Clinical and Molecular Implications of MED15 in Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) progression depends on various dysregulated pathways. Regulation of diverse pathways is mediated by the mediator complex. The mediator subunit MED15 is essential for transforming growth factor (TGF)-β signaling and involved in breast and prostate cancers. We investigated the implication of MED15 in HNSCC. IHC for MED15 was performed on 324 tissue samples, and TGF-β assessed the use of Ki-67 and pSMAD3 as markers. MED15 knockdown followed by proliferation and migration assays, as well as TGF-β1 treatment followed by MED15 analysis, was also performed. MED15 was overexpressed in 35% of primary tumors, 30% of lymph node metastases, and 70% of recurrences in contrast to no or low expression in benign tumors. MED15 overexpression in primary tumors from patients who developed recurrences was associated with higher mortality rates and occurred at highest frequency in oral cavity or oropharyngeal tumors. Furthermore, MED15 expression correlated between primary tumors and corresponding lymph node metastases. MED15 correlated with proliferation in tissues, and MED15 knockdown reduced proliferation and migration. We observed an association between MED15 and TGF-β activity in tissues because TGF-β activation led to increased MED15 expression and reduced pSMAD3 on MED15 knockdown. Taken together, our results implicate MED15 in HNSCC and hint that MED15 overexpression is a clonal event during HNSCC progression. MED15 may serve as a prognostic marker for recurrence and as a therapeutic target.

RCOR1 directly binds to MED28 and weakens its inducing effect on cancer stem cell‐like activity of oral cavity squamous cell carcinoma cells

“…Available evidence showed the dysregulation and functional role of the subunits might be cancer‐specific 3,4 . In HNSC, MED15 is hypomethylated and its upregulation was associated with some malignant behaviors, including lymph node metastases and disease recurrences 5 . Knockdown of MED15 inhibits proliferation and migration of tongue squamous cell carcinoma (TSCC) cells 5 .…”

MED28 and forkhead box M1 (FOXM1) mediate matrix metalloproteinase 2 (MMP2)‐dependent cellular migration in human nonsmall cell lung cancer (NSCLC) cells

“…Although the underlying mechanisms are not fully understood in each case, overexpression or mutation of the genes encoding for some of the subunits have been identified in several types of cancer (Schiano et al, ). For example, the expression of Mediator subunit MED15 with its clinical implications in head and neck squamous cell carcinoma has been identified (Shaikhibrahim et al, ). Recently, we have reported that MED28, another Mediator subunit, is involved in cell growth in human breast cancer cells and colorectal cancer cells (Huang et al, ; Lee, Hsieh, Huang, & Li, ).…”

Diagnostic accuracy of DNA methylation for head and neck cancer varies by sample type and number of markers tested

“…For this study, we selected from the literature reports of common squamous-cell carcinomas of the oral cavity, pharynx, and larynx (HSCC), which account for 90% of HNC [1]. Approximately 650,000 cases of HNC are identified per year [2] and the disease has high recurrence rates and poor prognoses due to distant metastasis [3].…”