PO-140 MAPKAPK2 regulates the transcript stability of TNF-α, VEGF, P27 and MKP-1 in the progression of head and neck squamous cell carcinoma

Abstract

IntroductionGlobally, head and neck squamous cell carcinoma (HNSCC) having an estimated annual burden of 6 33 000 new cases with 3 55 000 deaths is the sixth most common cancer. 90% of head and neck cancers are HNSCCs with environmental and lifestyle risk factors including sustained tobacco exposure and alcohol consumption as the primary causes. The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in a variety of pathological conditions including inflammation and metastasis. Post-transcriptional regulation of genes harbouring adenine/uridine-rich elements (AREs) in their 3’-untranslated region (3’-UTR) is controlled by MAPK-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of the p38 MAPK. In response to diverse extracellular stimuli, MK2 influences crucial signalling events, regulates inflammatory cytokine release, mRNA stability and cellular processes including cell cycle regulation, angiogenesis, proliferation, metastasis and cell death. Till date, the biological significance of MK2 pathway in cancer progression is not well elucidated.Material and methodsHuman clinical samples were processed for histopathological, immunohistochemical, western blotting and quantitative real time-polymerase chain reaction analysis. The findings were validated in vitro in HNSCC cell lines. Transcript levels of susceptible genes harbouring RNA-binding sites in their 3’-UTRs were evaluated along with their post-transcriptional stability in MK2-knockdown (MK2KD) cells in both normoxic and hypoxic conditions.Results and discussionsIn the present study, we have reported that MK2 is reproducibly overexpressed in HNSCC and plays a crucial role in its pathogenesis by altering the translational landscape. The increased stability of cyclin-dependent kinase inhibitor 1B (p27) and mitogen-activated protein kinase phosphatase-1 (MKP-1) transcripts and the decreased half-life of tumour necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) transcripts in MK2KD cells suggested that MK2 regulates their mRNA turnover.ConclusionTaken together, our results portray a critical role of MK2 in modulating HNSCC pathogenesis and implicate MK2 as a prominent tumour marker. Majority of p38 inhibitors have already failed in the clinical trials, hence, we have tried to unveil MK2 as a potential novel anticancer therapeutic target in the management of HNSCC.