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Molecular Pathological Mechanisms of Skin Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (16 June 2023) | Viewed by 7938

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Special Issue Editor

Prof. Dr. Jochen Sven Utikal

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Guest Editor

Skin Cancer Unit, German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany
Interests: malignant melanoma; melanoma cellular plasticity; therapy resistance; biomarkers; translational oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Skin cancer shows rising incidence rates. During recent years, new therapeutic options such as targeted therapies and immunotherapies have improved the outcome of patients with advanced skin cancer. Deciphering the molecular basis of tumor cells and their interaction with other cell types of the body has the potential to contribute to novel therapeutic strategies, which could lead to deeper and longer-lasting clinical responses.

In this Special Issue, we will publish reviews and original research that provide new insights into the molecular mechanisms of skin cancer.

Prof. Dr. Jochen Sven Utikal
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

skin cancer
melanoma
squamous cell carcinoma
basal cell carcinoma, merkel cell carcinoma, molecule
targeted therapy
immunotherapy
pathogenesis
treatment
genetics
epigenetics
signaling pathways
molecular mechanisms

Published Papers (3 papers)

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Research

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14 pages, 2173 KiB

Open AccessArticle

TIMP3 Gene Polymorphisms of -1296 T > C and -915 A > G Increase the Susceptibility to Arsenic-Induced Skin Cancer: A Cohort Study and In Silico Analysis of Mutation Impacts

by Meei-Maan Wu, Chi-Wei Chen, Chiu-Yi Chen, Chih-Hung Lee, Mark Chou, Ling-I Hsu, Te-Chang Lee and Chien-Jen Chen

Int. J. Mol. Sci. 2022, 23(23), 14980; https://doi.org/10.3390/ijms232314980 - 29 Nov 2022

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Abstract

Long-term exposure to arsenic may induce several human cancers, including non-melanoma skin cancer. The tissue inhibitor of metalloproteinase (TIMP)-3, encoded by the TIMP3 gene, may inhibit tumor growth, invasion, and metastasis of several cancer types. In this study, we aimed to investigate effects of the TIMP3 -1296 T > C (rs9619311) and -915 A > G (rs2234921) single-nucleotide polymorphisms (SNPs) on skin cancer risk in an arsenic-exposed population, and to evaluate the influence of allele-specific changes by an in silico analysis. In total, 1078 study participants were followed up for a median of 15 years for newly diagnosed skin cancer. New cases were identified through linkage to the National Cancer Registry of Taiwan. A Cox regression analysis was used to evaluate the effects of TIMP3 variants. Transcription factor (TF) profiling of binding sites of allele-specific changes in SNPs was conducted using the JASPAR scan tool. We observed borderline associations between TIMP3 genotypes and skin cancer risk. However, when combined with high arsenic exposure levels, the rs9619311 C allele, rs2234921 G allele, or C-G haplotype groups exhibited a greater risk of developing skin cancer compared to the respective common homozygous genotype group. The in silico analysis revealed several TF motifs located at or flanking the two SNP sites. We validated that the C allele of rs9619311 attenuated the binding affinity of BACH2, MEIS2, NFE2L2, and PBX2 to the TIMP3 promoter, and that the G allele of rs2234921 reduced the affinity of E2F8 and RUNX1 to bind to the promoter. Our findings suggest significant modifications of the effect of the association between arsenic exposure and skin cancer risk by the TIMP3 rs9619311 and rs2234921 variants. The predicted TFs and their differential binding affinities to the TIMP3 promoter provide insights into how TIMP3 interacts with arsenic through TFs in skin cancer formation. Full article

(This article belongs to the Special Issue Molecular Pathological Mechanisms of Skin Cancer)

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12 pages, 1696 KiB

Open AccessArticle

Tracking of Melanoma Cell Plasticity by Transcriptional Reporters

by Anna Vidal and Torben Redmer

Int. J. Mol. Sci. 2022, 23(3), 1199; https://doi.org/10.3390/ijms23031199 - 21 Jan 2022

Cited by 1 | Viewed by 2415

Abstract

Clonal evolution and cellular plasticity are the genetic and non-genetic driving forces of tumor heterogeneity, which in turn determine tumor cell responses towards therapeutic drugs. Several lines of evidence suggest that therapeutic interventions foster the selection of drug-resistant neural crest stem-like cells (NCSCs) that establish minimal residual disease (MRD) in melanoma. Here, we establish a dual-reporter system, enabling the tracking of NGFR expression and mRNA stability and providing insights into the maintenance of NCSC states. We observed that a transcriptional reporter that contained a 1-kilobase fragment of the human NGFR promoter was activated only in a minor subset (0.72 ± 0.49%, range 0.3–1.5), and ~2–4% of A375 melanoma cells revealed stable NGFR mRNA. The combination of both reporters provides insights into phenotype switching and reveals that both cellular subsets gave rise to cellular heterogeneity. Moreover, whole transcriptome profiling and gene-set enrichment analysis (GSEA) of the minor cellular subset revealed hypoxia-associated programs that might serve as potential drivers of an in vitro switching of NGFR-associated phenotypes and relapse of post-BRAF inhibitor-treated tumors. Concordantly, we observed that the minor cellular subset increased in response to dabrafenib over time. In summary, our reporter-based approach provides insights into plasticity and identified a cellular subset that might be responsible for the establishment of MRD in melanoma. Full article

(This article belongs to the Special Issue Molecular Pathological Mechanisms of Skin Cancer)

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Review

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19 pages, 990 KiB

Open AccessReview

Immunotherapy for the Treatment of Squamous Cell Carcinoma: Potential Benefits and Challenges

by Tuba M. Ansary, MD Razib Hossain, Mayumi Komine and Mamitaro Ohtsuki

Int. J. Mol. Sci. 2022, 23(15), 8530; https://doi.org/10.3390/ijms23158530 - 1 Aug 2022

Cited by 12 | Viewed by 3335

Abstract

Melanoma and nonmelanoma skin cancers (NMSCs) are recognized as among the most common neoplasms, mostly in white people, with an increasing incidence rate. Among the NMSCs, squamous cell carcinoma (SCC) is the most prevalent malignancy known to affect people with a fair complexion who are exposed to extreme ultraviolet radiation (UVR), have a hereditary predisposition, or are immunosuppressed. There are several extrinsic and intrinsic determinants that contribute to the pathophysiology of the SCC. The therapeutic modalities depend on the SCC stages, from actinic keratosis to late-stage multiple metastases. Standard treatments include surgical excision, radiotherapy, and chemotherapy. As SCC represents a favorable tumor microenvironment with high tumor mutational burden, infiltration of immune cells, and expression of immune checkpoints, the SCC tumors are highly responsive to immunotherapies. Until now, there are three checkpoint inhibitors, cemiplimab, pembrolizumab, and nivolumab, that are approved for the treatment of advanced, recurrent, or metastatic SCC patients in the United States. Immunotherapy possesses significant therapeutic benefits for patients with metastatic or locally advanced tumors not eligible for surgery or radiotherapy to avoid the potential toxicity caused by the chemotherapies. Despite the high tolerability and efficiency, the existence of some challenges has been revealed such as, resistance to immunotherapy, less availability of the biomarkers, and difficulty in appropriate patient selection. This review aims to accumulate evidence regarding the genetic alterations related to SCC, the factors that contribute to the potential benefits of immunotherapy, and the challenges to follow this treatment regime. Full article

(This article belongs to the Special Issue Molecular Pathological Mechanisms of Skin Cancer)

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