The prevalence and prognostic significance of endocrinology-related biomarkers in non-small cell lung cancer

Abstract

Lung cancer has become a global health issue, and accounts for over 1.6 million annual deaths worldwide. The need for an improved treatment strategy is pivotal to improve its poor prognosis. Non-small cell lung cancer (NSCLC) is the predominant histological subtype of lung cancer. Gender-related discrepancies in overall survival and prognosis have been observed among NSCLC patients. This fact has led researchers to focus on hormones as a potential disease contributor. We sought to determine the prevalence and prognostic role of the sex steroid hormone receptors (SHR) progesterone receptor (PR), estrogen receptor α (ERα) and β (ERβ) and the aromatase enzyme (AR), responsible for peripheral estradiol synthesis, in our cohort of surgically resected NSCLC patients. Further, we elucidated the prognostic role of the microRNA (miRNA) cluster miR 143/145, reported to be associated with the estrogenic pathway. By the use of immunohistochemistry and in situ hybridization on our tissue microarrays (TMAs), constructed from resected tumor tissue, we analyzed the expression of the SHRs and miRNAs in tumor epithelial cells and tumor surrounding stroma. We found that high stromal PR expression was associated with an improved prognosis in female and male NSCLC patients (HR 1.74; P=0.007). High PR expression in tumor epithelial cells was associated with a significant worse prognosis only in female patients (HR 3.46; P=0.001). Further, we reported that high AR expression in tumor epithelial cells was associated with an unfavorable prognosis in all patients (HR; 1.55; P=0.017) and high ERβ expression in tumor epithelial cells emerged as an independent negative prognosticator in female patients (HR: 3.03; P=0.005). High stromal miR-143 expression was associated with an improved prognosis in female patients (HR: 0.53; P=0.019), while high stromal miR-145 expression was a positive prognosticator in the male patient group (HR:0.53; P=0.021). Using functional studies, we revealed a tumor-suppressor function of the miRNA cluster by inhibiting both migration and proliferation of NSCLC cell lines in vitro. In conclusion, we revealed both a gender-related prognostic significance and a compartment-specific prognostic role of the investigated biomarkers. Clinical studies will be needed to evaluate a possible predictive role of these markers in NSCLC.