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The authors have addressed all the reviewers' comments.
Reviewer 1 did not re-review the revised version; however, I have checked their comments and can confirm the authors addressed them all. The manuscript is ready for publication.
[# PeerJ Staff Note - this decision was reviewed and approved by Paula Soares, a PeerJ Section Editor covering this Section #]
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**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.
The experimental methodology section should be more concise.
1. In this study, there were eight candidate genes, including SERPINE1, C6, GRP, GCG, IL1F10, IGFBP1, ITIH2, and APOD. Why was only SERPINE1 selected for biological validation? The reasons need to be clarified.
2. Which tumor tissue is the paracancerous tissue matched to？ Why are there three tumor tissues but only one paracancerous tissue?
3. In addition to ELISA, other methods are needed to validate the increased SERPINE1 protein secretion in gastric cancer tissues.
1. Could you clarify the rationale behind selecting AGS and HGC27 for overexpression (OE) and MKN7 for knockdown (sh) in the functional assays
2. Add the measurement of secreted protein levels in cell culture supernatant by ELISA upon co-culture with CAFs
1. A minor suggestion: The nomenclature of the cell line needs to be standardized—should it be 'HGC27' or 'HGC-27'?
2. All figures are insufficiently clear, and higher-resolution images are recommended.
This is a well-written paper with a wealth of supporting data, well-described methods, and good statistical support. However, the author’s claims are exaggerated considering the data, which shows an association of SERPINE1 with GC but a minimal association of the remaining 7 secreted proteins and a modest predictive power of the 8-SPCG signature.
Other concerns about the basic reporting are:
1) The figures are close to being unreadable, with some completely so. Higher resolution figures are necessary for adequate review.
2) Some of the figure legends are cut off partway through (Figs. 5 and 7).
3) All abbreviations need to be defined (ad punctum, alpha-SMA)
The experimental design is rigorous, the methods are well-described, and the statistical analysis was thorough. However, there are many outliers in the reported data. The authors should make clear how these outliers were handled in the statistical analysis, such as for the determination of the AUC plots and other correlations. Also, STR or other authentication should be stated for the cell lines.
The number of clinical samples is quite small, and so the broader relevance of these findings is unclear. The measurements show large variations in the levels of expression of these proteins and their mRNAs, which limits their predictive power. Rightly, the authors point out, a prospective study would strengthen the conclusions. A revised version should consider toning down the claims.
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