Non-Coding RNAs in Hepatocellular Carcinoma

Round 1

Reviewer 1 Report

The review article entitled ‘Non-coding RNAs in Hepatocellular Carcinoma’ discusses in detail the various non-coding RNAs implicated in liver cancer development and progression, with focus on major signaling pathways modulated by them as well as their potential for clinical translation. The review is well-written and well-organized. Moreover, the authors have covered relevant literature for ncRNAs that are major players in HCC.

I do have few suggestions that should further improve the review.

1.     The review is exhaustive and discusses several non-coding RNAs in terms of their cellular targets, signaling mechanisms and their role in contributing to cancer progression. The table 1. nicely summarizes all the ncRNAs discussed in detail in the text. The table would become more informative if the authors could list major signaling pathways modulated by them.

2.     Again, the review is exhaustive and addition of few subheadings would give a break and also better organize the structure that will make it easy to navigate the text for readers. I suggest adding subheadings based upon the type of ncRNAs discussed. As an example, under the heading 2. microRNAs, the authors can add 2.1. Tumor suppressor miRNAs and 2.2. OncomiRs.

3.     I find that some portion of texts in the review are repeated and hence can be removed. Page 13, para 3, ‘Very little is known about…..’. The information in this paragraph has already been discussed in previous two para and is hence redundant.

4.     Page 14, para 3, ‘A special class of snoRNAs……’ and Page 17, para 2, ‘Some lncRNAs are …. ‘ also reiterate information from previous two paragraphs. The paragraphs may be modified to avoid repetition.

5.     From the introduction it seems that the aim of the review does not include discussion regarding ncRNAs as HCC biomarkers, but some reference in this regard has been made under the section ‘Clinical Relevance’. It would be great if the authors could add a separate section regarding this. There are some recent publications regarding this area as well.

Author Response

1. The review is exhaustive and discusses several non-coding RNAs in terms of their cellular targets, signaling mechanisms and their role in contributing to cancer progression. The table 1. nicely summarizes all the ncRNAs discussed in detail in the text. The table would become more informative if the authors could list major signaling pathways modulated by them.

• Relevant/major signaling pathways have been added as a new column to Table 1.

2. Again, the review is exhaustive and addition of few subheadings would give a break and also better organize the structure that will make it easy to navigate the text for readers. I suggest adding subheadings based upon the type of ncRNAs discussed. As an example, under the heading 2. microRNAs, the authors can add 2.1. Tumor suppressor miRNAs and 2.2. OncomiRs.

• Subheadings have been included in order to alleviate any structural disorganization and break up the text.

3. I find that some portion of texts in the review are repeated and hence can be removed. Page 13, para 3, ‘Very little is known about…..’. The information in this paragraph has already been discussed in previous two para and is hence redundant.

• Redundancies have been removed and/or updated.

4. Page 14, para 3, ‘A special class of snoRNAs……’ and Page 17, para 2, ‘Some lncRNAs are …. ‘ also reiterate information from previous two paragraphs. The paragraphs may be modified to avoid repetition.

• Redundancies have been removed and/or updated.

5. From the introduction it seems that the aim of the review does not include discussion regarding ncRNAs as HCC biomarkers, but some reference in this regard has been made under the section ‘Clinical Relevance’. It would be great if the authors could add a separate section regarding this. There are some recent publications regarding this area as well.

• A separate section has now been included using recently published literature on biomarkers in HCC, this can be found in section 5, “Biomarkers in HCC”.

Reviewer 2 Report

In this manuscript, Korsch et al. reviewed non-coding RNAs in hepatocellular carcinoma. Non-coding RNA field is a large, uncovered area that should have crucial biological significance that has not been appreciated before. This is also applied to liver cancer. In this review, the authors focused on microRNA, snoRNA, and long non-coding RNA, three major non-coding RNAs which are widely studied in the last decade. This review is well written and provides ample information to better understand the function of ncRNAs in hepatocellular carcinoma. It is also a good resource for researchers who are unfamiliar with this area. Therefore, I think this review is qualified to be published in Livers when the authors can address the following minor questions:

1. In each section of the three ncRNA types, the paragraphs are not well organized. This makes readers quite hard to follow, although the info in table 1 is well presented. I suggest the authors use bullet points to re-organize each section in order to make the flow clearer.
2. For Figure2, I believe the authors messed up with the order of subfigure A and B, as A is showing the H/ACA, while B is showing the C/D type. This is inconsistent with the figure legend. Please double-check to keep it consistent.
3. On Page9, the authors mentioned that the microRNAs have been shown to play tissue/cell-specific roles. This is an interesting point, and they exemplified it by showing the HSC-specific OncomiR functions. To broaden the picture, can authors list the ncRNA-related study in other liver cell types, like endothelial cells and Kupffer cells?
4. There are some typo-like errors in this version, such as the last sentence of the first paragraph on Page2 (…of t well-described…), and the first line of Figure1 legend on Page 7 (…clasScheme 21…). Please carefully proofread the manuscript.

Author Response

1. In each section of the three ncRNA types, the paragraphs are not well organized. This makes readers quite hard to follow, although the info in table 1 is well presented. I suggest the authors use bullet points to re-organize each section in order to make the flow clearer.

• Subheadings have been included in order to alleviate any structural disorganization and break up the text.

2. For Figure2, I believe the authors messed up with the order of subfigure A and B, as A is showing the H/ACA, while B is showing the C/D type. This is inconsistent with the figure legend. Please double-check to keep it consistent.

• The legend of figure 2 has been corrected.

3. On Page9, the authors mentioned that the microRNAs have been shown to play tissue/cell-specific roles. This is an interesting point, and they exemplified it by showing the HSC-specific OncomiR functions. To broaden the picture, can authors list the ncRNA-related study in other liver cell types, like endothelial cells and Kupffer cells?

• A separate section has been included citing recent literature on tumor suppressor miRNAs in non-parenchymal cells. This can be found under 2.2 “Tumor suppressor microRNAs in non-parenchymal hepatic cells”

4. There are some typo-like errors in this version, such as the last sentence of the first paragraph on Page2 (…of t well-described…), and the first line of Figure1 legend on Page 7 (…clasScheme 21…). Please carefully proofread the manuscript.

• The legend of figure 1 was corrected and the manuscript has undergone additional proofreading to correct typos.