,Chunlei Huang,Eva Hu

doi:10.1186/s12885-015-1455-y

Abstract

BackgroundMAPK7/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 resultsFluorescence 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).ConclusionsTogether, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1455-y) contains supplementary material, which is available to authorized users.

Highlights

MAPK7/ERK5 functions within a canonical three-tiered MAPK signaling cascade comprising MEK (MAPK/ERK kinase) 5, MEKK(MEK kinase) 2/3 and ERK5 itself
In the work reported here, we identified genetic dysregulation of MAPK7 and protein overexpression in clinical samples of non-small cell lung cancer (NSCLC) and esophageal cancer (EC) of Asian origin, using array comparative genomic hybridization and Fluorescence in situ hybridization (FISH) technologies
Analysis revealed that all 3 MAPK7 amplified cases had corresponding high level MAPK7 protein expression, suggesting a good correlation of MAPK7 gene amplification with high level protein expression (Fig. 2A and Additional file 1: Figure S1)

Summary

Introduction

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. In the context of cancer, clinical evidence suggests a role for dysregulated MEK5/ERK5 signaling as a driver of tumorigenesis in several cancers. In breast cancer, increased ERK5 protein levels are associated with decreased disease-free survival and MEK5 expression is up-regulated by constitutive activation of STAT (signal transducer and activator of transcription) 3, commonly detected in advanced breast cancer [15, 16]. The ERK5 pathway appears to play a role in mediating chemoresistance in breast cancer cells and contributes to neuregulin signaling in breast cancer cells overexpressing ErbB2 [17, 18]. Preclinical validation work using small-interfering RNA (siRNA) suppression of MAPK7 expression in amplified cell lines confirmed a role for dysregulated MAPK7 in controlling mitotic entry

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