Membrane metalloendopeptidase (MME) is positively correlated with systemic lupus erythematosus and may inhibit the occurrence of breast cancer

Jiatong Ding; Chenxi Li; Kexin Shu; Wanying Chen; Chenxi Cai; Xin Zhang; Wenxiong Zhang

doi:10.1371/journal.pone.0289960

Peer Review History

Original SubmissionDecember 19, 2022
20 Mar 2023 Decision Letter - Samikshan Dutta, Editor PONE-D-22-34693 Membrane metalloendopeptidase (MME) is positively correlated with systemic lupus erythematosus and may inhibit the occurrence of breast cancer PLOS ONE Dear Dr. Zhang, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by May 03 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript by Ding et al. reports that Membrane metalloendopeptidase (MME) is positively correlated with systemic lupus erythematosus and may inhibit the occurrence of breast cancer. Authors also identified that MME is a highly accurate diagnostic biomarker for breast cancer. This is an excellent insight that will pique the readers' interest. However, few suggestions will increase the quality of manuscript. 1. The author should demonstrate the interaction between MME and the PI3K/AKT/FOXO signaling pathway in BRCA. 2. Authors should clarify the relationship between MME and all the different types of breast cancer. 3. According to this study, in Conclusion section author need to re-write this sentence “In summary, we identified that MME was negatively related to SLE but positively related to BRCA.” 4. Figure quality is very bad. Authors should improve. 5. There are couple of grammatical and spelling mistakes. Minor changes to the manuscript's writing will also help to reinforce the paper. Reviewer #2: The manuscript by Ding et al revealed an interesting rationale and finding to define aggressive BC pathology. Based on Weighted gene coexpression network analysis between BC dataset and systemic lupus erythematosus dataset, the auhtrs group identified membrane metalloendopeptidase hold the key in BC pathology. They have extensively performed bioinformatics analysis to give a strong rationale and reason t believe MME plays a major role in BC. As such the manuscript is interesting; however, the authors need to extensively address the manuscript. Some of the major comments are Though, we understood, majority of the data were analyzed using primary BC gene sequences and other parameters. It is important to confirm the hypothesis using any dataset from advanced BC or metastatic tissue derived gene sequences. The second major concern is the manuscript did not address to show the relation between the original function of MME upon the adverse pathology conditions. It Is important that being peptidases, there might be numerous substrates for MME, the manuscript should address the relevance in this manuscript. The methodology should be clear and brief. For example ¬ “Additionally, we visited the UALCAN website (http://ualcan.path.uab.edu/analysis-prot.html) to explore the protein expression level of MME in the CPTAC dataset [13]”. The website url details may not needed as it is abbreviated, and the detail should be give which dataset and cancer is analyzed Then, we visited the ROC plotter website (http://www.rocplot.org/) to investigate the relationship between MME expression and the response to therapy of breast cancer patients [22]. The rationale for this analysis DNA methylation, methyltransferases and mismatch repair correlation. further the correlation though significant, not very strong, it is better be removed from this manuscript unless there is strong relevance. In addition to the miRNA, TF analysis should give better evidence on the upstream regulator of MME. The manuscript should include the TF analysis. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. 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Revision 1
26 Apr 2023 Author Response Dear Editors and Reviewers: Thank you for the letter and for the reviewers’ comments concerning our manuscript, entitled “Membrane metalloendopeptidase (MME) is positively correlated with systemic lupus erythematosus and may inhibit the occurrence of breast cancer” (ID: PONE-D-22-34693). All of the authors read the peer reviewers’ comments carefully and provided point-by-point response. All of the comments were valuable and very helpful for revising and improving our paper and provided important guiding significance of our research. We have substantially revised the manuscript according to the reviewers' comments. Revised portions are marked in red in the paper. All things considered, the main corrections in the paper and the responses to the reviewers’ comments follow. Responses to the reviewer’s comments: Reviewer #1: 1. Comment: The author should demonstrate the interaction between MME and the PI3K/AKT/FOXO signaling pathway in BRCA. Response and changes: Thank you for your advice. We explored the roles of PTEN, BCL6, and CD19, the MME-binding proteins, in the FOXO and PI3K-AKT signaling pathways with the KEGG database in “Results” section. Although there is no evidence that MME is directly involved in these two signaling pathways, we believe that MME may regulate them indirectly through the interaction of the abovementioned proteins. 2. Comment: Authors should clarify the relationship between MME and all the different types of breast cancer. Response and changes: Thank you for your comments. In Figure 2G-J, we added the expression of MME in different histological types of breast cancer and metastases. 3. Comment: According to this study, in Conclusion section author need to re-write this sentence “In summary, we identified that MME was negatively related to SLE but positively related to BRCA.” Response and changes: Thank you for pointing out our clerical error; we have now corrected it in “Conclusion” section. 4. Comment: Figure quality is very bad. Authors should improve. Response and changes: Thank you for pointing this out. We have remade the figures. 5. Comment: There are couple of grammatical and spelling mistakes. Minor changes to the manuscript's writing will also help to reinforce the paper. Response: Thank you for pointing out our shortcomings, and we have carefully revised the text. Thank you for the comments and suggestions. Reviewer #2: 1. Comment: Though, we understood, majority of the data were analyzed using primary BC gene sequences and other parameters. It is important to confirm the hypothesis using any dataset from advanced BC or metastatic tissue derived gene sequences. Response and changes: Thank you for your comments. In Figure 2I and J, we compare the expression of MME between primary breast cancer and brain, lung, and bone metastases from breast cancer. 2. Comment: The second major concern is the manuscript did not address to show the relation between the original function of MME upon the adverse pathology conditions. It Is important that being peptidases, there might be numerous substrates for MME, the manuscript should address the relevance in this manuscript. Response: Thank you for pointing out our shortcomings. MME may act as a tumor suppressor in breast cancer by regulating the PI3K/Akt signaling pathway, especially its downstream FoxO signaling pathway. Moreover, the mechanism responsible for metastasis inhibition by MME seems to be associated with decreased activation of FAK, RhoA, and downstream MEK/ERK, which are involved in tumor migration and metastasis1. However, due to the limited current research, the specific mechanism of MME in BRCA still needs further study. Changes: We have further discussed the mechanism of MME in the “Discussion” section. However, due to the limited number of current studies, it is difficult to clearly explain the detailed mechanism of MME. It is hoped that our research will arouse the interest of the academic community in MME, which will help us better answer this question. 3. Comment: The methodology should be clear and brief. For example ¬ “Additionally, we visited the UALCAN website (http://ualcan.path.uab.edu/analysis-prot.html) to explore the protein expression level of MME in the CPTAC dataset [13]”. The website url details may not needed as it is abbreviated, and the detail should be give which dataset and cancer is analyzed Then, we visited the ROC plotter website (http://www.rocplot.org/) to investigate the relationship between MME expression and the response to therapy of breast cancer patients [22]. Response and changes: Thank you for your suggestions. We have simplified the “Method” section to avoid unnecessary descriptions. 4. Comment: The rationale for this analysis DNA methylation, methyltransferases and mismatch repair correlation. further the correlation though significant, not very strong, it is better be removed from this manuscript unless there is strong relevance. Response and changes: Thank you for your suggestion; we have deleted these unimportant results. 5. Comment: In addition to the miRNA, TF analysis should give better evidence on the upstream regulator of MME. The manuscript should include the TF analysis. Response and changes: Thank you for your advice. We supplemented this part of the results in the "Results" section. With the TRRUST website2, we identified HOXC6, MYC, SP1, and SPI1 as transcription factors that regulate the expression of MME (Table S4). Thank you for the comments and suggestions. We tried our best to improve the manuscript. These changes did not influence the framework of the paper. We did not list all changes here but marked them in red in the revised manuscript. We earnestly appreciate the editor’s/reviewers’ hard work and hope that the corrections meet with approval. Once again, thank you very much for the comments and suggestions. Reference 1. Li M, Wang L, Zhan Y, Zeng T, Zhang X, Guan XY, et al. Membrane Metalloendopeptidase (MME) Suppresses Metastasis of Esophageal Squamous Cell Carcinoma (ESCC) by Inhibiting FAK-RhoA Signaling Axis. Am J Pathol. 2019; 189(7):1462-1472. 2. Han H, Cho JW, Lee S, Yun A, Kim H, Bae D, et al. TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res. 2018 Jan 4;46(D1):D380-D386. Attachments Attachment Submitted filename: Response letter.docx https://doi.org/10.1371/journal.pone.0289960.r002
31 Jul 2023 Decision Letter - Samikshan Dutta, Editor Membrane metalloendopeptidase (MME) is positively correlated with systemic lupus erythematosus and may inhibit the occurrence of breast cancer PONE-D-22-34693R1 Dear Dr. Zhang, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Samikshan Dutta, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #3: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: (No Response) ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #3: (No Response) ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors have addressed all my comments for this paper. The paper has been significantly improved after revising. I will recommend the editor accept this paper and publish it. Reviewer #3: This manuscript describes the in-silico validation of association of membrane metalloendopeptidase with SLE mediated inhibition of breast cancer. Since this is revision, I have focussed mainly on whether the authors have addressed the concerns raised by the primary reviewers. All the comments have been addressed and I belive manuscript is ready for publication. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #3: No ******** https://doi.org/10.1371/journal.pone.0289960.r003
Formally Accepted
3 Aug 2023 Acceptance Letter - Samikshan Dutta, Editor PONE-D-22-34693R1 Membrane metalloendopeptidase (MME) is positively correlated with systemic lupus erythematosus and may inhibit the occurrence of breast cancer Dear Dr. Zhang: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Samikshan Dutta Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0289960.r004

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