We appreciate your review of our revised manuscript, constructive comments, and suggestions for improving the manuscript. We deeply understand the significance of the experiments using miR-98-resistant PGRMC stably expressing ESCs to directly prove the implication of the miR-mediated PGRMC1 regulation in decidualization. We are transfecting the miR-resistant PGRMC1 expression vector into ESCs cell lines to explore the role of PGRMC1 in decidualization but is not going well. As you advised, lentiviral transduction of the PGRMC1 along with fluorescent protein may enable us to effectively select the overexpressing cells without losing differentiation status in response to decidual stimuli. We have acknowledged this and suggested it as a topic for further research in the “Limitation” section of the revised manuscript following editor’s comment (page 10, lines 336-348). “Limitations: In this study, we proposed that miR-98-mediated PGRMC1 downregulation may be involved in decidualization, but were unable to examine the effects of miR-98-resistant PGRMC1 on differentiation due to technical difficulties establishing PGRMC1-overexpressing ESCs. miR-98 may not be the only miRNA that modulates PGRMC1 expression; therefore, comprehensive analysis of transcriptional, post-transcriptional, and post-translational regulation of endometrial PGRMC1 during decidualization is required. In addition, PGRMC1 can bind to various proteins, including receptors for epidermal growth factor [46] and insulin [47], cytochrome P450 [48], and serpine mRNA-binding protein 1 (SERBP1) [19]. Further, PGRMC1 may interact with proteins associated with endomembrane trafficking/cytoskeleton and mitochondrial functions in decidualizing ESCs [49]. Thus, we plan to investigate the modulation of endometrial PGRMC1 expression and the interaction between PGRMC1 and intracellular proteins during decidualization in the future.”
In conclusion, if this published was published in present form then it would invariably be cited as demonstrating that PGRMC1 downregulation by miR-98 causes decidualization. Since that is by no means certain, the study should not be published in its present form. The opportunity should remain open for the authors to convincingly demonstrate the requirement for PGRMC1 down-regulation in decidualization by performing the requested experiments, or others of their devising. However, in the first instance the manuscript cannot be published as it stands, and should therefore be rejected now with the stated option of subsequent resubmission only if new evidence is obtained.