Role of HMGB1 in Cutaneous Melanoma: State of the Art
, Francesco Borgia 1,*,†, Paolo Custurone 1, Mario Vaccaro 1, Giovanni Pioggia 2 and Sebastiano Gangemi 3
Round 1
Reviewer 1 Report
The review article titled Role of HMGB1 in Melanoma: State of the Art by Pomi et al., is a a review of Pubmed data showing an increasing interest in HMG1 over the last 5 years. The authors jave provided sufficient number of relevant articles to provide a relatively comprehensive review on the role of HMG1 in melanoma pathogenesis and metastasis. The authors have covered significant areas such as immunological cell death, gene regulation, etc. The only concern is the lack of discussion on the connection between HMG1 and apoptosis of melanoma cells. This section needs to be added.
Author Response
Dear Reviewer
Thank you for your suggestions. About the relationship between HMGB1 and apoptosis of melanoma cells, the review of the literature demonstrated a negative correlation. In fact, HMGB1 induces the switch of Tumor associated macrophages (TAMs) towards a M2 phenotype, which stimulates tumor growth, in contrast to M1 phenotype, which exerts pro-apoptotic effects.
A section detailing such relationship was added to the text (paragraph 2.1).
Hoping these match your remarks, we wait for any further suggestions. We thank you in advance for your attention and send our
Best regards
Francesco Borgia
Reviewer 2 Report
In the manuscript "Role of HMGB1 in Melanoma: State of the Art" by Federica Li Pomi et al., the authors attempt to perform a comprehensive review about the role of HMGB1 in melanoma. The theme is interesting and extremely relevant for the field. The paper is written in a clear manner. However, there are several aspects that merit the attention of the authors:
1. The current manuscript title is misleading, since the authors present a view only about cutaneous melanoma. There is no mention to the role of HMGB1 in other types of melanoma, such as uveal melanoma.
2. The sentence “The research has been conducted on the PubMed database, and the resulting articles are sorted by year of publication, showing an increasing interest in the last five years.” is also misleading, since the paper is not a research paper, but only a classical literature review manuscript about the role of HMGB1 in melanoma. The information about the increasing interest in HMGB1 is also not supported by data. How many paper about the topic were published in 2017? In 2018? In 2019? In 2020? In 2022?
3. Throughout the text, there is a global and continuous lack of citations in key sentences to support the data present. One of such examples is the section “1.1.2 Molecular categories and therapy”. This aspect needs to be considerably improved.
4. Figure 1 is confusing and not self explanatory. It should be either removed or considerably improved.
5. The paper would benefit from a summary table containing the most relevant findings on HMGB1 in melanoma, including adequate citations.
Therefore, the present review paper attempts to summarize relevant infomation about HMGB1 in melanoma, but it will be mandatory to perform extensive changes in the present manuscript if it is considered relevant for publication in the International Journal of Molecular Sciences.
Author Response
Dear Reviewer
We sincerely appreciate all valuable comments and suggestions, which helped us to improve the quality of the article. Here is a point-to-point letter response.
Comment 1: The current manuscript title is misleading, since the authors present a view only about cutaneous melanoma. There is no mention to the role of HMGB1 in other types of melanoma, such as uveal melanoma.
Response 1: The intended topic of this article is cutaneous melanoma. The title of the review has been changed accordingly.
Comment 2: The sentence “The research has been conducted on the PubMed database, and the resulting articles are sorted by year of publication, showing an increasing interest in the last five years.” is also misleading, since the paper is not a research paper, but only a classical literature review manuscript about the role of HMGB1 in melanoma. The information about the increasing interest in HMGB1 is also not supported by data. How many paper about the topic were published in 2017? In 2018? In 2019? In 2020? In 2022?
Response 2: It was our intention to state that in the past 5 years there was an increase in published material regarding the role of HMGB1 and melanoma skin cancer compared to the previous five years (59 vs 49). The above-mentioned sentence has been modified as here presented: “This review has been conducted by researching the PubMed database and the results sorted by year of publication.”
Comment 3: Throughout the text, there is a global and continuous lack of citations in key sentences to support the data present. One of such examples is the section “1.1.2 Molecular categories and therapy”. This aspect needs to be considerably improved.
Response 3: The missing citations have been added to the text.
Comment 4: Figure 1 is confusing and not self-explanatory. It should be either removed or considerably improved.
Response 4: Figure 1 (now called “Figure 2”) has been modified. Moreover, another figure that summarizes the main pathways involved in HMGB1-related melanoma growth has been added (“Figure 1”).
Comment 5: The paper would benefit from a summary table containing the most relevant findings on HMGB1 in melanoma, including adequate citations.
Response 5: A summary table with the most relevant findings on HMGB1 in melanoma, with citations, has been added as Table 1.
Hoping these match your remarks, we wait for any further suggestions. We thank you in advance for your attention and send our
Reviewer 3 Report
The authors summarize the works of literature about the High-mobility Group Box1 (HMGB1) expression and function in metastasis development of tumor cells, especially in melanoma. In the manuscript, the authors claimed that HMGB1 plays a key role in the pathogenesis of melanoma and discussed the future of HMGB1 as a potential diagnosis biomarker, even as a therapy strategy. The regulation of HMGB1 in melanoma is a very interesting topic. However, the role of HMGB1 isn’t highlighted in the manuscript. The authors wrote a lot about the other regulation pathway or regulators in melanoma metastasis. The link between HMGB1 and melanoma is not significantly showing up in the manuscript. The reader will lose in a lot of bypass content and cannot notice the main topic of this manuscript. My comments are following,
1. In paragraph 2.1, the authors involved more content about the PD-1 regulation upon UV exposure. If the HMGB1/TBK1/IRF3/NF-κB and PD-1 belong to two independent roles, the HMGB1 should be the most talked about.
2. In paragraph 2.2, the authors talked more about S100B than HMGB1.
Author Response
To Reviewer
Thank you for these suggestions.
Here is a point-by-point response to the reviewer's comments and concerns.
Comment 1: In paragraph 2.1, the authors involved more content about the PD-1 regulation upon UV exposure. If the HMGB1/TBK1/IRF3/NF-κB and PD-1 belong to two independent roles, the HMGB1 should be the most talked about.
Response 1: PD-L1 can be activated by various molecules, such as STAT3, INF-gamma, and NF-κB. As for the induced PD-L1-UVB expression, the key role is played by NF-κB. The study (reference 24) has in fact shown that NF-κB is, in turn, activated upstream by the RAGE/HMGB axis. Therefore, in the text, we refer to a single signaling pathway, in which upstream there is HMGB1/RAGE and downstream PD-L1. However, some changes have been made in the paragraph to make it clearer.
Comment 2: In paragraph 2.2, the authors talked more about S100B than HMGB1.
Response 2: The discussion about S100B has been shortened and moved to the bottom of the paragraph, thus giving more prominence to the role of HMGB1 as a marker. Moreover, the possible role of HMGB1 as a marker has been further explored.
Finally, a new paragraph about the role of HMGB1 in the pathogenesis and growth of melanoma has been added to the discussion section (paragraph 2.1), accordingly.
Hoping these match your remarks, we wait for any further suggestions. We thank you in advance for your attention and send our
Round 2
Reviewer 2 Report
In the revised manuscript "Role of HMGB1 in cutaneous Melanoma: State of the Art" by Federica Li Pomi et al., the authors minimally addressed all the points raised in the initial version of the paper. Thus, I have no further objections towards the publication of the paper in the International Journal of Molecular Sciences.
Author Response
Dear Reviewer,
we sincerely appreciated the suggestions you provided which helped us to improve the quality of the manuscript. Thank you for your support.
Reviewer 3 Report
The changes in the new manuscript well addressed my comments. I have one comment about the table. The topics listed in the table are close to the name of each section. The table is redundant in this manuscript. I suggest the authors can add a table, which summarizes the topics in one section. For example, in section 2.4 HMGB1 and Immunological cell death, the authors can add a table that summarized different ways HMGB1 was utilized in ICD.
Author Response
Dear Reviewer,
we sincerely appreciated the suggestions you provided which helped us to improve the quality of the manuscript.
A table summarizing the main findings about the role of HMGB1 in Melanoma metastases and HMGB-1-based possible future therapies has been added in paragraph 2.4. Similarly, in paragraph 2.5, a table summarizing the main findings about HMGB1 and Immunological cell death and its possible use as a novel therapeutic approach has been added.
Hoping these match your remarks, we send our best regards.
