The Role of miRNA in the Management of Localized and Advanced Renal Masses, a Narrative Review of the Literature

Round 1

Reviewer 1 Report

In the manuscript entitled “The role of miRNA in the management of localized and advanced renal masses, a narrative review of the literature,” Napolitano et al. summarized the published data about miRNAs in Renal cell carcinomas.

This interesting review clearly presents the recent findings about the potential use of miRNAs as a diagnosis and prognostic marker and, eventually, as a treatment target for RCC. It is a well-written manuscript that outlines current knowledge and gives further perspectives.

Author Response

First of all, we wish to thank you for reviewing our paper entitled “The role of miRNA in the management of localized and advanced renal masses, a narrative review of the literature”. We realize that your time is valuable, and we are very grateful for your efforts. We wish to thank you for your comment. Thanks for your appreciation. We improved our English according to your suggestion.

Author Response File: Author Response.docx

Reviewer 2 Report

This review summarized the progress of miRNAs as biomarkers, therapeutic targets, or modulators of response to treatment modalities in RCC patients

There are several comments on this manuscript.

Introduction section

A few details about the clinical management of RCC patients are reported. I would suggest deeply improving this section with the available clinical approaches for RCC patients.

Methods section

1.    Please, could the authors describe the screening methods in detail? The search terms used for title screening? Or for abstract screening? Or for full-text screening? How many manuscripts are screened by this method?

2.    Is it suitable to put “2.1 miRNA Isolation” in the Methods section?

Other parts

1.    Although the authors cite many references and introduced many miRNAs which were used for the diagnosis and prognosis of RCC, the authors did not describe their performance. Therefore, the information in this manuscript is limited.

2.    The comparison between the performance of miRNAs and clinically used diagnosis and prognosis markers of RCC is missing.

3.    There are many mistakes in the whole manuscript. For example,

a)     In lines 94-95, the period is missing, and the colors are different from other parts.

b)     In lines 101-102, the upper case and lower case are not unique.

c)      In reference, the style of the title is not unique.

Author Response

Review Report Form 2

This review summarized the progress of miRNAs as biomarkers, therapeutic targets, or modulators of response to treatment modalities in RCC patients

First of all, we wish to thank you for reviewing our paper entitled “The role of miRNA in the management of localized and advanced renal masses, a narrative review of the literature”. We realize that your time is valuable, and we are very grateful for your efforts. We have carefully read all your comments and we have tried to clarify all the concerns expressed, improving the quality of the paper according to your suggestions. For your convenience, in addition to the revised manuscript, we report below our responses to your comments. 

There are several comments on this manuscript.

Introduction section

A few details about the clinical management of RCC patients are reported. I would suggest deeply improving this section with the available clinical approaches for RCC patients.

Thanks for your review. We corrected it according to your suggestions.

“RCC treatment depends on tumor stage and grade, and overall health status of the patients. Surgery represents the standard treatment for localized RCC, while cytoreductive nephrectomy and systemic treatments (targeted therapies and immunotherapeutic agents) represent the standard of care for patients presenting metastatic RCC (mRCC). Recent evidence suggested that stereotactic body radiotherapy (SBRT) may represent as a new option in treatment of primary local RCC and oligometastatic RCC MiRNAs act also as tumor suppressors or oncogenes and can regulate several gene transcripts as well as the expression of other miRNAs. They are involved in cell proliferation and death, migration, epithelial-mesenchymal transition, tumor invasion and metastasis. MiRNAs can influence angiogenesis, energy metabolism and immune system activation and recruitment, as shown in Figure 1, binding a specific sequence at the 3′ or 5’ untranslated region (UTR) of genes or messenger RNA (mRNAs). Indeed, the miRNA interaction with 3’ and 5’ UTR induces repression and transcription, respectively, of genes”

Methods section

1. Please, could the authors describe the screening methods in detail? The search terms used for title screening. Or for abstract screening? Or for full-text screening? How many manuscripts are screened by this method?

We conducted a narrative review of the most relevant articles in the Medline (US National Library of Medicine, Bethesda, MD, USA), Scopus (Elsevier, Amsterdam, The Netherlands), and Web of Science Core Collection (Thomson Reuters, Toronto, ON, Canada) databases. We included articles from January 2016 to August 2022. The following terms were combined to capture relevant publications: “miRNA” OR “non-coding RNA”, OR “small RNA” AND “Kidney Cancer” OR “Local Renal Cell Carcinoma” OR “Advanced Renal Cell carcinoma”.  Only papers published in English and, available in full text were included in the analysis. References lists in relevant articles and reviews were also screened for additional studies. Case reports, conference abstracts, editorial comments, and letters to the editor were excluded. According to the predefined type of review, the results were qualitatively described, as reported in the primary studies, without quantitative synthesis. Two authors reviewed the records separately and individually to select relevant publications, with any discrepancies resolved by a third author. The search identified 297 articles. After removal of duplicates, 196 articles were included. After screening based on title and abstract, 78 articles were selected for full-text screening, of which 20 articles could be included based on the criteria outlined above.

2. Is it suitable to put “2.1 miRNA Isolation” in the Methods section?

Thanks for your review. We created a new section: 3 miRNA Isolation

Other parts

1. Although the authors cite many references and introduced many miRNAs which were used for the diagnosis and prognosis of RCC, the authors did not describe their performance. Therefore, the information in this manuscript is limited. The comparison between the performance of miRNAs and clinically used diagnosis and prognosis markers of RCC is missing.

Thanks for your review. We corrected it according to your suggestions.

Despite the promising data, miRNAs' performance as diagnosis and prognosis markers remains unclear. Several studies have been published in the last few years regarding the utility of miRNAs in diagnosis and prognosis. Regarding diagnosis, Gottardo et al. reported that miR-27, -28, -185, and let-7f-2 are overexpressed considerably in RCC specimens (p <0.05) in comparison to a healthy kidney [55]. Nakada et al. reported that 37 miRNAs are significantly under-expressed in conventional RCC, while the other 6 were overexpressed, especially miRNA 141 and miRNA-200 are down-regulated [56]. Mytsyk et al. also compared the expression of miRNA-15a in the urine of healthy renal parenchyma/benign tumours and RCC patients, and they found that it was upregulated in the second case (p <0.01) [57]. Liang et al. explored the potential in diagnosis and prognosis of three miRNA signatures: miR-21, miR-584, and miR-155 [58]. They showed a sensitivity of 98.3% and a specificity of 97.2% of these miRNAs in discriminating RCC from normal controls. Wulfken et al. reported that miRNA-1233 was increased in RCC patients, showing a sensitivity of 77.4% and specificity of 37.6%, as a diagnostic biomarker of RCC [59]. Regarding prognosis, Xu et al. identified nine miRNAs that strongly correlated with RCC prognosis (P < 0.01), in particular, they show high expression in patients with a poor prognosis [60]. Zhao et al. showed that miR-187 expression is downregulated in ccRCC specimens, decreased with advancing tumor grade and stage, and high levels correlate with survival after surgery [61]. The upregulation of miR-21 seems to be associated with cancer-specific survival of ccRCC patients [62]. Fritz et al. show that the ratio of miR-21 to miR-10B correlates independently with survival (P = 0.012) and TNM stage [63]. Vergho et al. reported that in RCC patients, miR-21, miR-126, and miRNA-221 could independently predict cancer-related death [64]. Fu et al. reported miRNA-125 as an independent adverse prognostic factor for recurrence and survival in RCC patients [65]. However, several investigations, including a higher number of patients, different stages and histologic subtypes or grades of differentiation of RCC, are required for the implementation of the current knowledge into clinical practice.

3. There are many mistakes in the whole manuscript. For example,

1. a)     In lines 94-95, the period is missing, and the colors are different from other parts.

Thanks for your review. We corrected it according to your suggestions.

1. b)     In lines 101-102, the upper case and lower case are not unique.

Thanks for your review. We corrected it according to your suggestions.

1. c)      In reference, the style of the title is not unique.

Thanks for your review. We corrected it according to your suggestions.

Author Response File: Author Response.docx

Reviewer 3 Report

Luigi Napolitano et.al, has summarized the role of micro-RNAs in the management of Renal Cell Carcinoma (RCC). The authors have thoroughly reviewed the literature and highlighted the miRs involved in renal tumor development, diagnosis, treatment, prognosis and drug resistance. Noteworthy is the inclusion of study on miR signature in lymphocytes after anti-PD-1 treatments. Although, no clinical trials were done with miR-based therapeutics for RCC, this review will lead to more pre-clinical studies in exploring the role of miR-based therapeutics either alone or in combination with existing therapeutic approaches in the treatment of RCC.

Author Response

First of all, we wish to thank you for reviewing our paper entitled “The role of miRNA in the management of localized and advanced renal masses, a narrative review of the literature”. We realize that your time is valuable, and we are very grateful for your efforts. Thanks for your appreciation. We wish to thank you for your comment. We improved English according to your suggestion 

Author Response File: Author Response.docx

Reviewer 4 Report

The review presented by Napolitano et coworkers summarizes the actual knowledge of microRNAs impact on renal cell carcinoma. The manuscript is potentially interesting for the readers and is easy to follow. Below I present some comments, which should be answered by authors before manuscript publication:

-          First of all, please  add more information about molecular involvement of each mentioned miRNA in cell activity regulation; I also suggest to present data from table 1 in regard to type of miRNA determined activity, not in regard to article and its authors; can the Authors present studies confirming the changes in miRNAs’ level during the tumor development and its impact?

-          The Authors can add a general mechanism of miRNA regulatory activity as a figure with short explanation in introduction

-          In chapter 3.3 there is mentioned genistein; could the Authors present more phytocompounds able to regulate cancer cell cycle via miRNA mechanism?

-          Line 122 – there is “by” lacking;

-          Line 128 – “was” should be delated;

-          Line 131 – instead of “the” word “this” is more suitable;

-          Line 134 – there should be “MiRNAs”

-          Line 146 – not all 48 miRNAs are mentioned – please add them;

-          Line 193 – there should be “is” instead of “in”

-          Lines 209-2012 – the sentence is quite complicated and not easy to understand, please modify it

-          Lines 203-204 and Lines 217-218 – there is the same sentence repeated, please modify one of them;

-          Lines 229-232 - the sentence is quite complicated and not easy to understand, please modify it

-          Lines 264-265 – please, add more information, since this topic is very interesting.

In summary, I suggest the major revision before the publication.

Author Response

Review Report Form 4

The review presented by Napolitano et coworkers summarizes the actual knowledge of microRNAs impact on renal cell carcinoma. The manuscript is potentially interesting for the readers and is easy to follow. Below I present some comments, which should be answered by authors before manuscript publication:

First of all, we wish to thank you for reviewing our paper entitled “The role of miRNA in the management of localized and advanced renal masses, a narrative review of the literature”. We realize that your time is valuable, and we are very grateful for your efforts. Thanks for your appreciation. We wish to thank you for your comment. 

• First of all, please add more information about molecular involvement of each mentioned miRNA in cell activity regulation; I also suggest to present data from table 1 in regard to type of miRNA determined activity, not in regard to article and its authors; can the Authors present studies confirming the changes in miRNAs’ level during the tumor development and its impact?

Thanks for your review. We corrected the Table 1 according to your suggestion 

• The Authors can add a general mechanism of miRNA regulatory activity as a figure with short explanation in introduction

Thanks for your review. We corrected it according to your suggestions. We added Figure 1 and Figure 2 

• In chapter 3.3 there is mentioned genistein; could the Authors present more phytocompounds able to regulate cancer cell cycle via miRNA mechanism? 

We wish to thank you for your comment. We add: Several phytocompounds are involved in miRNAs regulation, especially cancer for example: resveratrol binds miRNA-33a and miRNA-122 and increases their levels; resveratrol also regulates the expression of miRNA-17 and suppresses their level through c-Myc; (-)-epigallocatechin-3-gallate decreases levels of miRNA-33a and miRNA-122; Curcumin downregulates miRNA-21, that regulates the pathway of PTEN. Quercetin downregulates miRNA-103a-3p, miRNA-125b, and miRNA-1202. Sulforaphan increases the expression of miR-124, which regulates the IL-6 receptor.

• Line 122 – there is “by” lacking;

Thanks for your review. We corrected according to your suggestion 

• Line 128 – “was” should be deleted;

Thanks for your review. We corrected according to your suggestion 

• Line 131 – instead of “the” word “this” is more suitable.

Thanks for your review. We corrected it according to your suggestions.

• Line 134 – there should be “MiRNAs”

Thanks for your review. We corrected it according to your suggestions

• Line 146 – not all 48 miRNAs are mentioned – please add them;”

Thanks for your review. Huang et al. reported only some miRNAs. We corrected : “Huang et al. compared miRNA expression profiles between 11 renal tumors and identified 48 miRNA specific for ccRCC (for example miR-27a, miR-221, miR-34a, miR-103, miR143, miR-15a, miR-16, miR-17-5p, miR-24)

• Line 193 – there should be “is” instead of “in”

Thanks for your review. We corrected it according to your suggestions.

• Lines 209-2012 – the sentence is quite complicated and not easy to understand, please modify it

Thanks for your review. We corrected it according to your suggestions.

• Lines 203-204 and Lines 217-218 – there is the same sentence repeated, please modify one of them;

Thanks for your review. We corrected according to your suggestion 

• Lines 229-232 - the sentence is quite complicated and not easy to understand, please modify it

Thanks for your review. We corrected it according to your suggestions: “After the miRNAs discovery, the literature has reported their various roles in tumour pathogenesis, clinical progression and therapeutic management, according to the target gene.”

• Lines 264-265 – please, add more information, since this topic is very interesting.

Thanks for your review. We corrected according to your suggestions: “In conclusion, several pieces of evidence suggest miRNAs as a potential and non-invasive biomarker in RCC. They demonstrated high stability and specificity. Nowadays there is an imperious need for faster ways to detect and to treat different tumors. Since miRNAs are traceable in circulation and urine samples of patients, they could represent a good candidate in diagnosis, subtype classification, screening of chemo- or radio-resistance, prognosis, and recurrence of RCC. Although miRNAs play a pivotal role in different aspects of RCC biology and development, none of them are still used in clinical settings. Further larger scale studies and clinical trials are necessary to better assess mode of action and regulatory mechanism. MiRNAs could also serve to develop personalized patient profiles, and to support targeted therapeutic interventions in the future.”

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

I recommend the manuscript for publication.

Author Response

Thank you for the comment

Reviewer 4 Report

The authors answered my concerns and the manuscript has been improved, however within the text there is no reference to Table 1; after this correction the manuscript can be accepted for the publication.

Author Response

Reviewer 4: The authors answered my concerns and the manuscript has been improved, however within the text there is no reference to Table 1; after this correction the manuscript can be accepted for the

publication.

Thanks for your review. We corrected it according to your suggestions. We added Table 1 in paragraph 4.1

Author Response File: Author Response.docx