Objectives: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world. p38α which is required for cancer cell proliferation and survival, growth arrest and cell death in a cell type specific manner, is not well defined in HNSCC.
Methods: Our previous results revealed high levels of phospho-p38MAPK were observed in most (79%) of HNSCC tissue. We blocked p38 signaling in HNSCC cells using three independent approaches both in vitro and in vivo: retroinhibition approach, shRNA, and a specific p38 inhibitor.
Results: We found that blockade of p38 signaling in all approaches significantly inhibited the tumor growth both in vitro and in vivo. Retro-inhibition approach consisting in the use of the expression of an inhibitor-insensitive mutant form of p38α confirmed the effect of p38 inhibitor in cell proliferation in p38WT both in vitro and in vivo. In blockage of p38, xenograft tissues showed less angiogenesis and lymphangiogenesis as detected by CD31 and Lyve 1 stainings, respectively. p38α also controlled gene expression of several cancer-derived inflammatory mediators including IL-6, IL-8, COX-2, Gro-α and GM-CSF as well as the production of IL-6 in vitro. Furthermore, p38 inhibition had strong effects on the production of IL-1α, IL-1β, IL-6, IL-8, GM-CSF and VEGF in mice which corresponded to the effects on angiogenesis and lymphangiogenesis.
Conclusion: Our findings suggest that p38α functions as a positive regulator of head and neck cancer cell proliferation by controlling the cancer-derived inflammatory mediators as results in anti-angiogenic and lymphangiogenic effects.
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