MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability

Sourabh Soni,Yogendra S Padwad,Munish Kumar Saroch,Bal Chander,Narendra Vijay Tirpude

doi:10.1186/s13046-019-1167-2

Abstract

BackgroundHead and neck squamous-cell carcinoma (HNSCC) ranks sixth among cancers worldwide. Though several molecular mechanisms of tumor initiation and progression of HNSCC are known, others remain unclear. Significance of p38/MAPKAPK2 (Mitogen-activated protein kinase-activated protein kinase-2) pathway in cell stress and inflammation is well established and its role in tumor development is being widely studied.MethodsWe have elucidated the role of MAPKAPK2 (MK2) in HNSCC pathogenesis using clinical tissue samples, MK2-knockdown (MK2KD) cells and heterotropic xenograft mice model.ResultsIn patient-derived tissue samples, we observed that MK2 is reproducibly overexpressed. Increased stability of cyclin-dependent kinase inhibitor 1B (p27), mitogen-activated protein kinase phosphatase-1 (MKP-1) transcripts and decreased half-life of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) transcripts in MK2KD cells suggests that MK2 regulates their transcript stability. In vivo xenograft experiments established that knockdown of MK2 attenuates course of tumor progression in immunocompromised mice.ConclusionAltogether, MK2 is responsible for regulating the transcript stability and is functionally important to modulate HNSCC pathogenesis.

Highlights

Head and neck squamous-cell carcinoma (HNSCC) ranks sixth among cancers worldwide
Experimental evidences indicate that MK2, the prime target of p38, regulates the stability of essential genes involved in tumor pathogenesis that harbor adenine/uridine-rich elements (AREs) in their 3′-untranslated regions (3′-UTRs) [10]
We found that MK2KD in tumor milieu mimicking hypoxic conditions stabilized p27 and mitogen-activated protein kinase phosphatase-1 (MKP-1) but destabilized Tumor necrosis factor-alpha (TNF-α)

Summary

Introduction

Head and neck squamous-cell carcinoma (HNSCC) ranks sixth among cancers worldwide. Though several molecular mechanisms of tumor initiation and progression of HNSCC are known, others remain unclear. Significance of p38/MAPKAPK2 (Mitogen-activated protein kinase-activated protein kinase-2) pathway in cell stress and inflammation is well established and its role in tumor development is being widely studied. Head and neck squamous cell carcinoma (HNSCC) having an estimated annual burden of 633,000 new cases and 355,000 deaths is the sixth most common cancer with the male to female ratio ranging from 2:1 to 4:1 [1]. Systemic side effects like hepatic and cardiac toxicity as well as central nervous system disorders caused by the small molecules-based p38 inhibitors have hindered their translational use This might be attributed to the fact that p38 regulates more than sixty substrates and its direct inhibitors have failed in their clinical utility due to undesired side effects [6]. It has been established that MK2 plays a significant role in a variety of cellular processes like cytoskeleton reorganization, chromatin remodeling, cell-cycle regulation and cell migration as indicated by its downstream substrates [7]

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Conclusion