Potential clinical significance of downregulation of MAPK pathway components’ mRNA expressions in head and neck squamous cell carcinoma (HNSCC)

Abstract

We previously showed that the MAPK pathway can be mutationally activated, and may implicate drug sensitivity in HNSCC. Here, we report that RNA expression of MAPK pathway components may be associated with HNSCC patient outcome based on the TCGA data. We found that loss of DUSP4, an MAPK pathway negative regulator, was correlated with poor overall survival (P=0.0219) and disease free survival (DFS) in HNSCC (P=0.00137) which can potentially be explained by activation of oncogenic MAPK pathway upon DUSP4 underexpression. Interestingly, we identified a group of HNSCC patients with homozygous loss and mRNA downregulation of MAPK pathway scaffold protein components (GRB2, SHC2 and SHC3) with significantly poorer DFS (P=0.00231). RPPA analysis showed a trend of decreased phospho-RAFs, phospho-MEKs and phosphor-MAPKs protein expression, supportive of an overall decreased MAPK pathway signaling in this subset of patients with reduced MAPK scaffolding gene expression. Unexpectedly, downregulation of multiple MAPK pathway kinases (RAF1, MAPK1 and RPS6KA1) which normally support inactivation of the pathway was found to be significantly associated with poorer DFS (P=6.464x10^-5) with median time to progression of 18.17 months vs. 71.22 months in the unaltered group. Subsequent proteomic analysis of the respective patient tumors from the TCGA cohort (N=357 with RPPA data) showed that these patient tumors had elevated levels of E2F1 protein expression (P=9.383x10^-3). As E2F1 is involved in cell survival upon DNA damage, upregulation of E2F1 protein expression may enable cancer cells to survive after DNA insults by radiotherapy or chemotherapy, and contributes to disease relapse.