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The role of membrane progesterone receptors (mPRs), which belong to the progestin and adipoQ receptor (PAQR) family, in mediating rapid, nongenomic (non-classical) progestogen actions has been extensively studied since their identification 20 years ago. Although the mPRs have been implicated in progestogen regulation of numerous reproductive and non-reproductive functions in vertebrates, several critical aspects of their structure and signaling functions have been unresolved until recently and remain the subject of considerable debate. This paper briefly reviews recent developments in our understanding of the structure and functional characteristics of mPRs. The proposed membrane topology of mPRα, the structure of its ligand-binding site, and the binding affinities of steroids were predicted from homology modeling based on the structures of other PAQRs, adiponectin receptors, and confirmed by mutational analysis and ligand-binding assays. Extensive data demonstrating that mPR-dependent progestogen regulation of intracellular signaling through mPRs is mediated by activation of G proteins are reviewed. Close association of mPRα with progesterone membrane receptor component 1 (PGRMC1), its role as an adaptor protein to mediate cell-surface expression of mPRα and mPRα-dependent progestogen signaling has been demonstrated in several vertebrate models. In addition, evidence is presented that mPRs can regulate the activity of other hormone receptors.

Lung cancer remains a huge challenge to public health because of its high incidence and mortality, and lung adenocarcinoma (LUAD) is the main subtype of lung cancer. Hypoxia-induced vascular endothelial growth factor (VEGF) release and angiogenesis have been regarded as critical events in LUAD carcinogenesis. In the present study, membrane progesterone receptor α (mPRα) is deregulated within LUAD tissue samples; increased mPRα contributes to a higher microvessel density (MVD) in LUAD tissues. mPRα knockdown in A549 and PC-9 cells significantly inhibited STAT3 phosphorylation, as well as HIF1α and VEGF protein levels, decreasing cancer cell migration and invasion. The in vivo xenograft model further confirmed that mPRα enhanced the aggressiveness of LUAD cells. Furthermore, mPRα knockdown significantly inhibited hypoxia-induced upregulation in HIF1α and VEGF levels, as well as LUAD cell migration and invasion. Under the hypoxic condition, conditioned medium (CM) derived from mPRα knockdown A549 cells, namely si-mPRα-CM, significantly inhibited HUVEC migration and tube formation and decreased VEGF level in the culture medium. In contrast, CM derived from mPRα-overexpressing A549 cells, namely mPRα-CM, further enhanced HUVEC migration and tube formation and increased VEGF level under hypoxia, which was partially reversed by STAT3 inhibitor Stattic. In conclusion, in LUAD cells, highly expressed mPRα enhances the activation of cAMP/JAK/STAT3 signaling and increases HIF1α-induced VEGF secretion into the tumor microenvironment, promoting HUVEC migration and tube formation under hypoxia.

Background The aim of this study was to determine whether progesterone could inhibit the growth of lung adenocarcinoma cells via membrane progesterone receptor alpha (mPRα) and elucidate its potential mechanism. The relationship between mPRα expression and the survival prognosis of lung adenocarcinoma patients was studied. Methods A mPRα knockdown lung adenocarcinoma cell line was constructed and treated with P4 and Org (a derivative of P4 and specific agonist of mPRα). Cell proliferation was assessed using CCK‐8 and plate colony formation assays. Protein expression was detected by western blotting. A nude mouse model of lung adenocarcinoma was established to assess the antitumor effect of P4/Org in vivo. Results We initially determined that mPRα could promote the development of lung adenocarcinoma through the following lines of evidence. High expression of mPRα both at the mRNA and protein level was significantly associated with the poor prognosis of lung adenocarcinoma patients. The downregulation of mPRα inhibited the proliferation of lung adenocarcinoma cells. We further showed that mPRα mediates the ability of P4 to inhibit the growth of lung adenocarcinoma cells through the following lines of evidence: P4/Org inhibited the proliferation of lung adenocarcinoma cells; mPRα mediated the ability of P4/Org to inhibit lung adenocarcinoma cell proliferation; mPRα mediated the ability of P4/Org to inhibit the PKA (cAMP‐dependent protein kinase)/CREB (cAMP responsive element binding protein) and PKA/β‐catenin signaling pathways; and P4/Org inhibited the growth of a lung adenocarcinoma tumor model in vivo. Conclusions In summary, the results of our study show that progesterone can inhibit lung adenocarcinoma cell growth via mPRα.

Invasive breast cancer is the most common type of malignancy in women worldwide. However, the mechanism responsible for breast cancer metastasis is still unclear and needs further illustration. It has been proven that matrix metallopeptidase 9 (MMP-9) promotes metastasis of the cancer cells. However, the interaction between mPRα and MMP-9 has not been studied. Therefore, in the present research, the effect of MMP-9 on the malignant progression of invasive breast cancer promoted by membrane progesterone receptorα (mPRα) was investigated. The results showed that the protein expression of mPRα, p-Akt and MMP-9 increased in the cancerous tissues compared to that of the noncancerous breast tissue. Furthermore, a positive correlation was found between mPRα and C-erbB-2, as well as the number of involved local lymph nodes. On the other hand, a negative correlation was observed between mPRα and estrogen receptors (ER) along with progesterone receptors (PR). Similarly, a positive association was found between MMP-9 and the number of involved local lymph nodes. Besides, the high expression of MMP-9 also had a positive correlation with the tumor size. However, the high level of MMP-9 had a negative correlation with ER and PR. In addition, there was a positive correlation between mPRα and p-Akt together with MMP-9. The results confirm that mPRα was a major marker of harmful prognosis and it promoted the expression of MMP-9 during invasion to the local lymph nodes through the pathway of PI3K/Akt. The present study provided a novel therapeutic strategy to inhibit breast cancer growth by preventing mPRα signaling pathway.