Molecular Perspectives on Prostate Cancer: The Role of microRNAs in Androgen Receptor Regulation
, Alicia Rivera-Cameras 3, Luis E. Figuera 1,2, Guillermo Moisés Zúñiga-González 4, Belinda Claudia Gómez-Meda 5, José ElÃas GarcÃa-OrtÃz 1 and Martha Patricia Gallegos-Arreola 1,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsMajor Comments:
Introduction Section:
1. Author provides thorough review of miRNA functions and gene regulation, with detailed sections on miRNA biogenesis and gene silencing; however, this background is well-known and occupies too much of the manuscript, making the discussion on miRNA mechanisms redundant for readers familiar with these basics. To better highlight the core focus on miRNAs' role in androgen receptor (AR) regulation in prostate cancer, the extensive background should be condensed into a brief section. Emphasizing new insights into miRNA-AR interactions would enhance the manuscript's relevance and impact, aligning it more closely with its title and objectives. Moreover, while the introduction effectively discusses prostate cancer's prevalence and risk factors, it should more swiftly transition to the central theme of miRNAs in AR regulation, clearly explaining why this focus is critical and what gaps in the literature the review aims to address.
2. The introduction touches on various risk factors for PCa but could provide a more nuanced discussion of the interplay between genetic, epigenetic, and environmental factors, especially in the context of miRNA regulation.
Section on AR in PCa (2.3):
3. The section discussing the role of AR in PCa could benefit from a more detailed exploration of the specific mechanisms through which AR variants and signaling pathways contribute to therapy resistance and disease progression. Include recent studies that provide novel insights or therapeutic strategies targeting these mechanisms.
Biogenesis and Function of miRNAs (3.1):
4. This section, while informative, contains some redundancies and could be streamlined to focus more sharply on the aspects of miRNA biogenesis and function that are directly relevant to AR regulation and PCa.
Role of miRNAs in Cancer (4):
5. The discussion of miRNAs in cancer is broad. Narrowing this down to specific insights relevant to PCa would make the review more focused and aligned with its title. Emphasize the unique aspects of miRNA dysregulation in PCa compared to other cancers. herefore, it is recommended to remove Figure 2 and 3.
Regulation of AR by miRNAs in PCa (5.1):
6. The section on indirect regulation of AR by miRNAs needs more depth. Provide specific examples and elaborate on how these interactions contribute to PCa pathology and potential therapeutic avenues.
Database Analysis and Identification of miRNAs (5.2, 5.3):
7. The identification of miRNAs targeting AR using databases is valuable. However, integrating these findings more thoroughly with the discussion of experimental evidence and their implications for PCa would strengthen the manuscript. Discuss how these database predictions align with known experimental data and what future research could validate these interactions.
Conclusion Section:
8. The conclusion needs to clearly summarize the key points discussed in the manuscript and outline their implications for future research and clinical practice, specifically highlighting the potential for miRNAs as biomarkers and therapeutic targets in prostate cancer (PCa), and suggesting specific areas where further investigation is needed. However, the current conclusion is too weak and lacks specificity, as it does not effectively summarize the main points or provide insights into future research directions, instead reiterating general statements without offering concrete takeaways or actionable recommendations for the research community.
Minor Comments:
1. Address grammatical issues and typos to enhance readability. For instance, Prostate cancer (PCa) is a type of cancer characterized by a malignant growth in the prostate gland." → Consider revising for clarity: "Prostate cancer (PCa) is characterized by malignant growth in the prostate gland."
2. Mismanagement of Abbreviations throughout the manuscript For instance, line 29, page 1 and 73, page 2 androgen receptor gene (AR) and androgen receptor (AR) respectively.
3. Maintain consistency in referring to specific miRNAs and their roles. For example, use standardized nomenclature for miRNAs and avoid switching between different formats (e.g., hsa-miR-21 vs. miR-21) or miRNAs (e.g., "miR-21" vs. "mir-21")
4. By addressing these comments, the manuscript can significantly improve its clarity, depth, and overall impact in the field of prostate cancer research.
Comments on the Quality of English LanguageQuality of language is fine but grammatical issues and typos need to be addressed to enhance readability.
Author Response
We sincerely appreciate your comments and suggestions. We highly value your contribution, as we believe they have significantly enhanced the quality of our manuscript. Attached, you will find the file containing our responses to your comments and observations.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsOverall, the paper “Molecular Perspectives on Prostate Cancer: The Role of miRNAs in Androgen Receptor Regulation” provides a summarized perspective on the role of miRNAs in AR regulation and offers scientific insights for further investigation. Here are some comments:
1. In Line 47: Please ensure the data is accurate. According to the referenced database GLOBOCAN, the statement "African men have a higher risk of developing PCa than men of other ethnicities" should be revised to "African men have a higher risk of developing PCa than other cancer types."
2. For Section 2.3: The section "AR in PCa" lacks coherent organization. The logic between paragraphs is not well-structured. Please revise this section to improve clarity and flow.
3. Figure 4A: The graph indicates that the AR promoter is methylated by MMT1, which purportedly increases AR gene transcription. This is incorrect, as methylation is well-known to repress gene activation. Additionally, there is inconsistency between the figure and the legend, where MMT1 is depicted in the figure but DMT1 is mentioned in the legend. Please verify and correct this discrepancy. Furthermore, provide the full name of the gene upon its first occurrence in the text for clarity.
4. Figure 5: Enhance the specificity of the regulatory interactions among AR, miRNAs, and PTEN/YB1. Use activation or repression arrows to indicate the nature of these relationships clearly.
Comments on the Quality of English LanguageSome words may not be accurate like "deregulated" in line 217 and 336. "Dysregulated" is more accurate. Please check the manuscript more carefully.
Author Response
We sincerely appreciate your comments and suggestions. We highly value your contribution, as we believe they have significantly enhanced the quality of our manuscript. Attached, you will find the file containing our responses to your comments and observations.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsI noticed ambiguity, redundancy, inconsistent formatting, and grammatical mistakes throughout the manuscript. The paragraphs lack smooth transitions between ideas, making it difficult to follow the logical progression of the argument. Additionally, there are several long, complex sentences throughout the manuscript that make the paragraphs difficult to read and understand. Here are my comments.
Comment 1: In the abstract section, line 36, this could be written as, “these molecules on AR regulation” instead of “regulation of this gene” for more clarity.
Comment 2: in section 2.3, The description of AR variants and their impact on PCa treatment could be clearer, particularly regarding the relationship between AR variants and therapeutic resistance.
Comment 3: Abbreviations should be avoided in the headings, for example, “2. AR in PCa “
Comment4: line 301-312, There are several instances where "hsa-miR" is incorrectly written as "has-miR."
Comment 5: line 298-317, “by directly regulating AR” is repeated multiple times, leading to redundancy.
Comment 6: Line 314-315, the statement "Thus, proposing that miRNAs that regulate AR play an important role in AR activity and PCa" is somewhat vague and could be more precise.
Comment 7: section 5.1. lacks the flow as the paragraph jumps between different miRNAs and their roles without a smooth transition, making it harder to follow.
Comment 9: section 5.1.2 talks about the relationship between hsa-miR-141 and SHP without sufficient context and thus gives incomplete information.
Comment 10: Section 5.3, line 451-452, “These dysregulations in the miRNAs that regulate AR can profoundly impact the expression of this gene," lacks specificity.
Comments on the Quality of English LanguageThere are some minor grammatical mistakes throughout the manuscript that should be corrected.
Author Response
Dear Reviewer,
We are deeply grateful for your insightful comments and observations, each of which has significantly contributed to enhancing the quality of our manuscript.
Comment 1: In the abstract section, line 36, this could be written as, “these molecules on AR regulation” instead of “regulation of this gene” for more clarity.
Response 1: We have revised the phrasing in the abstract to state “these molecules on AR regulation” instead of “regulation of this gene.”
Comment 2: in section 2.3, The description of AR variants and their impact on PCa treatment could be clearer, particularly regarding the relationship between AR variants and therapeutic resistance.
Response 2: We have revised section 2.3 to make the description of AR variants and their impact on therapeutic resistance in prostate cancer clearer.
Comment 3: Abbreviations should be avoided in the headings, for example, “2. AR in PCa “
Response 3: We have removed abbreviations from the headings to ensure clarity and improve readability.
Comment4: line 301-312, There are several instances where "hsa-miR" is incorrectly written as "has-miR."
Response 4: We have thoroughly reviewed the manuscript and corrected all instances of "has-miR" to "hsa-miR" as indicated. We appreciate your attention to detail in ensuring the accuracy of the terminology used in the text.
Comment 5: line 298-317, “by directly regulating AR” is repeated multiple times, leading to redundancy.
Response 5: We have revised the text to eliminate the repeated phrase “by directly regulating AR.” This has improved the overall flow and clarity of the section, making the information more concise and easier to read.
Comment 6: Line 314-315, the statement "Thus, proposing that miRNAs that regulate AR play an important role in AR activity and PCa" is somewhat vague and could be more precise.
Response 6: We have revised both the sentence and the surrounding paragraph to enhance clarity and specificity. The updated text now more accurately conveys the significance of miRNAs in regulating AR activity and their implications for prostate cancer progression.
Comment 7: section 5.1. lacks the flow as the paragraph jumps between different miRNAs and their roles without a smooth transition, making it harder to follow.
Response 7: We have reorganized Section 5.1 to create smoother transitions between different miRNAs and their respective roles. This restructuring enhances the overall flow of the text and improves readability, making the information more digestible for the reader.
Comment 8: section 5.1.2 talks about the relationship between hsa-miR-141 and SHP without sufficient context and thus gives incomplete information.
Response 8: We have revised the paragraph in Section 5.1.2 to provide additional context regarding the relationship between hsa-miR-141 and SHP. This enhancement ensures that the information presented is more comprehensive and clearly conveys the significance of their interaction in the context of prostate cancer.
Comment 9: Section 5.3, line 451-452, “These dysregulations in the miRNAs that regulate AR can profoundly impact the expression of this gene," lacks specificity.
Response 9: We have revised this statement to include more specific examples of how dysregulation of certain miRNAs affects AR expression. The updated text now clarifies the mechanisms through which these miRNAs influence AR signaling pathways and their implications for prostate cancer progression, thereby enhancing the overall specificity of the discussion.
Reviewer 2 Report
Comments and Suggestions for AuthorsPlease provide the full name of the gene abbreviation upon its first occurrence in the text for clarity, or list them in a table.
Author Response
Dear Reviewer,
We are deeply grateful for your insightful comments and observations, each of which has significantly contributed to enhancing the quality of our manuscript.
Comment 1: Please provide the full name of the gene abbreviation upon its first occurrence in the text for clarity, or list them in a table.
Response 1: We have added the full names of the gene abbreviations upon their first occurrence in the text to enhance clarity.
Round 3
Reviewer 2 Report
Comments and Suggestions for AuthorsAll my concerns were addressed.
