A new study has provided the first evidence that the mediator complex subunit 15 ( MED15 ) may play a crucial role in the pathophysiology of head and neck squamous cell carcinoma ( HNSCC ).
MED15 overexpression was found to be associated with higher mortality rates in head and neck squamous cell carcinoma patients with cancer recurrence, particularly in oral cavity / oropharyngeal tumors.
MED15 overexpression was also associated with heavy alcohol consumption, which is an risk factor for head and neck squamous cell carcinoma.
Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and has a high rate of recurrence and early metastatic disease, resulting in approximately 350,000 deaths each year.
The findings suggest that MED15 may serve as a prognostic marker for recurrence of head and neck squamous cell carcinoma and as a therapeutic target in patients with head and neck squamous cell carcinoma suffering from recurrences.
Mediator is a multiprotein complex that regulates many signaling pathways. In humans, it consists of 30 subunits including MED15, which has been implicated in breast and prostate cancer, with particular attention being given to its link to transforming growth factor-beta ( TGF-beta ) signaling.
To investigate the role of MED15 in head and neck squamous cell carcinoma, the researchers at the University Hospital of Bonn ( Germany ), analyzed tissues from 113 patients with primary tumors, 30 recurrent tumor tissues, 85 lymph node metastases, and 20 control samples of normal squamous epithelial tissue.
Using immunohistochemical staining, expression scores were calculated by multiplying staining intensity by the index of immunoreactive cells and categorized as no expression ( less than 0.07 ), low expression ( 0.07, less than 0.2 ), or overexpression ( 0.2 ).
They found that 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 control samples.
To determine the extent to which MED15 levels correlated with mortality, the investigators performed immunohistochemical analysis of primary tumor tissues from the 108 patients who developed recurrent tumors.
They found that the mortality rate ( defined as death within 1 to 12 years after first diagnosis ) increased from 58% overall to 78% in the subset of patients whose tumors showed MED15 overexpression, with a significant association found between MED15 overexpression and high mortality.
Further investigation revealed that the mortality rate of patients with tumors in the oropharynx or oral cavity was significantly higher than that of patients with tumors in the hypopharynx or larynx.
Likewise, the expression of MED15 was found to be higher in oral cavity / oropharyngeal tumors compared with tumors from the hypopharynx or larynx.
The study also investigated whether MED15 levels were associated with any of the risk factors for head and neck squamous cell carcinoma, such as tobacco use, alcohol consumption, or chronic oncogenic human papillomavirus infections.
Only heavy alcohol consumption was found to be significantly associated with MED15 overexpression, shedding light on the possible mechanism of action of alcohol's adverse influence.
Researchers believe MED15 may be a molecular marker that can be used to predict the risk for development of tumor recurrence or metastases that can help clinicians make early diagnosis and treatment decisions. Support for this hypothesis comes from their observations that in 74% of cases, there was a concordance for the presence or absence of MED15 overexpression in samples from a patient's primary tumor and corresponding lymph node metastasis.
In addition, MED15 expression correlated with high proliferative activity in HNSCC tissues and genetic inhibition of MED15 reduced both cell proliferation and migration.
They also found that MED15 was highly expressed in the HNSCC malignant cell lines HSC-3 and SCC-25.
Such observations indicate that MED15 overexpression is likely to be a clonal event in the progression of head and neck squamous cell carcinoma. A clonal event is a mutation, deletion, or translocation that occurs within a tumor and recurs in a significant proportion of patients.
These findings regarding MED15 overexpression are particularly significant, as genetic alterations that provide cells with growth advantages and metastatic potential may be present only in subpopulations of cells in the primary tumor, but increase in tissue from metastases and relapsed HNSCC tumors.
A MED15 inhibitor may be a future therapeutic option, especially for patients with advanced disease and tumor recurrence. ( Xagena )
Source: American Journal of Pathology, 2015