Gene Expression Profiling and Prognostic Significance of Nuclear and Membrane Progesterone Receptors in Head and Neck Squamous Cell Carcinoma

The risk of developing some types of head and neck squamous cell carcinoma (HNSCC) is seven times higher in males, and such disparities may not be associated only with tobacco and alcohol consumption or HPV infection. Therefore, the endocrine microenvironment is considered another risk factor, as epidemiologic studies have unequivocally shown the protective effect of estrogen in women. This research was focused on progesterone receptors (PRs), the least-studied sex hormone receptors in HNSCC. Our study included fresh tissue samples from 95 primary tumors, 25 metastatic lymph nodes and 40 healthy oral mucosa. Gene expression of nuclear (<i>PGR</i>) and seven membrane PRs (<i>PAQR5</i>, <i>PAQR6</i>, <i>PAQR7</i>, <i>PAQR8</i>, <i>PAQR9</i>, <i>PGRMC1</i> and <i>PGRMC2</i>) was analyzed by qRT-PCR and associated with clinicopathological characteristics. The results showed that, compared to control tissue, <i>PGR</i> was increased in metastatic lymph nodes, while <i>PAQR5</i>, <i>PAQR7</i>, <i>PAQR8</i> and <i>PAQR9</i> were decreased in primary tumors (all <i>p</i> < 0.05). The expression of almost all PRs was greater in older patients and showed moderate to strong positive mutual correlations in both tumors and controls. <i>PARQ8</i> and <i>PAQR9</i> were increased in females and pT4 tumors (all <i>p</i> < 0.05). Survival analysis showed that higher <i>PAQR5</i> (hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.19-6.57, <i>p</i> = 0.019) and <i>PAQR7</i> (HR 2.0, 95% CI 1.01-3.81, <i>p</i> = 0.048) were associated with worse overall survival, but their independence was not proven in multivariate analysis. Although most PRs were reduced in primary tumors, an increased <i>PAQR5</i> expression, also associated with tumor invasion markers, could likely mark a specific aggressive, advanced stage of primary tumors and potentially serve as a negative prognostic biomarker for HNSCC.