Progesterone Receptor isoform B exerts inhibitory effects on tumor cell proliferation regulated by let-7b in Progesterone receptor-positive non-small cell lung cancer

概要

Sex steroids and their receptors have been well-known to play pivotal roles in cancer progression in female reproductive and other malignancies including non-small cell lung cancer (NSCLC). Total progesterone receptor (PR) and PR isoform B (PRB) amounts were generally correlated with better clinical outcomes of NSCLC patients with lower tumor cell proliferation. However, the mechanisms of progesterone-induced inhibition of cell proliferation have remained virtually unknown. Therefore, in this study, I attempted to elucidate the potential mechanisms of inhibition of tumor cell proliferation through PRB in NSCLC by focusing on the role of microRNA (mi-RNA) in NSCLC. I first immunolocalized PRB in 124 NSCLC cases and also mi-RNA expression profiled using a mi-RNA PCR array. TCGA databases for NSCLC and breast cancer were used to confirm the correlation between mi-RNAs and PR expression. I subsequently performed in vitro study of cell proliferation using PRB-expressing cell lines. Of particular interest, in my present study, the presence of PR and PRB were inversely correlated with NSCLC cell proliferation and only let-7b expression was significantly positively correlated with PR expression in both NSCLC and breast cancer. In addition, ectopic expression of let-7b significantly inhibited cell proliferation by inducing both PR and PRB in T47D and BT474 cells. Based on those findings above, I then explored how let-7b mediated PRB expression using TCGA database analysis. Results indicated that E2F1 expression was inversely correlated with both let-7b and PR and was significantly inhibited by let-7b. Inhibition of E2F1 also significantly induced PRB expression compared to PR expression and let-7b activation in T47D and BT474 cells. This study firstly revealed that PRB inhibited cell proliferation in PRB-expressing NSCLC carcinoma cells. This inhibitory effect was regulated by let-7b-E2F1 interaction. Results of my present study could contribute to the development of a novel therapeutic approach targeting let-7b and/or PRB for PRB-positive NSCLC patients.