Non-Coding RNAs and Wnt/β-Catenin Signaling Pathway in Gastric Cancer: From EMT to Drug Resistance

Round 1

Reviewer 1 Report

This review gives a broad overview of studies on various noncoding RNAs including micro RNAs and long noncoding RNAs in gastric carcinoma. The focus is on the potential role of these RNAs in the regulation of the Wnt/b-catenin pathway. As such, the review covers in depth current literature but there are problems related to the critical evaluation of the significance of these studies for gastric cancer and Wnt signaling.

First, what is the evidence that the Wnt pathway is indeed activated in gastric cancer tissues, i.e. real tumors. Are mutations in pathway components e.g. APC, Axin and b-catenin found in GC? Are specific target genes of Wnt signaling such as axin2 and RNF43 upregulated? Is the b-catenin protein detected in the nucleus of gastric cancer cells? Is there genetic evidence that alterations of Wnt/b-catenin signaling leads to gastric cacrcinoma in animal models? Such information is important to judge the significance of the cited work, which is mainly performed in cell lines, and should be easily extractable from the literature and databases.

Second, review lacks a critical evaluation of the significance of the cited work with respect to claims that the Wnt pathway regulation by miRnas and lnRNAs are functionally relevant. For instance, ref 57 randomly chosen from the reference list shows that the miRNA analyzed in this study downregulates Smad4 and has a small effect on Wnt pathway parameters, which was reversed by Smad4 overexpression, but it was not shown that altered Wnt signaling is actually responsible for cellular miRNA effects. Similarly, ref. 76 shows a correlation between a lnc RNA and some Wnt components but shows no data actually supporting a role of Wnt signaling in the functional effects of the lnc RNA. Other studies have obvious flaws in their data. For instance, Ref. 59 claims that Bcl-2 (considered as a Wnt target gene) is upregulated by the miRNA analyzed in this study, although data presented in Fig. 4 of this paper shows the opposite, i.e. downregulation of Bcl2. It is also remarkable that almost none of the noncoding RNAs in Tables 1-4 have been detected in more than one study and thus have not been independently confirmed.

I suggest that the authors be more cautious in the interpretation of the literature. They should focus on those studies where the functional connection e.g. between "miRNA X" and Wnt signaling in the GC parameters are clearly shown, for instance by altering Wnt signaling to reverse effects of RNAs. These studies could be highlighted and separated from the correlative studies, which may be kept as lists in the Tables.   

Author Response

Dear reviewer, thank you for your comments and considerations.

We have addressed the points you suggested as highlighted in the attached file.

Also, the MS word “Track Changes” function indicates in the revised manuscript file, these and additional improvements.

Author Response File: Author Response.docx

Reviewer 2 Report

In the paper entitled “Non-Coding RNAs and Wnt/ß-Catenin Signaling Pathway in Gastric Cancer: From EMT to Drug Resistance” the authors have the objective to describe the current knowledge of the role played by microRNAs and long non-coding RNAs in gastric cancer tumorigenesis focusing on Wnt/ß-catenin signaling pathway. Although the authors have made quite a number of statements and arguments that have been published in the literature, in the present form, the review it lacks novelty in several viewpoints. Although the topic could be of interest, due to how the reported information were presented and discussed, this work, unfortunately, cannot be accepted for publication. In fact, there are several points that render the herein paper not suitable for publication: - Every section of the paper is a set of notions not properly discussed. So, it is necessary to rewrite the paragraphs giving a critical interpretation. - In the main text the reference’s numbers are reported, but the list of reference is totally missing

Author Response

Dear reviewer, thank you for your comments and considerations.

We have modified the manuscript as the MS word “Track Changes” function indicates in the revised manuscript file.

The reference list can be found from pages 17 to 23 in our first manuscript draft and pages 15 to 22 in the revised manuscript. However, we now also submitted a separated file containing the references.

Author Response File: Author Response.docx

Reviewer 3 Report

This review titled ‘Non-Coding RNAs and Wnt/β-Catenin Signaling Pathway in Gastric Cancer: From EMT to Drug Resistance’ aims to describe the involvement of Long non-coding RNAs and microRNAs in the development of Gastric Cancer (GC) through modulating Wnt signaling. Aberration of Wnt signaling is one of the major factors responsible for the development of GC. Wnt pathway modulates cellular process that are known to connect with gastric cancer such as cell proliferation, cell differentiation and epithelial to mesenchymal transition (EMT). Since Wnt pathway is closely coupled to cellular proliferation and EMT that leads to Gastric Cancer development, the non-coding RNAs that modulates Wnt signaling can also be a contributing factor as tumor suppressors or oncogenic factors in Gastric Cancer.

The authors successfully collated up to date information about non-coding RNAs involved in Gastric cancer, with a specific emphasis on Long non-coding RNAs and microRNAs that modulates gastric cancer progression through controlling Wnt signaling. Since the regulation of cancer through targeting the non-coding RNA is an evolving therapeutic strategy, this review is relevant and worth publishing in this journal.  However, I have a few criticisms about the review, which needs to be addressed, before publication.

1. The English style used in this review needs to be improved to enhance its readability. For instance, the line 75 states that “For many years, molecular biology scientists believed that the RNA primary function was to encode sequence information.” This should be changed to “For many years, molecular biologists believed that the primary function of RNA was to encode sequence information.”

Similarly line 62 states that “New and molecular approaches have been described in attempt to propose a comprehensive classification as previously reviewed by our group.” It should be changed to “Novel molecular approaches have been described in an attempt to propose a comprehensive classification as previously reviewed by our group.”

The authors should give attention to correct such subtle errors present in the manuscript by a careful editing.

4. The figure 5 needs further improvement. The figure has too much information and is not easy to understand. The authors can either simplify the figure with only core points involved or convert the information in the figure to a list, which makes it easy to understand.
5. The conclusion section of this manuscript needs to be modified. A good conclusion should illustrate the key connections between the major points described in this review and its significance in short sentences. Such factors found missing from the conclusion. Moreover, the conclusion appears too lengthy and lacks the brevity expected in the section. In addition, new information and questions, which are not the focus of the review, is also found in the conclusion section. For instance, the conclusion section opens with questions about the representative value of GC cell lines used in the studies and about the interconnection of Wnt/β-catenin pathway with other signaling pathways in tumorigenesis process. These are new questions and not the focus of the review. (Line 452: there are three main questions that need to be answered: how cancer cells evade the negative regulation by Wnt/β-catenin? Do the cell lines used in the studies correctly represent heterogeneous populations? How Wnt/β-catenin pathway interconnects with other signaling pathways in tumorigenesis process). The authors should attempt to improve the conclusion section by reducing the length of the section and by focusing on the main points discussed in this review.
6. Some of the recent information regarding the connection of noncoding RNA to gastric cancer cells are missing from the review. For instance, the role of MIR-876-5p in regulating gastric cancer cell proliferation and apoptosis through modulating components of Wnt signaling pathway has been recently reported (PMID: 31171711) and such information should also be included in this review.

Author Response

Dear reviewer, thank you for your comments and considerations.

We have addressed the points you suggested as highlighted in the attached file.

Also, the MS word “Track Changes” function indicates in the revised manuscript file, these and additional improvements.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Authors have introduced some changes in the ms that underline general aspects of Wnt signaaling in gastric cancer and added a few sentences to clarify the correlative nature of several studies. As such, the review provides a broad compedium of publications dealing with noncoding RNAS in gastric cancer, which might be of interest to those studying similar topics.

Author Response

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Reviewer 3 Report

The authors response are satisfactory. These manuscript is now eligible for publication with a few English editing, which can be done at the proof reading stage by the Journal.  

Author Response

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