Comprehensive analysis of differentially expressed miRNAs in hepatocellular carcinoma: Prognostic, predictive significance and pathway insights

Kayleigh Smith; Dan Beach; Roger Silva; Gyorffy Balazs; Francesca Salani; Francesco Crea

doi:10.1371/journal.pone.0296198

Peer Review History

Original SubmissionDecember 6, 2023
3 Jan 2024 Decision Letter - Junming Yue, Editor PONE-D-23-40355Comprehensive analysis of differentially expressed miRNAs in Hepatocellular carcinoma: prognostic significance and pathway insightsPLOS ONE Dear Dr. Salani, 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. Authors need to address following concerns:1. There is a similar study on miRNA profile in HCC. please address how this study is different from published one. In particular, need to address those novel miRNAs identified in this study.2. It is not clear how important those miRNAs identified and correlated with clinical signatures including overall or progression free survival. Is there any evidence to show they are potential biomarkers for diagnosis or prognosis. Please submit your revised manuscript by Feb 17 2024 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. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. 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[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: Yes 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: In this study, the authors studied the miRNAs in hepatocellular carcinoma to identify a set of miRNA that can potentially be used for HCC prognosis prediction. While some of these miRNAs have already been reported in literature to be associated with HCC, the authors were generally transparent about this and provided clear comparisons between their results versus the reported ones. Overall I found this manuscript of potential interest to the readers of this journal and could provide some value to researchers in this field. However, the following comments need to be addressed: 1. In the title there is no need to capitalize the first letter of "Hepatocellular" 2. What does "co-last authors" mean? I thought it means co-corresponding, but only one of them is labeled as the corresponding author, so I am a bit confused. 3. line 31, the authors claimed they identified "novel miRNAs" with is misleading since most of their reported miRNAs have already been shown in literature to be associated with HCC. Please revise this sentence to be more objective. 4. line 53 "bioinformatic" is a single world 5. line 108 please specify how many genes have been removed in this step, and how many are left to proceed with next steps. 6. Section 2.4.5 needs more details. Please specify how many pathways were identified to be enriched by both methods, and how many are not. Did the authors proceed with only the ones enriched in both methods? 7. line 232-240, it is interesting that the authors found the role of miR-877 to be contradicting with some literature. The authors provided a plausible hypothesis that miR-877 could be playing opposite roles in different stages of HCC. However, following this hypothesis, should we still consider miR-877 as a prognostic biomarker for HCC? The authors should comment on this in their discussion based on their own study and analysis. 8. line 250-251, I think it is too assertive to claim that these 9-miRNA signature "robustly predicts prognosis" since this study solely relies on pubic database with no additional experimental validation. Reviewer #2: The manuscript by K Smith analyzed miRNA data of HCC patients from public database (TCGA) and identified a 9-miRNA signature for HCC patient’s prognosis. The authors also did some pathway analysis and compared their findings with the published HCC and pan cancer associated genes. Here are some concerns: 1. Novelty. This manuscript is very similar to an article published in 2020 (DOI: https://doi.org/10.1038/s41598-020-71324-z), which identified a 23-miRNA signature for HCC stage and prognosis using machine learning. The authors did not discuss this publication in this manuscript. 2. The authors compared the miRNA target genes with published cancer associated gene set, and then concluded that there are ‘direct miRNA interactions with cancer driver genes’, which is not sound enough for the conclusion. 3. Figure 1B and 1C show big differences between White-Caucasians and Asians patients. It would be more interesting and meaningful if the authors discussed the possible reasons. 4. It is worth to show the survival rate of patients related with each miRNA in the 9 miRNAs. ****** 6. 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Revision 1
22 Feb 2024 Author Response All the information are given in the rebuttal letter uploaded. Please find the same information cut and pasted here as well. We thank the Editor for having considered our work for publication in PlosOne journal, and we would like to thank the Reviewers for their valuable suggestions. Herein we provide a specific rebuttal for each point raised by the two Reviewers and the general comments of the Editor. Editor’s comments 1. There is a similar study on miRNA profile in HCC. please address how this study is different from published one. In particular, need to address those novel miRNAs identified in this study. We have now extensively discussed the study and the substantial novelty of our findings. Please see response “I” (to Reviewer 2) and associated amendments to the manuscript. 2. It is not clear how important those miRNAs identified and correlated with clinical signatures including overall or progression free survival. Is there any evidence to show they are potential biomarkers for diagnosis or prognosis. Our study has identified miRNAs that are up-regulated in HCC and prognostically relevant. These two aspects are crucial for diagnosis and prognosis. To highlight the clinical relevance of this signature, we have now discussed the feasibility of detecting these transcripts in biological fluids (see lines 285-288 and references 35-37). To further increase the clinical relevance of our findings, we have investigated whether any of the predicted mRNA target genes is associated with response to sorafenib in HCC patients (Figure 3). As discussed, sorafenib is currently used in the treatment of this malignancy. Unfortunately, we could not study the predictive role of miRNAs in sorafenib-treated patients as the dataset only contained protein-coding genes. Nonetheless, we think that these two amendments will increase the clinical relevance of our study. Reviewer 1: A) In the title there is no need to capitalize the first letter of "Hepatocellular" Edited as suggested. B) What does "co-last authors" mean? I thought it means co-corresponding, but only one of them is labelled as the corresponding author, so I am a bit confused. During the process of submission, we had asked the Editor if it would have been possible to identify two co-last Authors (similarly to the two co-primary ones), since Crea and Salani had contributed equally to study conception, student supervision, data interpretation and critical revision. This possibility is granted by some international journals, but we had not received a clear reply from the Editor in this regard. If not allowed by PlosOne, we will edit according to the Editor’s recommendation. C) line 31, the authors claimed they identified "novel miRNAs" which is misleading since most of their reported miRNAs have already been shown in literature to be associated with HCC. Please revise this sentence to be more objective. We acknowledge that each of the 10 miRNAs has been already identified as HCC-related, mainly in pre-clinical studies. We discuss previously published evidence in lines 248-275, whilst noting that the prognostic role of some transcripts is novel (see for example new added sentence in line 252-254). In addition, we would like to point out that these transcripts have never been comprehensively included in a single prognostic HCC signature (https://doi.org/10.1093/carcin/bgad062; https://doi.org/10.1371/journal.pone.0128628;https://doi.org/10.1002/hep.22160). Considering the Reviewer’s suggestion, we rephrased “novel miRNAs” with “a novel miRNA signature”. D) line 53 "bioinformatic" is a single world Edited as suggested. E) line 108 please specify how many genes have been removed in this step, and how many are left to proceed with next steps. There was a 100% match between target genes in the mirPathDB and mirTargetLink database, so it was not necessary to remove any genes at this stage. We have now specified this in Methods (current line 109). F). Section 2.4.5 needs more details. Please specify how many pathways were identified to be enriched by both methods, and how many are not. Did the authors proceed with only the ones enriched in both methods? We thank the Reviewer for this important question, which allowed us to clarify our methodology. In the Results section (lines 138, 187-191, 194) we now specify how many pathways were present in both datasets and which ones were overlapping. G) Line 232-240, it is interesting that the authors found the role of miR-877 to be contradicting with some literature. The authors provided a plausible hypothesis that miR-877 could be playing opposite roles in different stages of HCC. However, following this hypothesis, should we still consider miR-877 as a prognostic biomarker for HCC? The authors should comment on this in their discussion based on their own study and analysis. We thank the Reviewer for the point raised. As requested, we have explained why we have maintained this miRNA in our prognostic signature: we found internally coherent results in our datasets (up-regulation in HCC vs normal; negative prognostic value. See line 257-266). We acknowledge that further studies are needed to elucidate miR-877 function in HCC and to “test” (not to “confirm” as previously stated) its prognostic role in independent datasets. H) Line 250-251, I think it is too assertive to claim that these 9-miRNA signature "robustly predicts prognosis" since this study solely relies on public database with no additional experimental validation. We thank the Reviewer for the suggestion. We amended the sentence to “significantly predict prognosis”. Reviewer 2: The manuscript by K Smith analyzed miRNA data of HCC patients from public database (TCGA) and identified a 9-miRNA signature for HCC patient’s prognosis. The authors also did some pathway analysis and compared their findings with the published HCC and pan cancer associated genes. Here are some concerns: I) Novelty. This manuscript is very similar to an article published in 2020 (DOI: https://doi.org/10.1038/), which identified a 23-miRNA signature for HCC stage and prognosis using machine learning. The authors did not discuss this publication in this manuscript. We thank the Reviewer for highlighting this interesting study, which is now cited in the Introduction (line 53) and extensively discussed in lines 276-288. To further increase the novelty of our findings, we have explored whether the protein-coding genes targeted by our prognostic miRNAs were associated with sorafenib response (Figure 3). This correlation had been never investigated in similar studies. This analysis was enabled by the availability of a small but well curated dataset that contained only mRNA genes. Our results are interesting and provide potential explanations on the prognostic role of mir-326 (see lines 295-300). J) The authors compared the miRNA target genes with published cancer associated gene set, and then concluded that there are ‘direct miRNA interactions with cancer driver genes’, which is not sound enough for the conclusion. We apologies for the over-statement, and we agree with the Reviewer that we only performed a bioinformatic prediction. To reflect this, we have changed the title of section 2.4.6 which is now:” Identifying potential miRNA interactions with cancer driver genes”. K) Figure 1B and 1C show big differences between White-Caucasians and Asians patients. It would be more interesting and meaningful if the authors discussed the possible reasons. The substantial overall survival difference between Asian and Caucasian patients is probably due to divergent HCC aetiology as highlighted by many epidemiological studies: HBV-related (Asians) vs HCV or non-viral aetiology (Caucasians). See this study for reference https://doi.org/10.1111/liv.15251, 10.4254/wjh.v7.i12.1708. We now discuss this aspect in lines 237-241. L) It is worth to show the survival rate of patients related with each miRNA in the 9 miRNAs. Kaplan Meier plots of overall survival associated with the 9 different miRNAs have been added to the supplementary material, as Figure S2 (lines 173-174). https://doi.org/10.1371/journal.pone.0296198.r002
6 Mar 2024 Decision Letter - Junming Yue, Editor PONE-D-23-40355R1Comprehensive analysis of differentially expressed miRNAs in hepatocellular carcinoma: prognostic, predictive significance and pathway insightsPLOS ONE Dear Dr. Salani, 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 Apr 20 2024 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. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Junming Yue Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments:==============================Please reconcile miR-326 with 10 miRNA signature throughout the manuscript and have to be consistent including in discussion. ============================== [Note: HTML markup is below. Please do not edit.] 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 #2: 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 #2: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ****** 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 #2: Yes ****** 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 #2: 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 #2: One concern now is that the authors stated they found a 9--miRNA signature for HCC based on their hypothesis, miRNA-326 was removed because of its unexpected correlation with prognosis. However, the following study of pathways and miRNA-target genes all included miRNA-326 (line 184), which makes it very confusing. It also says 10-miRNA signature in the discussion (line 285), which needs to be clarified. The pathways and target genes of niRNA-326 could be studied and discussed separately since it has opposite correlation with prognosis than expected. ****** 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 #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. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0296198.r003
Revision 2
18 Mar 2024 Author Response We would like to thank the Editor and Reviewer2 for pointing out the inconsistency in the miRNA-signature definition. We have now carefully reviewed the manuscript, making sure that the phrase “prognostic signature” is applied only to the group of 9 (not 10) miRNAs. We hope this will reduce confusion. In this study, we have also tried to investigate potential molecular pathways associated with notable miRNAs. For this mechanistical analysis, we decided to keep the “odd” miRNA that showed opposite correlation between prognosis and expression patterns in normal vs neoplastic liver tissue (mir-326). In the new version of the manuscript, we have made this distinction clear (lines 179-188). As suggested by the reviewer, this miRNA has been discussed separately (lines 300-305). In the process of this further manuscript’s revision, we also edited: - A missing reference in line 242 (added between bracket) - A typo in line 295 - . instead of , in line 32-33 - Patients’ instead of patients, in line 34 - Pathway instead of pathways, in line 45 - “The Cancer Genome Atlas (TCGA)” was misspelled through out the text and not it has been reconciled. - Ran instead of run, in line 189 - And removed from line 290 https://doi.org/10.1371/journal.pone.0296198.r004
20 Mar 2024 Decision Letter - Junming Yue, Editor Comprehensive analysis of differentially expressed miRNAs in hepatocellular carcinoma: prognostic, predictive significance and pathway insights PONE-D-23-40355R2 Dear Dr. Salani, 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 Editorial Manager® , 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, Junming Yue Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0296198.r005
Formally Accepted
27 Mar 2024 Acceptance Letter - Junming Yue, Editor PONE-D-23-40355R2 PLOS ONE Dear Dr. Salani, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Junming Yue Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0296198.r006

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