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You have addressed all reviewers' and editorial concerns in a statisfactory manner.
[# PeerJ Staff Note - this decision was reviewed and approved by Vladimir Uversky, a PeerJ Section Editor covering this Section #]
The analyses that have been performed to address some questions of reviewer 1 and which are presented in the rebuttal letter as supplementary Figures 1 and 2 should be included in the manuscript, for the benefit of the readers who may have these questions. These data may be introduced after the overexpression data in the experimental system, to indicate the possibility of subtle effects.
**PeerJ Staff Note:** Please ensure that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
The experts found that the investigation is original but that the experiments are mostly descriptive and lack mechanistic studies. Please address the concerns of Reviewer 1 with the experimental approaches that have been suggested. Also, as suggested by Reviewer 2, some weaknesses should at least be discussed.
**PeerJ Staff Note:** Please ensure that all review, editorial, and staff comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
**Language Note:** PeerJ staff have identified that the English language needs to be improved. When you prepare your next revision, please either (i) have a colleague who is proficient in English and familiar with the subject matter review your manuscript, or (ii) contact a professional editing service to review your manuscript. PeerJ can provide language editing services - you can contact us at [email protected] for pricing (be sure to provide your manuscript number and title). – PeerJ Staff
In this manuscript, Ding et al analyze the importance of MAFF expression in NSCLC. They observe reduced MAFF expression in more aggressive tumors. They then identify YAP1 as a putative downstream target of MAFF and show that MAFF overexpression results in reduced YAP1 expression as well as reduced VEGF expression and MVD. The experiments are mostly descriptive and lack mechanistic studies (eg are the effects of MAFF on YAP1 localization direct or indirect)? I have several comments.
Main:
Do they observe decreased MAFF expression also in endothelial cells (sc-RNA-Seq data)?
Do they observe increased/decreased YAP/TAZ expression and activity (measured by expression of YAP1 target genes – CTGF, CYR61, AMOTL2, ANKRD1) in RNA-Seq data of MAFF low versus high tumors?
Do they observe decreased YAP activity (expression of YAP target genes) in MAFF treated cells?
The effect of nuclear versus cytoplasmic YAP1 localization in MAFF treated versus untreated cells seems to be quite subtle and is hard to assess for the reader from the presented IF images. Could the authors perform cell fractionation experiments followed by Western blots?
The number of mice per group for the in vivo experiments is rather small (n = 4).
To more conclusively show that the effect of MAFF overexpression on in vivo tumor growth and MVD formation is primarily dependent on its effect on YAP1 activity, the authors should treat tumor mice with YAP1-TEAD inhibitors and observe the affect on tumor growth as well as MVD formation.
Does treatment of HUVEC cells with YAP1-TEAD inhibitors reduce VEGF expression?
How does MAFF inhibit the YAP1 nuclear localization? Does it directly inhibit the trafficking of YAP1 or act via the upregulation of YAP1 inhibitors (LATS, NF2, FATs etc)? Can the authors perform western blots for known members of the inhibitory Hippo Pathway cascade?
Minor:
It would be easier for the reader to follow if the authors could list the sample numbers in the results section (instead of the materials).
no comment
no comment
no comment
The authors demonstrate the importance of YAP1 in non-small cell lung cancer research. They propose that by researching the possible regulation and interaction bewteen MAFF and YAP1 will lead to more effective treatment of cancer. This lead to a comprehensive analysis of transcriptome for MAFF expression across different cancers. Compared to the single cell RNA sequencing analysis and other experiments, authors demontrate the inhibition of YAP1 expression and tumor cell growth by MAFF.Overall the English is clear and they demonstrated accurate literature references with shared data.
The research is within the scope of the journal with original research. The research question is clearly defined in introduction. For the method part, I suggest to modify some of those paragraphs to help reader clearly understand the experiment method. For example between line 121-127, the analysis process is a little bit unclear despite an overall description of the workflow.
They provide data to prove their points. However, in some figures, the data may not be strong enough to fully support their point. For example in the figure8, despite the p value, difference between two groups are relatively small. They should discuss those result more in the discussion part of the paper.
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