|
1
|
Yamagiwa H, Hashimoto R, Arakane K, Murakami K, Soeda S, Oyama M, Zhu Y, Okada M, Shimodaira H. Predicting drug-gene relations via analogy tasks with word embeddings. Sci Rep 2025; 15:17240. [PMID: 40383732 PMCID: PMC12086191 DOI: 10.1038/s41598-025-01418-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 05/06/2025] [Indexed: 05/20/2025] Open
Abstract
Natural language processing is utilized in a wide range of fields, where words in text are typically transformed into feature vectors called embeddings. BioConceptVec is a specific example of embeddings tailored for biology, trained on approximately 30 million PubMed abstracts using models such as skip-gram. Generally, word embeddings are known to solve analogy tasks through simple vector arithmetic. For example, subtracting the vector for man from that of king and then adding the vector for woman yields a point that lies closer to queen in the embedding space. In this study, we demonstrate that BioConceptVec embeddings, along with our own embeddings trained on PubMed abstracts, contain information about drug-gene relations and can predict target genes from a given drug through analogy computations. We also show that categorizing drugs and genes using biological pathways improves performance. Furthermore, we illustrate that vectors derived from known relations in the past can predict unknown future relations in datasets divided by year. Despite the simplicity of implementing analogy tasks as vector additions, our approach demonstrated performance comparable to that of large language models such as GPT-4 in predicting drug-gene relations.
Collapse
Affiliation(s)
| | | | - Kiwamu Arakane
- Institute for Protein Research, Osaka University, Osaka, Japan
| | - Ken Murakami
- Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
| | - Shou Soeda
- Institute for Protein Research, Osaka University, Osaka, Japan
| | - Momose Oyama
- Kyoto University, Kyoto, Japan
- RIKEN, Tokyo, Japan
| | | | - Mariko Okada
- Institute for Protein Research, Osaka University, Osaka, Japan
| | | |
Collapse
|
|
2
|
Bernal-Masferrer L, Gracia-Cazaña T, Najera-Botello L, Gomez-Mateo MC, Cerro P, Matei MC, Gallego-Rentero M, González S, Juarranz A, Gilaberte Y. Analysis of tumoral, stromal and glycolitic markers in the response basal cell carcinoma and Bowen disease to photodynamic therapy in real life. Photodiagnosis Photodyn Ther 2025; 51:104442. [PMID: 39667651 DOI: 10.1016/j.pdpdt.2024.104442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND Photodynamic therapy (PDT) is a widely-used non-surgical treatment for non-melanoma skin cancers, including basal cell carcinoma (BCC), actinic keratoses (AK), and Bowen's disease (BD). PDT has high success rates, but various factors, can influence treatment response. This study investigates the clinical, histological, and molecular factors that affect the efficacy of methyl aminolevulinate PDT (MAL-PDT) for BCC and BD. METHODS AND PATIENTS Prospective observational multicentric study performed between May 2019 and January 2021 with 64 patients included. Clinical data such as tumor thickness, location, and histological subtype were recorded. Immunohistochemical analysis was performed on tumor samples to assess the expression of biomarkers including p53, β-catenin, and GLUT1. RESULTS Tumor thickness was found to be a critical determinant of MAL-PDT response, with thicker nodular BCCs showing reduced response rates compared to thinner, superficial BCCs and BD lesions. Immunohistochemical analysis revealed that p53 positivity was associated with better treatment outcomes, while increased β-catenin and cytoplasmic GLUT1 expression correlated with resistance to PDT. On the other hand, the metabolic profile of the tumors indicated that tumors with higher glycolytic activity were less responsive to treatment, therefore, using metformin, a glycolytic inhibitor, as a potential adjuvant therapy to improve outcomes in resistant tumors should be considered. CONCLUSION This study emphasizes the importance of personalized approaches in the use of MAL-PDT, tailoring treatment according to tumor-specific characteristics. Biomarkers such as p53, β-catenin, and GLUT1 can serve as predictive tools for PDT response, helping clinicians identify patients who may benefit from alternative or combined treatments to enhance therapeutic efficacy.
Collapse
Affiliation(s)
- L Bernal-Masferrer
- Department of Dermatology, Miguel Servet University Hospital, University of Zaragoza, IIS Aragón. Zaragoza, Spain
| | - T Gracia-Cazaña
- Department of Dermatology, Miguel Servet University Hospital, University of Zaragoza, IIS Aragón. Zaragoza, Spain.
| | - L Najera-Botello
- Department of Pathology, Puerta de Hierro University Hospital, Universidad Autónoma, Majadahonda, Madrid, Spain
| | - M C Gomez-Mateo
- Department of Pathology, Miguel Servet University Hospital, Zaragoza, Spain
| | | | - M C Matei
- Department of Dermatology, Miguel Servet University Hospital, University of Zaragoza, IIS Aragón. Zaragoza, Spain
| | - M Gallego-Rentero
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain; Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación, IRYCIS, Madrid, Spain
| | - S González
- Department of Medicine and Medical Specialties, Universidad de Alcalá, 28871 Madrid, Spain; Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS, Madrid, Spain
| | - A Juarranz
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain; Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación, IRYCIS, Madrid, Spain
| | - Y Gilaberte
- Department of Dermatology, Miguel Servet University Hospital, University of Zaragoza, IIS Aragón. Zaragoza, Spain
| |
Collapse
|
|
3
|
Li C, Sun C, Mahapatra KD, Riihilä P, Knuutila J, Nissinen L, Lapins J, Kähäri VM, Homey B, Sonkoly E, Pivarcsi A. Long noncoding RNA plasmacytoma variant translocation 1 is overexpressed in cutaneous squamous cell carcinoma and exon 2 is critical for its oncogenicity. Br J Dermatol 2024; 190:415-426. [PMID: 37930852 DOI: 10.1093/bjd/ljad419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/19/2023] [Accepted: 10/21/2023] [Indexed: 11/08/2023]
Abstract
BACKGROUND Cutaneous squamous cell carcinoma (cSCC) is one of the most common and fastest increasing forms of cancer worldwide with metastatic potential. Long noncoding RNAs (lncRNAs) are a group of RNA molecules with essential regulatory functions in both physiological and pathological processes. OBJECTIVES To investigate the function and mode of action of lncRNA plasmacytoma variant translocation 1 (PVT1) in cSCC. METHODS Quantitative reverse transcriptase polymerase chain reaction and single-molecule in situ hybridization were used to quantify the expression level of PVT1 in normal skin, premalignant skin lesions, actinic keratosis (AK) and primary and metastatic cSCCs. The function of PVT1 in cSCC was investigated both in vivo (tumour xenografts) and in vitro (competitive cell growth assay, 5-ethynyl-2'-deoxyuridine incorporation assay, colony formation assay and tumour spheroid formation assay) upon CRISPR-Cas9-mediated knockout of the entire PVT1 locus, the knockout of exon 2 of PVT1, and locked nucleic acid (LNA) gapmer-mediated PVT1 knockdown. RNA sequencing analysis was conducted to identify genes and processes regulated by PVT1. RESULTS We identified PVT1 as a lncRNA upregulated in cSCC in situ and cSCC, associated with the malignant phenotype of cSCC. We showed that the expression of PVT1 in cSCC was regulated by MYC. Both CRISPR-Cas9 deletion of the entire PVT1 locus and LNA gapmer-mediated knockdown of PVT1 transcript impaired the malignant behaviour of cSCC cells, suggesting that PVT1 is an oncogenic transcript in cSCC. Furthermore, knockout of PVT1 exon 2 inhibited cSCC tumour growth both in vivo and in vitro, demonstrating that exon 2 is a critical element for the oncogenic role of PVT1. Mechanistically, we showed that PVT1 was localized in the cell nucleus and its deletion resulted in cellular senescence, increased cyclin-dependent kinase inhibitor 1 (p21/CDKN1A) expression and cell cycle arrest. CONCLUSIONS Our study revealed a previously unrecognized role for exon 2 of PVT1 in its oncogenic role and that PVT1 suppresses cellular senescence in cSCC. PVT1 may be a potential biomarker and therapeutic target in cSCC.
Collapse
Affiliation(s)
- Chen Li
- Department of Medical Biochemistry and Microbiology (IMBIM)
| | - Chengxi Sun
- Department of Medical Biochemistry and Microbiology (IMBIM)
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China
| | | | - Pilvi Riihilä
- Department of Dermatology
- FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Jaakko Knuutila
- Department of Dermatology
- FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Liisa Nissinen
- Department of Dermatology
- FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Jan Lapins
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Veli-Matti Kähäri
- Department of Dermatology
- FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Bernhard Homey
- Department of Dermatology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Enikö Sonkoly
- Department of Medical Biochemistry and Microbiology (IMBIM)
- Dermatology and Venereology Division, Department of Medicine Solna
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Andor Pivarcsi
- Department of Medical Biochemistry and Microbiology (IMBIM)
- Dermatology and Venereology Division, Department of Medicine Solna
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
4
|
Adamus-Grabicka AA, Hikisz P, Sikora J. Nanotechnology as a Promising Method in the Treatment of Skin Cancer. Int J Mol Sci 2024; 25:2165. [PMID: 38396841 PMCID: PMC10889690 DOI: 10.3390/ijms25042165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
The incidence of skin cancer continues to grow. There are an estimated 1.5 million new cases each year, of which nearly 350,000 are melanoma, which is often fatal. Treatment is challenging and often ineffective, with conventional chemotherapy playing a limited role in this context. These disadvantages can be overcome by the use of nanoparticles and may allow for the early detection and monitoring of neoplastic changes and determining the effectiveness of treatment. This article briefly reviews the present understanding of the characteristics of skin cancers, their epidemiology, and risk factors. It also outlines the possibilities of using nanotechnology, especially nanoparticles, for the transport of medicinal substances. Research over the previous decade on carriers of active substances indicates that drugs can be delivered more accurately to the tumor site, resulting in higher therapeutic efficacy. The article describes the application of liposomes, carbon nanotubes, metal nanoparticles, and polymer nanoparticles in existing therapies. It discusses the challenges encountered in nanoparticle therapy and the possibilities of improving their performance. Undoubtedly, the use of nanoparticles is a promising method that can help in the fight against skin cancer.
Collapse
Affiliation(s)
- Angelika A. Adamus-Grabicka
- Department of Bioinorganic Chemistry, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland;
| | - Pawel Hikisz
- Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland;
| | - Joanna Sikora
- Department of Bioinorganic Chemistry, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland;
| |
Collapse
|
|
5
|
pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation. Nat Commun 2022; 13:6840. [PMID: 36369429 PMCID: PMC9652315 DOI: 10.1038/s41467-022-34529-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/27/2022] [Indexed: 11/13/2022] Open
Abstract
The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.
Collapse
|
|
6
|
Xu J, Li J. Construction of a three commitment points for S phase entry cell cycle model and immune-related ceRNA network to explore novel therapeutic options for psoriasis. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2022; 19:13483-13525. [PMID: 36654055 DOI: 10.3934/mbe.2022630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
While competing endogenous RNAs (ceRNAs) play pivotal roles in various diseases, the proliferation and differentiation of keratinocytes are becoming a research focus in psoriasis. Therefore, the three commitment points for S phase entry (CP1-3) cell cycle model has pointed to a new research direction in these areas. However, it is unclear what role ceRNA regulatory mechanisms play in the interaction between keratinocytes and the immune system in psoriasis. In addition, the ceRNA network-based screening of potential therapeutic agents for psoriasis has not been explored. Therefore, we used multiple bioinformatics approaches to construct a ceRNA network for psoriasis, identified CTGF as the hub gene, and constructed a ceRNA subnetwork, after which validation datasets authenticated the results' accuracy. Subsequently, we used multiple online databases and the single-sample gene-set enrichment analysis algorithm, including the CP1-3 cell cycle model, to explore the mechanisms accounting for the increased proliferation and differentiation of keratinocytes and the possible roles of the ceRNA subnetwork in psoriasis. Next, we performed cell cycle and cell trajectory analyses based on a single-cell RNA-seq dataset of psoriatic skin biopsies. We also used weighted gene co-expression network analysis and single-gene batch correlation analysis-based gene set enrichment analysis to explore the functions of CTGF. Finally, we used the Connectivity Map to identify MS-275 (entinostat) as a novel treatment for psoriasis, SwissTargetPrediction to predict drug targets, and molecular docking to investigate the minimum binding energy and binding sites of the drug to target proteins.
Collapse
Affiliation(s)
- Jingxi Xu
- North Sichuan Medical College, Nanchong 637000, China
- Department of Rheumatology and Immunology, The First People's Hospital of Yibin, Yibin 644000, China
| | - Jiangtao Li
- Department of Rheumatology and Immunology, The First People's Hospital of Yibin, Yibin 644000, China
| |
Collapse
|
|
7
|
Cheng L, Sun B, Xiong Y, Hu L, Gao L, Li J, Xie H, Chen X, Zhang W, Zhou HH. WGCNA-Based DNA Methylation Profiling Analysis on Allopurinol-Induced Severe Cutaneous Adverse Reactions: A DNA Methylation Signature for Predisposing Drug Hypersensitivity. J Pers Med 2022; 12:jpm12040525. [PMID: 35455641 PMCID: PMC9027774 DOI: 10.3390/jpm12040525] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/08/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
Background: The role of aberrant DNA methylation in allopurinol-induced severe cutaneous adverse reactions (SCARs) is incompletely understood. To fill the gap, we analyze the DNA methylation profiling in allopurinol-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) patients and identify the DNA methylation signature for predisposing allopurinol hypersensitivity. Methods: Genome-scale methylation analysis was conducted using the Illumina® HumanMethylation450 BeadChip. Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to analyze the data. Results: A total of 21,497 annotated promoter regions were analyzed. Ten modules were identified between allopurinol hypersensitivity and tolerance, with turquoise and yellow modules being the most significant correlation. ATG13, EPM2AIP1, and SRSF11 were the top three hub genes in the turquoise module. MIR412, MIR369, and MIR409 were the top three hub genes in the yellow module. Gene Ontology (GO) analysis revealed that the turquoise module was related to the metabolic process in intracellular organelles and the binding of various compounds, proteins, or nucleotides. The yellow module, however, was related to stimulus sensory perception in cytoskeletal elements and the activity of the receptor or transducer. Conclusion: DNA methylation plays a vital role in allopurinol-induced severe cutaneous adverse reactions (SCARs). DNA methylation profiling of SJS/TEN is significantly related to autophagy and microRNAs (miRNAs).
Collapse
Affiliation(s)
- Lin Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
- Correspondence: (L.C.); (H.-H.Z.)
| | - Bao Sun
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; (B.S.); (Y.X.); (L.H.); (X.C.); (W.Z.)
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha 410078, China
| | - Yan Xiong
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; (B.S.); (Y.X.); (L.H.); (X.C.); (W.Z.)
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha 410078, China
| | - Lei Hu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; (B.S.); (Y.X.); (L.H.); (X.C.); (W.Z.)
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha 410078, China
| | - Lichen Gao
- Department of Pharmacy, Department of Oncology, Cancer Institute, Changsha Central Hospital, Changsha 410004, China;
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; (J.L.); (H.X.)
| | - Hongfu Xie
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; (J.L.); (H.X.)
| | - Xiaoping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; (B.S.); (Y.X.); (L.H.); (X.C.); (W.Z.)
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha 410078, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; (B.S.); (Y.X.); (L.H.); (X.C.); (W.Z.)
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha 410078, China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; (B.S.); (Y.X.); (L.H.); (X.C.); (W.Z.)
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha 410078, China
- Correspondence: (L.C.); (H.-H.Z.)
| |
Collapse
|
|
8
|
Frommeyer TC, Rohan CA, Spandau DF, Kemp MG, Wanner MA, Tanzi E, Travers JB. Wounding Therapies for Prevention of Photocarcinogenesis. Front Oncol 2022; 11:813132. [PMID: 35071017 PMCID: PMC8776632 DOI: 10.3389/fonc.2021.813132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/14/2021] [Indexed: 01/01/2023] Open
Abstract
The occurrence of non-melanoma skin cancer (NMSC) is closely linked with advanced age and ultraviolet-B (UVB) exposure. More specifically, the development of NMSC is linked to diminished insulin-like growth factor-1 (IGF-1) signaling from senescent dermal fibroblasts in geriatric skin. Consequently, keratinocyte IGF-1 receptor (IGF-1R) remains inactive, resulting in failure to induce appropriate protective responses including DNA repair and cell cycle checkpoint signaling. This allows UVB-induced DNA damage to proliferate unchecked, which increases the likelihood of malignant transformation. NMSC is estimated to occur in 3.3 million individuals annually. The rising incidence results in increased morbidity and significant healthcare costs, which necessitate identification of effective treatment modalities. In this review, we highlight the pathogenesis of NMSC and discuss the potential of novel preventative therapies. In particular, wounding therapies such as dermabrasion, microneedling, chemical peeling, and fractionated laser resurfacing have been shown to restore IGF-1/IGF-1R signaling in geriatric skin and suppress the propagation of UVB-damaged keratinocytes. This wounding response effectively rejuvenates geriatric skin and decreases the incidence of age-associated NMSC.
Collapse
Affiliation(s)
- Timothy C. Frommeyer
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Craig A. Rohan
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Dermatology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Dayton Veterans Administration Medical Center, Dayton, OH, United States
| | - Dan F. Spandau
- Departments of Dermatology and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Richard A. Roudebush Veterans Administration (VA) Medical Center, Indianapolis, IN, United States
| | - Michael G. Kemp
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Dayton Veterans Administration Medical Center, Dayton, OH, United States
| | - Molly A. Wanner
- Department of Dermatology, Massachusetts General Hospital, Boston, MA, United States
| | | | - Jeffrey B. Travers
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Dermatology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Dayton Veterans Administration Medical Center, Dayton, OH, United States
| |
Collapse
|
|
9
|
de Pedro I, Galán-Vidal J, Freije A, de Diego E, Gandarillas A. p21CIP1 controls the squamous differentiation response to replication stress. Oncogene 2020; 40:152-162. [PMID: 33097856 DOI: 10.1038/s41388-020-01520-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/05/2020] [Accepted: 10/09/2020] [Indexed: 11/09/2022]
Abstract
The control of cell fate is critical to homeostasis and cancer. Cell cycle cdk inhibitor p21CIP1 has a central and paradoxical role in the regulatory crossroads leading to senescence, apoptosis, or differentiation. p21 is an essential target of tumor suppressor p53, but it also is regulated independently. In squamous self-renewal epithelia continuously exposed to mutagenesis, p21 controls cell fate by mechanisms still intriguing. We previously identified a novel epidermoid DNA damage-differentiation response. We here show that p21 intervenes in the mitosis block that is required for the squamous differentiation response to cell cycle deregulation and replication stress. The inactivation of endogenous p21 in human primary keratinocytes alleviated the differentiation response to oncogenic loss of p53 or overexpression of the DNA replication major regulator Cyclin E. The bypass of p21-induced mitotic block involving upregulation of Cyclin B allowed DNA damaged cells to escape differentiation and continue to proliferate. In addition, loss of p21 drove keratinocytes from differentiation to apoptosis upon moderate UV irradiation. The results show that p21 is required to drive keratinocytes towards differentiation in response to genomic stress and shed light into its dual and paradoxical role in carcinogenesis.
Collapse
Affiliation(s)
- Isabel de Pedro
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute for Research Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
| | - Jesús Galán-Vidal
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute for Research Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
| | - Ana Freije
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute for Research Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
| | - Ernesto de Diego
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute for Research Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain.,Paediatric Surgery, Hospital Universitario Marqués de Valdecilla, 39008, Santander, Spain
| | - Alberto Gandarillas
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute for Research Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain. .,INSERM, Languedoc-Roussillon, 34394, Montpellier, France.
| |
Collapse
|
|
10
|
Abstract
DNA damage response (DDR) and DNA repair pathways determine neoplastic cell transformation and therapeutic responses, as well as the aging process. Altered DDR functioning results in accumulation of unrepaired DNA damage, increased frequency of tumorigenic mutations, and premature aging. Recent evidence suggests that polypeptide hormones play a role in modulating DDR and DNA damage repair, while DNA damage accumulation may also affect hormonal status. We review the available reports elucidating involvement of insulin-like growth factor 1 (IGF1), growth hormone (GH), α-melanocyte stimulating hormone (αMSH), and gonadotropin-releasing hormone (GnRH)/gonadotropins in DDR and DNA repair as well as the current understanding of pathways enabling these actions. We discuss effects of DNA damage pathway mutations, including Fanconi anemia, on endocrine function and consider mechanisms underlying these phenotypes. (Endocrine Reviews 41: 1 - 19, 2020).
Collapse
Affiliation(s)
- Vera Chesnokova
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Shlomo Melmed
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| |
Collapse
|
|
11
|
Alkawar AMM, Castellanos AJ, Carpenter MA, Hutcherson RJ, Madkhali MAO, Johnson RM, Bottomley M, Kemp MG. Insulin-like Growth Factor-1 Impacts p53 Target Gene Induction in UVB-irradiated Keratinocytes and Human Skin. Photochem Photobiol 2020; 96:1332-1341. [PMID: 32416609 DOI: 10.1111/php.13279] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 05/05/2020] [Indexed: 12/19/2022]
Abstract
The tumor suppressor protein p53 limits mutagenesis in response to ultraviolet-B (UVB) light exposure by activating the transcription of genes that mitigate the damaging effects of UVB radiation on DNA. Because most nonmelanoma skin cancers (NMSCs) occur in older individuals, it is important to understand the process of mutagenesis in the geriatric skin microenvironment. Based on previous studies demonstrating that geriatric skin expresses lower levels of the growth factor insulin-like growth factor-1 (IGF-1) than young adult skin, a role for IGF-1 in the regulation of p53 target genes was investigated in both human keratinocytes in vitro and human skin explants ex vivo. The products of the p53 target genes p21 and DNA polymerase eta (pol η) were found to be increased by UVB exposure in both experimental systems, and this induction was observed to be partially abrogated by depriving keratinocytes of IGF-1 in vitro or by the treatment of keratinocytes in vitro and human skin explants with an IGF-1 receptor antagonist. Because p21 and pol η function to limit mutagenic DNA replication following UVB exposure, these results suggest that NMSC risk in geriatric populations may be due to age-dependent decreases in IGF-1 signaling that disrupt p53 function in the skin.
Collapse
Affiliation(s)
- Abdulrahman M M Alkawar
- Departments of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH
| | - Amber J Castellanos
- Departments of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH
| | - Mae Alexandra Carpenter
- Departments of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH
| | - Rebekah J Hutcherson
- Departments of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH
| | - Mariyyah A O Madkhali
- Departments of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH
| | - Ron Michael Johnson
- Department of Surgery, Boonshoft School of Medicine, Wright State University, Dayton, OH
| | | | - Michael G Kemp
- Departments of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH
| |
Collapse
|
|
12
|
Biomarkers of basal cell carcinoma resistance to methyl-aminolevulinate photodynamic therapy. PLoS One 2019; 14:e0215537. [PMID: 31017970 PMCID: PMC6481917 DOI: 10.1371/journal.pone.0215537] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 04/03/2019] [Indexed: 01/15/2023] Open
Abstract
Background Methyl-aminolevulinate photodynamic therapy (MAL-PDT) is an excellent option for the treatment of basal cell carcinoma (BCC). However, up to 25% of cases are resistant to this treatment modality. Objective The aim of this study was to identify potential biomarkers of BCC response to MAL-PDT. Material and methods Clinical, histological, and immunohistochemical (p53, Ki-67, CD-31, COX2, β-catenin, EGFR, and survivin) variables were analyzed in a retrospective study of consecutive BCC patients treated with MAL-PDT at the San Jorge Hospital, Huesca, Spain between January 2006 and December 2015. To deepen on these markers, the effects on p53 and cyclin D1 expression, in vitro response to MAL-PDT of 2 murine BCC cell lines (ASZ and BSZ), was also evaluated. Results The retrospective study examined the response to MAL-PDT of 390 BCCs from 182 patients. The overall clinical response rate was 82.8%, with a mean follow-up time of 35.96 months (SD = 23.46). Immunohistochemistry revealed positive p53 in 84.6% of responders but only 15.4% of nonresponsive tumors (p = 0.011). Tumors with increased peripheral palisading of basal cell islands to immunostaining β-catenin responded poorly to PDT (p = 0.01). In line with our findings in patients, in vitro studies revealed a better response to PDT in the p53-positive ASZ cell line than the p53-negative BSZ cell line (p<0.01). Multivariate analysis revealed that the following variables were significantly associated with response to PDT: age, nBCC, presence of peritumoral inflammatory infiltrate, and p53 immunopositivity. Patients with positive p53 immunostaining were 68.54 times more likely to achieve cure than p53-negative patients (CI95% 2.94–159.8) Conclusion Our finding suggest that certain clinicopathological and immunohistochemical variables, particularly p53 expression, may serve as indicators of BCC response to MAL-PDT, and thus facilitate the selection of patients who are most likely to benefit from this therapy.
Collapse
|
|
13
|
Lee MP, Agarwal A, Zullo SW, Etzkorn JR. Cells to Surgery Quiz: March 2019. J Invest Dermatol 2019. [DOI: 10.1016/j.jid.2018.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
14
|
|
|
15
|
Szewczyk M, Pazdrowski J, Golusiński P, Dańczak-Pazdrowska A, Pawlaczyk M, Sygut J, Marszałek A, Golusiński W. Outdoor work as a risk factor for high-grade cutaneous squamous cell carcinoma of the head and neck. Postepy Dermatol Alergol 2018; 35:408-412. [PMID: 30206456 PMCID: PMC6130134 DOI: 10.5114/ada.2018.75841] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 07/12/2017] [Indexed: 11/28/2022] Open
Abstract
INTRODUCTION While it is clear that individuals with outdoor occupations are at a significantly greater risk of developing cutaneous squamous cell carcinoma (cSCC), no previous studies have investigated the potential association between the tumour grade and occupation in this patient population. AIM To assess occupation as a risk factor for the development of high-grade cSCC. Secondarily, to determine the association between the tumour grade and other clinical characteristics. MATERIAL AND METHODS Retrospective analysis of 256 patients treated for head and neck cSCC at our institution in 2007-2016. The following patient characteristics and variables were assessed: age; sex; tumour location and grade; profession; and education level. A univariate analysis was performed to assess the association between each study variable and grade 3 tumour differentiation. RESULTS The following variables were significantly associated (p < 0.05) with grade 3 (G3) cSCC tumours: outdoor work vs. indoor work; primary school vs. high school education; and age. Additionally, patients with low-grade (G1) tumours were significantly younger (mean age: 72) than patients with high-grade (G3) tumours (mean age: 79) (p = 0.046). CONCLUSIONS To our knowledge, this is the first study to assess the variables associated with the tumour grade among outdoor workers. These findings suggest that outdoor workers who develop cSCC are at a greater risk of developing more aggressive cancers. These findings provide additional support for classifying cSCC as an occupational disease. Early education about the dangers of sun exposure during the first years of school is essential to minimize the risks of developing high-grade skin cancer.
Collapse
Affiliation(s)
- Mateusz Szewczyk
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Jakub Pazdrowski
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Paweł Golusiński
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
- Department of Biology and Environmental Studies, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Mariola Pawlaczyk
- Department of Gerontology and Geriatric Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Jacek Sygut
- Department of Cancer Pathology and Prophylaxis, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Andrzej Marszałek
- Department of Cancer Pathology and Prophylaxis, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Wojciech Golusiński
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| |
Collapse
|
|
16
|
Lesiak A, Sobolewska-Sztychny D, Bednarski IA, Wódz K, Sobjanek M, Woźniacka A, Narbutt J. Alternative activation of hedgehog pathway induced by ultraviolet B radiation: preliminary study. Clin Exp Dermatol 2018; 43:518-524. [PMID: 29424103 DOI: 10.1111/ced.13394] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2017] [Indexed: 11/28/2022]
Abstract
BACKGROUND There is still much ambiguity in studies of Sonic hedgehog (Shh) pathways and its dysregulation. Some studies concerning the role of the Shh pathway in basal cell carcinoma (BCC) have been conducted, but there is a lack of studies about Shh pathway dysregulation under the influence of ultraviolet (UV)B radiation. AIM To evaluate skin expression of Shh, Ptch1, Ptch2, Smo and Gli1 proteins in BCCs with and without the influence of UVB radiation. METHODS In total, 34 healthy controls (HCs) and 42 patients with nodular BCC were recruited into the study. Patients were divided into five groups (A-E), depending on UVB dose received and BCC status. In all skin specimens, expression of Shh, Ptch1, Ptch2, Smo and Gli1 protein was evaluated. RESULTS Comparing the BCC group with the HC group, there was significantly higher expression of Shh, Ptch1, Ptch2, Smo and Gli1 proteins. Expression of Ptch2, Smo and Gli1 was increased in response to UVB doses of 3 MED (minimal erythema dose), whereas expression of Ptch1 and Shh was unaffected. CONCLUSION The lack of change in expression of Shh and Ptch1 after exposure to UVB suggests that the Shh pathway may be activated through a noncanonical pathway under the influence of strong UVB doses.
Collapse
Affiliation(s)
- A Lesiak
- Department of Dermatology and Pediatric and Oncologic Dermatology, Medical University of Łódź, Łódź, Poland
| | | | - I A Bednarski
- Student Research Group at Department of Dermatology and Venereology, Medical University of Łódź, Łódź, Poland
| | - K Wódz
- Department of Experimental Immunology, Medical University of Łódź, Łódź, Poland
| | - M Sobjanek
- Department of Dermatology and Venereology, Medical University of Gdańsk, Gdańsk, Poland
| | - A Woźniacka
- Department of Dermatology and Venereology, Medical University of Łódź, Łódź, Poland
| | - J Narbutt
- Department of Dermatology and Pediatric and Oncologic Dermatology, Medical University of Łódź, Łódź, Poland
| |
Collapse
|
|
17
|
Anand S, Rollakanti KR, Brankov N, Brash DE, Hasan T, Maytin EV. Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death. Mol Cancer Ther 2017; 16:1092-1101. [PMID: 28336806 DOI: 10.1158/1535-7163.mct-16-0608] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/07/2016] [Accepted: 03/15/2017] [Indexed: 11/16/2022]
Abstract
Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) to drive synthesis of protoporphryin IX (PpIX) is a promising, scar-free alternative to surgery for skin cancers, including squamous cell carcinoma (SCC) and SCC precursors called actinic keratoses. In the United States, PDT is only FDA approved for treatment of actinic keratoses; this narrow range of indications could be broadened if PDT efficacy were improved. Toward that goal, we developed a mechanism-based combination approach using 5-fluorouracil (5-FU) as a neoadjuvant for ALA-based PDT. In mouse models of SCC (orthotopic UV-induced lesions, and subcutaneous A431 and 4T1 tumors), pretreatment with 5-FU for 3 days followed by ALA for 4 hours led to large, tumor-selective increases in PpIX levels, and enhanced cell death upon illumination. Several mechanisms were identified that might explain the relatively improved therapeutic response. First, the expression of key enzymes in the heme synthesis pathway was altered, including upregulated coproporphyrinogen oxidase and downregulated ferrochelatase. Second, a 3- to 6-fold induction of p53 in 5-FU-pretreated tumors was noted. The fact that A431 contains a mutant form p53 did not prevent the development of a neoadjuvantal 5-FU effect. Furthermore, 5-FU pretreatment of 4T1 tumors (cells that completely lack p53), still led to significant beneficial inductions, that is, 2.5-fold for both PpIX and PDT-induced cell death. Thus, neoadjuvantal 5-FU combined with PDT represents a new therapeutic approach that appears useful even for p53-mutant and p53-null tumors. Mol Cancer Ther; 16(6); 1092-101. ©2017 AACR.
Collapse
Affiliation(s)
- Sanjay Anand
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio. .,Department of Dermatology, Cleveland Clinic, Cleveland, Ohio
| | | | - Nikoleta Brankov
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio
| | - Douglas E Brash
- Departments of Therapeutic Radiology and Dermatology, Yale School of Medicine, New Haven, Connecticut
| | - Tayyaba Hasan
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Edward V Maytin
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio. .,Department of Dermatology, Cleveland Clinic, Cleveland, Ohio.,Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts
| |
Collapse
|
|
18
|
Molinuevo R, Freije A, de Pedro I, Stoll SW, Elder JT, Gandarillas A. FOXM1 allows human keratinocytes to bypass the oncogene-induced differentiation checkpoint in response to gain of MYC or loss of p53. Oncogene 2017; 36:956-965. [PMID: 27452522 PMCID: PMC5318665 DOI: 10.1038/onc.2016.262] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 06/02/2016] [Accepted: 06/16/2016] [Indexed: 02/06/2023]
Abstract
Tumour suppressor p53 or proto-oncogene MYC is frequently altered in squamous carcinomas, but this is insufficient to drive carcinogenesis. We have shown that overactivation of MYC or loss of p53 via DNA damage triggers an anti-oncogenic differentiation-mitosis checkpoint in human epidermal keratinocytes, resulting in impaired cell division and squamous differentiation. Forkhead box M1 (FOXM1) is a transcription factor recently proposed to govern the expression of a set of mitotic genes. Deregulation of FOXM1 occurs in a wide variety of epithelial malignancies. We have ectopically expressed FOXM1 in keratinocytes of the skin after overexpression of MYC or inactivation of endogenous p53. Ectopic FOXM1 rescues the proliferative capacity of MYC- or p53-mutant cells in spite of higher genetic damage and a larger cell size typical of differentiation. As a consequence, differentiation induced by loss of p53 or MYC is converted into increased proliferation and keratinocytes displaying genomic instability are maintained within the proliferative compartment. The results demonstrate that keratinocyte oncogene-induced differentiation is caused by mitosis control and provide new insight into the mechanisms driving malignant progression in squamous cancer.
Collapse
Affiliation(s)
- R Molinuevo
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute of Research Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - A Freije
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute of Research Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - I de Pedro
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute of Research Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - S W Stoll
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - J T Elder
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Department of Ann Arbor Veterans Affairs Health System, Ann Arbor, MI, USA
| | - A Gandarillas
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute of Research Marqués de Valdecilla (IDIVAL), Santander, Spain
- INSERM, Languedoc-Roussillon, Montpellier, France
| |
Collapse
|
|
19
|
UV-Induced Molecular Signaling Differences in Melanoma and Non-melanoma Skin Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 996:27-40. [PMID: 29124688 DOI: 10.1007/978-3-319-56017-5_3] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
There are three major types of skin cancer: melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC and SCC are often referred to as non-melanoma skin cancer (NMSC). NMSCs are relatively non-lethal and curable by surgery, hence are not reportable in most cancer registries all over the world. Melanoma is the deadliest skin cancer. Its incidence rate (case number) is about 1/10th of that for NMSC, yet its death toll is ~8 fold higher than NMSC.Melanomas arise from melanocytes which are normally located on the basement membrane with dendrites extending into the epidermal keratinocytes. A major known function of melanocytes is to produce pigments which are enclosed by lipid membrane (termed melanosomes) and distribute them into keratinocytes, thus give different shade of skin colors. BCCs arise from basal cells, which are a layer of cells located at the deepest part of epidermis. Basal cells are recently considered to be skin stem cells as they are constantly proliferating and generating keratinocytes which are continuously pushed to the surface and eventually become a dead layer of stratum corneum. Squamous cells are the keratinocytes which resembles fish scale shape, ie, those initiated from basal cells and differentiated into squamous cells. Both basal cells and squamous cells belong to keratinocytes, therefore sometimes BCC and SCC are termed keratinocyte cancer.These three types of cancer share many characteristics, yet they are very different from etiology to progression. One shared characteristic of skin cancer is that, according to the current views, they all are caused by solar or artificial ultraviolet radiation (UVR). UVA and UVB from solar UVR are the major UV bands reaching the earth surface. Both UV types cause DNA damage and immune suppression which play crucial roles in skin carcinogenesis. UVB can be directly absorbed by DNA molecules and thus causes UV-signature DNA damages; UVA, on the other hand, may function through inducing cellular ROS which then causes oxidative DNA damages [1-4]. This chapter will discuss the molecular signaling differences of UVR in melanoma and NMSC.
Collapse
|
|
20
|
Voiculescu V, Calenic B, Ghita M, Lupu M, Caruntu A, Moraru L, Voiculescu S, Ion A, Greabu M, Ishkitiev N, Caruntu C. From Normal Skin to Squamous Cell Carcinoma: A Quest for Novel Biomarkers. DISEASE MARKERS 2016; 2016:4517492. [PMID: 27642215 PMCID: PMC5011506 DOI: 10.1155/2016/4517492] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 07/25/2016] [Indexed: 12/14/2022]
Abstract
Squamous cells carcinoma (SCC) is the second most frequent of the keratinocyte-derived malignancies after basal cell carcinoma and is associated with a significant psychosocial and economic burden for both the patient himself and society. Reported risk factors for the malignant transformation of keratinocytes and development of SCC include ultraviolet light exposure, followed by chronic scarring and inflammation, exposure to chemical compounds (arsenic, insecticides, and pesticides), and immune-suppression. Despite various available treatment methods and recent advances in noninvasive or minimal invasive diagnostic techniques, the risk recurrence and metastasis are far from being negligible, even in patients with negative histological margins and lymph nodes. Analyzing normal, dysplastic, and malignant keratinocyte proteome holds special promise for novel biomarker discovery in SCC that could be used in the future for early detection, risk assessment, tumor monitoring, and development of targeted therapeutic strategies.
Collapse
Affiliation(s)
- Vlad Voiculescu
- Department of Dermatology and Allergology, Elias Emergency University Hospital, Bucharest, Romania
| | - Bogdan Calenic
- Department of Biochemistry, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Mihaela Ghita
- Dermatology Research Laboratory, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Mihai Lupu
- Department of Dermatology and Allergology, Elias Emergency University Hospital, Bucharest, Romania
| | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, “Carol Davila” Central Military Emergency Hospital, Bucharest, Romania
| | - Liliana Moraru
- Department of Oral and Maxillofacial Surgery, “Carol Davila” Central Military Emergency Hospital, Bucharest, Romania
| | - Suzana Voiculescu
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Alexandra Ion
- Department of Dermatology and Allergology, Elias Emergency University Hospital, Bucharest, Romania
| | - Maria Greabu
- Department of Biochemistry, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Nikolay Ishkitiev
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine, Medical University, Sofia, Bulgaria
| | - Constantin Caruntu
- Dermatology Research Laboratory, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| |
Collapse
|
|
21
|
Calapre L, Gray ES, Kurdykowski S, David A, Hart P, Descargues P, Ziman M. Heat-mediated reduction of apoptosis in UVB-damaged keratinocytes in vitro and in human skin ex vivo. BMC DERMATOLOGY 2016; 16:6. [PMID: 27230291 PMCID: PMC4882820 DOI: 10.1186/s12895-016-0043-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 05/18/2016] [Indexed: 01/18/2023]
Abstract
Background UV radiation induces significant DNA damage in keratinocytes and is a known risk factor for skin carcinogenesis. However, it has been reported previously that repeated and simultaneous exposure to UV and heat stress increases the rate of cutaneous tumour formation in mice. Since constant exposure to high temperatures and UV are often experienced in the environment, the effects of exposure to UV and heat needs to be clearly addressed in human epidermal cells. Methods In this study, we determined the effects of repeated UVB exposure 1 kJ/m2 followed by heat (39 °C) to human keratinocytes. Normal human ex vivo skin models and primary keratinocytes (NHEK) were exposed once a day to UVB and/or heat stress for four consecutive days. Cells were then assessed for changes in proliferation, apoptosis and gene expression at 2 days post-exposure, to determine the cumulative and persistent effects of UV and/or heat in skin keratinocytes. Results Using ex vivo skin models and primary keratinocytes in vitro, we showed that UVB plus heat treated keratinocytes exhibit persistent DNA damage, as observed with UVB alone. However, we found that apoptosis was significantly reduced in UVB plus heat treated samples. Immunohistochemical and whole genome transcription analysis showed that multiple UVB plus heat exposures induced inactivation of the p53-mediated stress response. Furthermore, we demonstrated that repeated exposure to UV plus heat induced SIRT1 expression and a decrease in acetylated p53 in keratinocytes, which is consistent with the significant downregulation of p53-regulated pro-apoptotic and DNA damage repair genes in these cells. Conclusion Our results suggest that UVB-induced p53-mediated cell cycle arrest and apoptosis are reduced in the presence of heat stress, leading to increased survival of DNA damaged cells. Thus, exposure to UVB and heat stress may act synergistically to allow survival of damaged cells, which could have implications for initiation skin carcinogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12895-016-0043-4) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Leslie Calapre
- School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia
| | - Elin S Gray
- School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia
| | | | - Anthony David
- GENOSKIN Centre Pierre Potier, Oncopole, Toulouse, France
| | - Prue Hart
- Telethon Kids Institute, University of Western Australia, 100 Roberts Road, Subiaco, Perth, 6008, Australia
| | | | - Mel Ziman
- School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA, 6027, Australia. .,Department of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.
| |
Collapse
|
|
22
|
Cantariño N, Fernández-Figueras MT, Valero V, Musulén E, Malinverni R, Granada I, Goldie SJ, Martín-Caballero J, Douet J, Forcales SV, Buschbeck M. A cellular model reflecting the phenotypic heterogeneity of mutant HRAS driven squamous cell carcinoma. Int J Cancer 2016; 139:1106-16. [PMID: 27074337 DOI: 10.1002/ijc.30139] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 01/07/2016] [Indexed: 12/28/2022]
Abstract
Squamous cell carcinomas have a range of histopathological manifestations. The parameters that determine this clinically observed heterogeneity are not fully understood. Here, we report the generation of a cell culture model that reflects part of this heterogeneity. We have used the catalytic subunit of human telomerase hTERT and large T to immortalize primary UV-unexposed keratinocytes. Then, mutant HRAS G12V has been introduced to transform these immortal keratinocytes. When injected into immunosuppressed mice, transformed cells grew as xenografts with distinct histopathological characteristics. We observed three major tissue architectures: solid, sarcomatoid and cystic growth types, which were primarily composed of pleomorphic and basaloid cells but in some cases displayed focal apocrine differentiation. We demonstrate that the cells generated represent different stages of skin cancerogenesis and as such can be used to identify novel tumor-promoting alterations such as the overexpression of the PADI2 oncogene in solid-type SCC. Importantly, the cultured cells maintain the characteristics from the xenograft they were derived from while being amenable to manipulation and analysis. The availability of cell lines representing different clinical manifestations opens a new tool to study the stochastic and deterministic factors that cause case-to-case heterogeneity despite departing from the same set of oncogenes and the same genetic background.
Collapse
Affiliation(s)
- Neus Cantariño
- Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain
| | | | - Vanesa Valero
- Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain.,Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain
| | - Eva Musulén
- Department Of Pathology, Hospital Universitari Germans Trias I Pujol, Campus Can Ruti, Badalona, Spain
| | - Roberto Malinverni
- Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain.,Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain
| | - Isabel Granada
- Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain.,Department of Hematology, Instituto Catalán De Oncología (ICO) - Hospital Universitari Germans Trias I Pujol, Universitat Autònoma De Barcelona, Campus Can Ruti, Badalona, Spain
| | - Stephen J Goldie
- Li KaShing Centre, Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge, CB2 0RE, United Kingdom
| | | | - Julien Douet
- Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain
| | - Sonia-Vanina Forcales
- Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain
| | - Marcus Buschbeck
- Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain.,Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain
| |
Collapse
|
|
23
|
Greinert R, de Vries E, Erdmann F, Espina C, Auvinen A, Kesminiene A, Schüz J. European Code against Cancer 4th Edition: Ultraviolet radiation and cancer. Cancer Epidemiol 2015; 39 Suppl 1:S75-83. [PMID: 26096748 DOI: 10.1016/j.canep.2014.12.014] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 10/10/2014] [Accepted: 12/14/2014] [Indexed: 12/31/2022]
Abstract
Ultraviolet radiation (UVR) is part of the electromagnetic spectrum emitted naturally from the sun or from artificial sources such as tanning devices. Acute skin reactions induced by UVR exposure are erythema (skin reddening), or sunburn, and the acquisition of a suntan triggered by UVR-induced DNA damage. UVR exposure is the main cause of skin cancer, including cutaneous malignant melanoma, basal-cell carcinoma, and squamous-cell carcinoma. Skin cancer is the most common cancer in fair-skinned populations, and its incidence has increased steeply over recent decades. According to estimates for 2012, about 100,000 new cases of cutaneous melanoma and about 22,000 deaths from it occurred in Europe. The main mechanisms by which UVR causes cancer are well understood. Exposure during childhood appears to be particularly harmful. Exposure to UVR is a risk factor modifiable by individuals' behaviour. Excessive exposure from natural sources can be avoided by seeking shade when the sun is strongest, by wearing appropriate clothing, and by appropriately applying sunscreens if direct sunlight is unavoidable. Exposure from artificial sources can be completely avoided by not using sunbeds. Beneficial effects of sun or UVR exposure, such as for vitamin D production, can be fully achieved while still avoiding too much sun exposure and the use of sunbeds. Taking all the scientific evidence together, the recommendation of the 4th edition of the European Code Against Cancer for ultraviolet radiation is: "Avoid too much sun, especially for children. Use sun protection. Do not use sunbeds."
Collapse
Affiliation(s)
- Rüdiger Greinert
- Center of Dermatology, Department of Molecular Cell Biology, Elbekliniken Stade/Buxtehude, Am Krankenhaus 1, D-21614 Buxtehude, Germany
| | - Esther de Vries
- Department of Public Health, Erasmus MC/Section of Cancer Information, Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - Friederike Erdmann
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon, France
| | - Carolina Espina
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon, France
| | - Anssi Auvinen
- School of Health Sciences, University of Tampere, FI-33014 Tampere, Finland; STUK - Radiation and Nuclear Safety Authority, Research and Environmental Surveillance, Helsinki, Finland
| | - Ausrele Kesminiene
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon, France
| | - Joachim Schüz
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon, France.
| |
Collapse
|
|
24
|
Muenyi CS, Ljungman M, States JC. Arsenic Disruption of DNA Damage Responses-Potential Role in Carcinogenesis and Chemotherapy. Biomolecules 2015; 5:2184-93. [PMID: 26404387 PMCID: PMC4693233 DOI: 10.3390/biom5042184] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 09/06/2015] [Accepted: 09/09/2015] [Indexed: 12/26/2022] Open
Abstract
Arsenic is a Class I human carcinogen and is widespread in the environment. Chronic arsenic exposure causes cancer in skin, lung and bladder, as well as in other organs. Paradoxically, arsenic also is a potent chemotherapeutic against acute promyelocytic leukemia and can potentiate the cytotoxic effects of DNA damaging chemotherapeutics, such as cisplatin, in vitro. Arsenic has long been implicated in DNA repair inhibition, cell cycle disruption, and ubiquitination dysregulation, all negatively impacting the DNA damage response and potentially contributing to both the carcinogenic and chemotherapeutic potential of arsenic. Recent studies have provided mechanistic insights into how arsenic interferes with these processes including disruption of zinc fingers and suppression of gene expression. This review discusses these effects of arsenic with a view toward understanding the impact on the DNA damage response.
Collapse
Affiliation(s)
- Clarisse S Muenyi
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
| | - Mats Ljungman
- Departments of Radiation Oncology and Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109-2800, USA.
| | - J Christopher States
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
| |
Collapse
|
|
25
|
Yajima I, Kumasaka MY, Ohnuma S, Ohgami N, Naito H, Shekhar HU, Omata Y, Kato M. Arsenite-mediated promotion of anchorage-independent growth of HaCaT cells through placental growth factor. J Invest Dermatol 2015; 135:1147-1156. [PMID: 25493652 DOI: 10.1038/jid.2014.514] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 11/09/2014] [Accepted: 11/25/2014] [Indexed: 12/19/2022]
Abstract
Various cancers including skin cancer are increasing in 45 million people exposed to arsenic above the World Health Organization's guideline value of 10 μg l(-1). However, there is limited information on key molecules regulating arsenic-mediated carcinogenesis. Our fieldwork in Bangladesh demonstrated that levels of placental growth factor (PlGF) in urine samples from residents of cancer-prone areas with arsenic-polluted drinking water were higher than those in urine samples from residents of an area that was not polluted with arsenic. Our experimental study in human nontumorigenic HaCaT skin keratinocytes showed that arsenite promoted anchorage-independent growth with increased expression and secretion of PlGF, a ligand of vascular endothelial growth factor receptor1 (VEGFR1), and increased VEGFR1/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) activities. The arsenite-mediated promotion of anchorage-independent growth was strongly inhibited by PlGF depletion with decreased activities of the PlGF/VEGFR1/MEK/ERK pathway. Moreover, arsenite proteasome-dependently degrades metal-regulatory transcription factor-1 (MTF-1) protein, resulting in a decreased amount of MTF-1 protein binding to the PlGF promoter. MTF-1 negatively controlled PlGF transcription in HaCaT cells, resulting in increased PlGF transcription. These results suggest that arsenite-mediated MTF-1 degradation enhances the activity of PlGF/VEGFR1/MEK/ERK signaling, resulting in promotion of the malignant transformation of keratinocytes. Thus, this study proposed a molecular mechanism for arsenite-mediated development of skin cancer.
Collapse
Affiliation(s)
- Ichiro Yajima
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan; Voluntary Body for International Health Care in Universities, Nagoya, Japan
| | - Mayuko Y Kumasaka
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan; Voluntary Body for International Health Care in Universities, Nagoya, Japan
| | - Shoko Ohnuma
- Voluntary Body for International Health Care in Universities, Nagoya, Japan
| | - Nobutaka Ohgami
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan; Voluntary Body for International Health Care in Universities, Nagoya, Japan
| | - Hisao Naito
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hossain U Shekhar
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka-1000, Bangladesh
| | - Yasuhiro Omata
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masashi Kato
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan; Voluntary Body for International Health Care in Universities, Nagoya, Japan; Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka-1000, Bangladesh.
| |
Collapse
|
|
26
|
Zhilova MB, Smolyannikova VA. Squamous cell carcinoma in a psoriasis patient after multiple courses of phototherapy. VESTNIK DERMATOLOGII I VENEROLOGII 2015. [DOI: 10.25208/0042-4609-2015-91-1-92-98] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
The authors present a clinical case study of squamous cell carcinoma in a psoriasis patient after 24 courses of phototherapy (22 courses of PUVA therapy and two courses of mid-wavelength ultraviolet therapy (311 nm)). The malignant neoplasm developed against the background of signs of a chronic photodamage of the skin: lentigo, actinic elastosis, diffuse hyperpigmentation, spotty skin pigmentation.
Collapse
|
|
27
|
Gandarillas A, Molinuevo R, Freije A, Alonso-Lecue P. The mitosis-differentiation checkpoint, another guardian of the epidermal genome. Mol Cell Oncol 2015; 2:e997127. [PMID: 27308487 PMCID: PMC4905324 DOI: 10.1080/23723556.2014.997127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 12/05/2014] [Accepted: 12/08/2014] [Indexed: 10/25/2022]
Abstract
The role of p53, the original "guardian of the genome", in skin has remained elusive. We have explored p53 function in human epidermal cells and demonstrated the importance of a mitosis-differentiation checkpoint to suppress potentially precancerous cells. This model places epidermal endoreplication as an antioncogenic mechanism in the face of irreparable genetic alterations.
Collapse
Affiliation(s)
- Alberto Gandarillas
- Cell Cycle; Stem cell Fate and Cancer Laboratory; Instituto de Investigación Marqués de Valdecilla (IDIVAL); Santander, Spain; INSERM; Languedoc-Roussillon; Montpellier, France
| | - Rut Molinuevo
- Cell Cycle; Stem cell Fate and Cancer Laboratory; Instituto de Investigación Marqués de Valdecilla (IDIVAL) ; Santander, Spain
| | - Ana Freije
- Cell Cycle; Stem cell Fate and Cancer Laboratory; Instituto de Investigación Marqués de Valdecilla (IDIVAL) ; Santander, Spain
| | - Pilar Alonso-Lecue
- Cell Cycle; Stem cell Fate and Cancer Laboratory; Instituto de Investigación Marqués de Valdecilla (IDIVAL) ; Santander, Spain
| |
Collapse
|
|
28
|
Freije A, Molinuevo R, Ceballos L, Cagigas M, Alonso-Lecue P, Rodriguez R, Menendez P, Aberdam D, De Diego E, Gandarillas A. Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage. Cell Rep 2014; 9:1349-60. [PMID: 25453755 DOI: 10.1016/j.celrep.2014.10.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 08/14/2014] [Accepted: 10/03/2014] [Indexed: 11/28/2022] Open
Abstract
Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear.
Collapse
Affiliation(s)
- Ana Freije
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain
| | - Rut Molinuevo
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain
| | - Laura Ceballos
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain
| | - Marta Cagigas
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain
| | - Pilar Alonso-Lecue
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain
| | - René Rodriguez
- Lab 2-ORL, Instituto Universitario de Oncología de Asturias (IUOPA) Hospital Universitario Central de Asturias (HUCA), Oviedo 33006, Spain
| | - Pablo Menendez
- Josep Carreras Leukaemia Research Institute, School of Medicine, University of Barcelona, Barcelona 08036, Spain; Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Avenida Lluis Companys, Barcelona 08010, Spain
| | - Daniel Aberdam
- INSERM UMR-S976, University Paris Didero, Hôpital Saint-Louis, Equerre Bazin, Paris 75475, France
| | - Ernesto De Diego
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain; Paediatric Surgery, Hospital Universitario Marqués de Valdecilla (HUMV), Santander 39011, Spain
| | - Alberto Gandarillas
- Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain; INSERM, Languedoc-Roussillon, Montpellier 34394, France.
| |
Collapse
|
|
29
|
Poligone B, Gilmore ES, Alexander CV, Oleksyn D, Gillespie K, Zhao J, Ibrahim SF, Pentland AP, Brown MD, Chen L. PKK suppresses tumor growth and is decreased in squamous cell carcinoma of the skin. J Invest Dermatol 2014; 135:869-876. [PMID: 25285922 PMCID: PMC4324088 DOI: 10.1038/jid.2014.428] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 08/26/2014] [Accepted: 09/13/2014] [Indexed: 01/06/2023]
Abstract
Non-melanoma skin cancer (NMSC) represents the most common cancer in the United States. Squamous cell carcinoma (SCC) of the skin is a sub-type of NMSC that shows a greater potential for invasion and metastasis. The current study identifies the Protein Kinase C-associated Kinase (PKK), which is also known as the Receptor-Interacting Protein Kinase 4 (RIPK4), as a suppressor of tumor growth in SCC of the skin. We show that expression of PKK is decreased in human SCC of the skin compared to normal skin. Further, suppression of PKK in human keratinocytes leads to increased cell proliferation. Use of RNA interference to reduce PKK expression in keratinocytes leads to an increase in S phase and in proteins that promote cell cycle progression. Consistent with the results obtained from cell culture, there is a dramatic increased tumorigenesis after PKK knockdown in a xenotransplant model and in soft agar assays. The loss of tumor suppression involves the NF-κB and p63 pathways. NF-κB is inhibited through inhibition of IKK function and there is increased nuclear TP63 activity after PKK knockdown. This study opens new avenues both in the discovery of disease pathogenesis and for potential treatments.
Collapse
Affiliation(s)
- Brian Poligone
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA.
| | - Elaine S Gilmore
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
| | - Carolina V Alexander
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA
| | - David Oleksyn
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA
| | - Kathleen Gillespie
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA
| | - Jiyong Zhao
- Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, New York, USA
| | - Sherrif F Ibrahim
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
| | - Alice P Pentland
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
| | - Marc D Brown
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
| | - Luojing Chen
- Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA
| |
Collapse
|
|
30
|
Paniz-Mondolfi A, Singh R, Jour G, Mahmoodi M, Diwan AH, Barkoh BA, Cason R, Huttenbach Y, Benaim G, Galbincea J, Luthra R. Cutaneous carcinosarcoma: further insights into its mutational landscape through massive parallel genome sequencing. Virchows Arch 2014; 465:339-50. [DOI: 10.1007/s00428-014-1628-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 06/17/2014] [Accepted: 07/02/2014] [Indexed: 01/06/2023]
|
|
31
|
Kubo Y, Matsudate Y, Fukui N, Nakasuka A, Sogawa M, Oshima M, Mizutani T, Otsu M, Murao K, Hashimoto I. Molecular tumorigenesis of the skin. THE JOURNAL OF MEDICAL INVESTIGATION 2014; 61:7-14. [DOI: 10.2152/jmi.61.7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
- Yoshiaki Kubo
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Yoshihiro Matsudate
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Nozomi Fukui
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Ayaka Nakasuka
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Maiko Sogawa
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Mika Oshima
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Tomoya Mizutani
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Masanobu Otsu
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Kazutoshi Murao
- Department of Dermatology, Institute of Health Biosciences, the University of Tokushima Graduate School
| | - Ichiro Hashimoto
- Department of Plastic and Reconstructive Surgery, Institute of Health Biosciences, the University of Tokushima Graduate School
| |
Collapse
|
|
32
|
Lee SM, Zhang W, Fernandez MP. Atypical fibroxanthoma arising in a young patient with Li-Fraumeni syndrome. J Cutan Pathol 2013; 41:303-7. [DOI: 10.1111/cup.12274] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 10/23/2013] [Accepted: 11/17/2013] [Indexed: 11/28/2022]
Affiliation(s)
- Sun Mi Lee
- Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA
| | | | | |
Collapse
|
|
33
|
Kivisaari A, Kähäri VM. Squamous cell carcinoma of the skin: Emerging need for novel biomarkers. World J Clin Oncol 2013; 4:85-90. [PMID: 24926428 PMCID: PMC4053710 DOI: 10.5306/wjco.v4.i4.85] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 06/26/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
The incidence of non-melanoma skin cancers (NMSC) is rising worldwide resulting in demand for clinically useful prognostic biomarkers for these malignant tumors, especially for invasive and metastatic cutaneous squamous cell carcinoma (cSCC). Important risk factors for the development and progression of cSCC include ultraviolet radiation, chronic skin ulcers and immunosuppression. Due to the role of cumulative long-term sun exposure, cSCC is usually a disease of the elderly, but the incidence is also growing in younger individuals due to increased recreational exposure to sunlight. Although clinical diagnosis of cSCC is usually easy and treatment with surgical excision curable, it is responsible for the majority of NMSC related deaths. Clinicians treating skin cancer patients are aware that certain cSCCs grow rapidly and metastasize, but the underlying molecular mechanisms responsible for the aggressive progression of a subpopulation of cSCCs remain incompletely understood. Recently, new molecular markers for progression of cSCC have been identified.
Collapse
|
|
34
|
Poligone B, Hayden MS, Chen L, Pentland AP, Jimi E, Ghosh S. A role for NF-κB activity in skin hyperplasia and the development of keratoacanthomata in mice. PLoS One 2013; 8:e71887. [PMID: 23977171 PMCID: PMC3747062 DOI: 10.1371/journal.pone.0071887] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 07/10/2013] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Previous studies have implicated NF-κB signaling in both cutaneous development and oncogenesis. However, these studies have been limited in part by the lethality that results from extreme over- or under-expression of NF-κB in available mouse models. Even cre-driven tissue specific expression of transgenes, or targeted deletion of NF-κB can cause cell death. Therefore, the present study was undertaken to evaluate a novel mouse model of enhanced NF-κB activity in the skin. METHODS A knock-in homologous recombination technique was utilized to develop a mouse model (referred to as PD mice) with increased NF-κB activity. RESULTS The data show that increased NF-κB activity leads to hyperproliferation and dysplasia of the mouse epidermis. Chemical carcinogenesis in the context of enhanced NF-κB activity promotes the development of keratoacanthomata. CONCLUSION Our findings support an important role for NF-κB in keratinocyte dysplasia. We have found that enhanced NF-κB activity renders keratinocytes susceptible to hyperproliferation and keratoacanthoma (KA) development but is not sufficient for transformation and SCC development. We therefore propose that NF-κB activation in the absence of additional oncogenic events can promote TNF-dependent, actinic keratosis-like dysplasia and TNF-independent, KAs upon chemical carcinogensis. These studies suggest that resolution of KA cannot occur when NF-κB activation is constitutively enforced.
Collapse
Affiliation(s)
- Brian Poligone
- Department of Dermatology and the James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, New York, United States of America
- * E-mail:
| | - Matthew S. Hayden
- Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
- Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Luojing Chen
- Department of Dermatology and the James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, New York, United States of America
| | - Alice P. Pentland
- Department of Dermatology and the James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, New York, United States of America
| | - Eijiro Jimi
- Division of Molecular Signaling and Biochemistry, Kyushu Dental College, Kitakyushu, Fukuoka, Japan
| | - Sankar Ghosh
- Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| |
Collapse
|
|
35
|
Heat stress: A risk factor for skin carcinogenesis. Cancer Lett 2013; 337:35-40. [DOI: 10.1016/j.canlet.2013.05.039] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 05/24/2013] [Accepted: 05/27/2013] [Indexed: 11/18/2022]
|
|
36
|
Huang HC, Chang TM, Chang YJ, Wen HY. UVB irradiation regulates ERK1/2- and p53-dependent thrombomodulin expression in human keratinocytes. PLoS One 2013; 8:e67632. [PMID: 23844043 PMCID: PMC3699658 DOI: 10.1371/journal.pone.0067632] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 05/20/2013] [Indexed: 11/19/2022] Open
Abstract
Thrombomodulin (TM) is highly expressed in endothelial cells and acts as a natural anticoagulation factor to maintain circulation homeostasis. TM is an interesting molecule with many physiological functions, including anti-inflammation, anti-thrombosis, and carcinogenesis inhibition. TM can also be detected on the spinous layer of epidermal keratinocytes. However, the role of epidermal TM is still under investigation. In this study, we investigated keratinocyte TM expression and regulation in response to sub-cytotoxic ultraviolet B (UVB) irradiation. Oxidative stress was assessed with DCF and the results revealed that UVB irradiation significantly and dose-dependently augmented reactive oxygen species (ROS) production in HaCaT cells. In addition, low-dose UVB irradiation decreased TM mRNA and protein levels. Blocking ROS production and ERK activation prevented UVB-induced TM down-regulation. The nuclear p53 accumulation and TM promoter binding was observed within 3 h after UVB exposure. Small interfering RNA-mediated p53 knockdown disrupted the UVB-mediated TM protein down-regulation. Our study demonstrates that UVB irradiation results in ROS accumulation and ERK activation, which causes the nuclear p53 accumulation and TM promoter binding to inhibit TM expression. This study provides novel evidence demonstrating that p53 serves as a key regulator of keratinocyte TM expression.
Collapse
Affiliation(s)
- Huey-Chun Huang
- Department of Medical Laboratory Science and Biotechnology, College of Health Care, China Medical University, Taichung, Taiwan.
| | | | | | | |
Collapse
|
|
37
|
Sklar LR, Almutawa F, Lim HW, Hamzavi I. Effects of ultraviolet radiation, visible light, and infrared radiation on erythema and pigmentation: a review. Photochem Photobiol Sci 2013; 12:54-64. [PMID: 23111621 DOI: 10.1039/c2pp25152c] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The effects of ultraviolet radiation, visible light, and infrared radiation on cutaneous erythema, immediate pigment darkening, persistent pigment darkening, and delayed tanning are affected by a variety of factors. Some of these factors include the depth of cutaneous penetration of the specific wavelength, the individual skin type, and the absorption spectra of the different chromophores in the skin. UVB is an effective spectrum to induce erythema, which is followed by delayed tanning. UVA induces immediate pigment darkening, persistent pigment darkening, and delayed tanning. At high doses, UVA (primarily UVA2) can also induce erythema in individuals with skin types I-II. Visible light has been shown to induce erythema and a tanning response in dark skin, but not in fair skinned individuals. Infrared radiation produces erythema, which is probably a thermal effect. In this article we reviewed the available literature on the effects of ultraviolet radiation, visible light, and infrared radiation on the skin in regards to erythema and pigmentation. Much remains to be learned on the cutaneous effects of visible light and infrared radiation.
Collapse
Affiliation(s)
- Lindsay R Sklar
- Multicultural Dermatology Center, Department of Dermatology, Henry Ford Hospital, 3031 West Grand Boulevard, Detroit, MI 48202, USA
| | | | | | | |
Collapse
|
|
38
|
Budden T, Bowden NA. The role of altered nucleotide excision repair and UVB-induced DNA damage in melanomagenesis. Int J Mol Sci 2013; 14:1132-51. [PMID: 23303275 PMCID: PMC3565312 DOI: 10.3390/ijms14011132] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 11/29/2012] [Accepted: 12/26/2012] [Indexed: 01/12/2023] Open
Abstract
UVB radiation is the most mutagenic component of the UV spectrum that reaches the earth's surface and causes the development of DNA damage in the form of cyclobutane pyrimidine dimers and 6-4 photoproducts. UV radiation usually results in cellular death, but if left unchecked, it can affect DNA integrity, cell and tissue homeostasis and cause mutations in oncogenes and tumour-suppressor genes. These mutations, if unrepaired, can lead to abnormal cell growth, increasing the risk of cancer development. Epidemiological data strongly associates UV exposure as a major factor in melanoma development, but the exact biological mechanisms involved in this process are yet to be fully elucidated. The nucleotide excision repair (NER) pathway is responsible for the repair of UV-induced lesions. Patients with the genetic disorder Xeroderma Pigmentosum have a mutation in one of eight NER genes associated with the XP complementation groups XP-A to XP-G and XP variant (XP-V). XP is characterized by diminished repair capacity, as well as a 1000-fold increase in the incidence of skin cancers, including melanoma. This has suggested a significant role for NER in melanoma development as a result of UVB exposure. This review discusses the current research surrounding UVB radiation and NER capacity and how further investigation of NER could elucidate the role of NER in avoiding UV-induced cellular death resulting in melanomagenesis.
Collapse
Affiliation(s)
- Timothy Budden
- Centre for Information Based Medicine, Hunter Medical Research Institute, and School of Biomedical Sciences & Pharmacy, Faculty of Health, University of Newcastle, Newcastle, NSW 2289, Australia.
| | | |
Collapse
|
|
39
|
Cav1 suppresses tumor growth and metastasis in a murine model of cutaneous SCC through modulation of MAPK/AP-1 activation. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 182:992-1004. [PMID: 23267770 DOI: 10.1016/j.ajpath.2012.11.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2012] [Revised: 10/03/2012] [Accepted: 11/08/2012] [Indexed: 01/17/2023]
Abstract
Caveolin-1 (Cav1) is a scaffolding protein that serves to regulate the activity of several signaling molecules. Its loss has been implicated in the pathogenesis of several types of cancer, but its role in the development and progression of cutaneous squamous cell carcinoma (cSCC) remains largely unexplored. Herein, we use the keratinocyte cell line PAM212, a murine model of cSCC, to determine the function of Cav1 in skin tumor biology. We first show that Cav1 overexpression decreases cell and tumor growth, whereas Cav1 knockdown increases these attributes in PAM212 cells. In addition, Cav1 knockdown increases the invasive ability and incidence of spontaneous lymph node metastasis. Finally, we demonstrate that Cav1 knockdown increases extracellular signaling-related kinase 1/2 mitogen-activated protein kinase/activator protein-1 pathway activation. We attribute the growth and invasive advantage conferred by Cav1 knockdown to increased expression of activator protein-1 transcriptional targets, including cyclin D1 and keratin 18, which show inverse expression in PAM212 based on the expression level of Cav1. In summary, we demonstrate that loss of Cav1 affects several characteristics associated with aggressive human skin tumors and that this protein may be an important modulator of tumor growth and invasion in cSCC.
Collapse
|
|
40
|
Guinea-Viniegra J, Zenz R, Scheuch H, Jiménez M, Bakiri L, Petzelbauer P, Wagner EF. Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17. J Clin Invest 2012; 122:2898-910. [PMID: 22772468 DOI: 10.1172/jci63103] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 05/30/2012] [Indexed: 12/22/2022] Open
Abstract
Squamous cell carcinomas (SCCs) are heterogeneous and aggressive skin tumors for which innovative, targeted therapies are needed. Here, we identify a p53/TACE pathway that is negatively regulated by FOS and show that the FOS/p53/TACE axis suppresses SCC by inducing differentiation. We found that epidermal Fos deletion in mouse tumor models or pharmacological FOS/AP-1 inhibition in human SCC cell lines induced p53 expression. Epidermal cell differentiation and skin tumor suppression were caused by a p53-dependent transcriptional activation of the metalloprotease TACE/ADAM17 (TNF-α-converting enzyme), a previously unknown p53 target gene that was required for NOTCH1 activation. Although half of cutaneous human SCCs display p53-inactivating mutations, restoring p53/TACE activity in mouse and human skin SCCs induced tumor cell differentiation independently of the p53 status. We propose FOS/AP-1 inhibition or p53/TACE reactivating strategies as differentiation-inducing therapies for SCCs.
Collapse
Affiliation(s)
- Juan Guinea-Viniegra
- Fundación Banco Bilbao Vizcaya (F-BBVA) - CNIO Cancer Cell Biology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | | | | | | | | | | | | |
Collapse
|
|
41
|
Einspahr JG, Calvert V, Alberts DS, Curiel-Lewandrowski C, Warneke J, Krouse R, Stratton SP, Liotta L, Longo C, Pellacani G, Pellicani G, Prasad A, Sagerman P, Bermudez Y, Deng J, Bowden GT, Petricoin EF. Functional protein pathway activation mapping of the progression of normal skin to squamous cell carcinoma. Cancer Prev Res (Phila) 2012; 5:403-13. [PMID: 22389437 PMCID: PMC3297971 DOI: 10.1158/1940-6207.capr-11-0427] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Reverse phase protein microarray analysis was used to identify cell signaling derangements in squamous cell carcinoma (SCC) compared with actinic keratosis (AK) and upper inner arm (UIA). We analyzed two independent tissue sets with isolation and enrichment of epithelial cells by laser capture microdissection. Set 1 served as a pilot and a means to identify protein pathway activation alterations that could be further validated in a second independent set. Set 1 was comprised of 4 AK, 13 SCC, and 20 UIA. Set 2 included 15 AK, 9 SCCs, and 20 UIAs. Activation of 51 signaling proteins, known to be involved in tumorigenesis, were assessed for set 1 and showed that the MEK-ERK [mitogen-activated protein (MAP)/extracellular signal-regulated (ERK; MEK)] pathway was activated in SCC compared with AK and UIA, and that epidermal growth factor receptor (EGFR) and mTOR pathways were aberrantly activated in SCC. Unsupervised two-way hierarchical clustering revealed that AK and UIA shared a common signaling network activation architecture while SCC was dramatically different. Statistical analysis found that prosurvival signaling through phosphorylation of ASK and 4EBP1 as well as increased Bax and Bak expression was higher in AK compared with UIA. We expanded pathway network activation mapping in set 2 to 101 key signaling proteins, which corroborated activation of MEK-ERK, EGFR, and mTOR pathways through discovery of a number of upstream and downstream signaling molecules within these pathways to conclude that SCC is indeed a pathway activation-driven disease. Pathway activation mapping of SCC compared with AK revealed several interconnected networks that could be targeted with drug therapy for potential chemoprevention and therapeutic applications.
Collapse
Affiliation(s)
- Janine G Einspahr
- University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Rebel H, Bodmann C, van de Glind G, de Gruijl F. UV-induced ablation of the epidermal basal layer including p53-mutant clones resets UV carcinogenesis showing squamous cell carcinomas to originate from interfollicular epidermis. Carcinogenesis 2012; 33:714-20. [DOI: 10.1093/carcin/bgs004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
|
|
43
|
Smith KA, Tong X, Abu-Yousif AO, Mikulec CC, Gottardi CJ, Fischer SM, Pelling JC. UVB radiation-induced β-catenin signaling is enhanced by COX-2 expression in keratinocytes. Mol Carcinog 2011; 51:734-45. [PMID: 21853475 DOI: 10.1002/mc.20840] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 06/15/2011] [Accepted: 07/13/2011] [Indexed: 11/10/2022]
Abstract
UVB radiation is the major carcinogen responsible for skin carcinogenesis, thus elucidation of the molecular pathways altered in skin in response to UVB would reveal novel targets for therapeutic intervention. It is well established that UVB leads to upregulation of cyclooxygenase 2 (COX-2) in the skin which contributes to skin carcinogenesis. Overexpression of COX-2 has been shown to promote colon cancer cell growth through β-catenin signaling, however, little is known about the connection between UVB, COX-2, and β-catenin in the skin. In the present study, we have identified a novel pathway in which UVB induces β-catenin signaling in keratinocytes, which is modulated by COX-2 expression. Exposure of the mouse 308 keratinocyte cell line (308 cells) and primary normal human epidermal keratinocytes (NHEKs) to UVB resulted in increased protein levels of both N-terminally unphosphorylated and total β-catenin. In addition, we found that UVB-enhanced β-catenin-dependent TOPflash reporter activity and expression of a downstream β-catenin target gene. We demonstrated that UVB-induced β-catenin signaling is modulated by COX-2, as treatment of keratinocytes with the specific COX-2 inhibitor NS398 blocked UVB induction of β-catenin. Additionally, β-catenin target gene expression was reduced in UVB-treated COX-2 knockout (KO) MEFs compared to wild-type (WT) MEFs. Furthermore, epidermis from UVB-exposed SKH-1 mice exhibited increased N-terminally unphosphorylated and total β-catenin protein levels and increased staining for total β-catenin, and both responses were reduced in COX-2 heterozygous mice. Taken together, these results suggest a novel pathway in which UVB induces β-catenin signaling in keratinocytes which is enhanced by COX-2 expression.
Collapse
Affiliation(s)
- Kimberly A Smith
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Sand JM, Bin Hafeez B, Aziz MH, Siebers EM, Dreckschmidt NE, Verma AK. Ultraviolet radiation and 12-O-tetradecanoylphorbol-13-acetate-induced interaction of mouse epidermal protein kinase Cε with Stat3 involve integration with ERK1/2. Mol Carcinog 2011; 51:291-302. [PMID: 21480396 DOI: 10.1002/mc.20776] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2010] [Revised: 02/15/2011] [Accepted: 03/04/2011] [Indexed: 01/20/2023]
Abstract
We have reported that protein kinase C epsilon (PKCε) expression level in epidermis dictates the susceptibility of mice to the development of squamous cell carcinomas (SCC) elicited either by repeated exposure to ultraviolet radiation (UVR) or by the DMBA-TPA tumor promotion protocol. To find clues about the mechanism by which PKCε mediates susceptibility to UVR-induced development of SCC, we found that PKCε-over-expressing transgenic mice, as compared to their wild-type littermates, when exposed to UVR, elicit enhanced phosphorylation of Stat3 at Ser727 residues. Stat3 is constitutively activated in SCC and UVR fails to induce SCC in Stat3 mutant mice. Stat3Ser727 phosphorylation is essential for Stat3 transcriptional activity (Cancer Res. 67: 1385, 2007). We now present several novel findings including that PKCε integrates with its downstream partner ERK1/2 to phosphorylate Stat3Ser727. In these experiments, mice were either exposed to UVR (2 kJ/m(2)/dose) emitted by Kodacel-filtered FS-40 sun lamps or treated with TPA (5 nmol). Both UVR and TPA treatment stimulated PKCε-Stat3 interaction, Stat3Ser727 phosphorylation and Stat3-regulated gene COX-2 expression. PKCε-Stat3 interaction and Stat3Ser727 phosphorylation was also observed in SCC elicited by repeated UVR exposures of mice. PKCε-Stat3 interaction was PKCε specific. UVR or TPA-stimulated Stat3Ser727 phosphorylation accompanied interaction of PKCε with ERK1/2 in intact mouse skin in vivo. Deletion of PKCε in wild-type mice attenuated both TPA and UVR-induced expression of phosphoforms of ERK1/2 and Stat3Ser727. These results indicate that PKCε integrates with ERK1/2 to mediate both TPA and UVR-induced epidermal Stat3Ser727 phosphorylation. PKCε and Stat3 may be potential molecular targets for SCC prevention.
Collapse
Affiliation(s)
- Jordan Marshall Sand
- Department of Human Oncology, Wisconsin Institutes for Medical Research, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin 53705; Department of Molecular and Environmental Toxicology Center, Wisconsin Institutes for Medical Research, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin 53705
| | | | | | | | | | | |
Collapse
|
|
45
|
Seité S, Fourtanier A, Moyal D, Young A. Photodamage to human skin by suberythemal exposure to solar ultraviolet radiation can be attenuated by sunscreens: a review. Br J Dermatol 2010; 163:903-14. [DOI: 10.1111/j.1365-2133.2010.10018.x] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
46
|
Marrot L, Planel E, Ginestet AC, Belaïdi JP, Jones C, Meunier JR. In vitro tools for photobiological testing: molecular responses to simulated solar UV of keratinocytes growing as monolayers or as part of reconstructed skin. Photochem Photobiol Sci 2010; 9:448-58. [PMID: 20354637 DOI: 10.1039/b9pp00145j] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Epidermal keratinocytes are critical targets for UV-induced genotoxicity as their transformation by sunlight overexposure can lead to skin cancer such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Therefore, assessment of photoprotection should involve early markers associated with DNA photodamage. Here, the same normal human keratinocytes either in monoculture (KC) or in full thickness reconstructed skin (RS) were compared with respect to their response to simulated solar UV (SSUV) exposure. Irradiation conditions (spectral power distribution and doses) were designed to mimic environmental zenithal UV from sunlight. At doses where survival was higher than 80%, comet assay showed more single strand breaks (SSB) and cyclobutane pyrimidine dimers (CPD) in keratinocytes in RS than in KC one hour post-exposure. The transcription factor p53 was activated in both models. While in KC p53 accumulation displayed a linear dose-dependency up to 24 h post-exposure, in RS it followed a bell-shaped profile and reverted to its basal rate. QRT-PCR demonstrated that among genes controlled by p53, P21 and MDM2 were clearly induced by SSUV in KC, whereas GADD45 expression was strongly and almost exclusively up-regulated in RS. Nrf2-dependent antioxidant genes (Ferritin light chain, NQO1) were only induced in RS, yet at low doses for NQO1. In vitro models such as KC or RS allowing the development of quantitative methodologies should be used as surrogates for in vivo tests assessing photogenotoxicity.
Collapse
Affiliation(s)
- Laurent Marrot
- L'OREAL, International Department of Safety Research, Aulnay sous bois, France
| | | | | | | | | | | |
Collapse
|
|
47
|
Agelli M, Clegg LX, Becker JC, Rollison DE. The etiology and epidemiology of merkel cell carcinoma. Curr Probl Cancer 2010; 34:14-37. [PMID: 20371072 DOI: 10.1016/j.currproblcancer.2010.01.001] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Maria Agelli
- Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Bethesda, MD, USA
| | | | | | | |
Collapse
|
|
48
|
Abstract
The rising incidence and morbidity of non-melanoma skin cancers has generated great interest in unravelling of their pathogenesis and in the search for new non-invasive treatments. Whereas the role of cumulative sun exposure in pathogenesis of squamous-cell carcinoma seems clear, the relation between sun-exposure patterns and subtypes of basal-cell carcinoma remains undetermined. Several complex genotypic, phenotypic, and environmental factors contribute to pathogenesis of non-melanoma skin cancers. Unlike basal-cell carcinoma, squamous-cell carcinomas can arise from precursor lesions. Diagnosis of non-melanoma skin cancer is made clinically and confirmed by histological testing. Prognosis depends on lesion and host characteristics, which also dictate choice of treatment. Prevention strategies aim at reduction of sun exposure, but are of unproven benefit, especially for basal-cell carcinoma. Surgical excision with predetermined margins is the mainstay of treatment for squamous-cell carcinoma and for most basal-cell carcinomas. Of the new non-invasive treatments, only photodynamic therapy and topical imiquimod have become established treatments for specific subtypes of basal-cell carcinoma, and the search for more effective and tissue-salvaging therapies continues.
Collapse
Affiliation(s)
- Vishal Madan
- Dermatology Centre, Salford Royal Hospital NHS Foundation Trust, Salford, UK
| | | | | |
Collapse
|
|
49
|
Woo DK, Eide MJ. Tanning beds, skin cancer, and vitamin D: an examination of the scientific evidence and public health implications. Dermatol Ther 2010; 23:61-71. [DOI: 10.1111/j.1529-8019.2009.01291.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
50
|
Protein Kinase Cε Reveals Importance of Extrinsic Apoptosis in Preventing UV Carcinogenesis. J Invest Dermatol 2009; 129:1853-6. [DOI: 10.1038/jid.2009.170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|