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Sahane P, Puri N, Khairnar P, Phatale V, Shukla S, Priyadarshinee A, Srivastava S. Harnessing Folate Receptors: A Comprehensive Review on the Applications of Folate-Adorned Nanocarriers for the Management of Melanoma. ACS APPLIED BIO MATERIALS 2025; 8:3623-3656. [PMID: 40275606 DOI: 10.1021/acsabm.5c00077] [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] [Indexed: 04/26/2025]
Abstract
The advancement in exclusively tailored therapeutic delivery systems has escalated a great deal of interest in targeted delivery to augment therapeutic efficacy and to lessen adverse effects. The targeted delivery approach promisingly helps to surmount the unmet clinical needs of conventional therapies, including chemoresistance, limited penetration, and side effects. In the case of melanoma, various receptors were overexpressed on the tumor site, among which folate receptor (FR) targeting is considered to be a progressive approach for managing melanoma. FRs are the macromolecules of the glycosyl phosphatidylinositol-attached protein that possess globular assembly with a greater affinity toward specific ligands. So, the functional ligands can be utilized to design targeted nanocarriers (NCs) that can effectively bind to overexpressed FRs. Hence, folate-adorned NCs (FNCs) offer various benefits such as site-specific targeting, cargo protection, and minimizing toxicity. This review focuses on the insights and implications of FRs, targeting FRs, and mechanisms, challenges, and advantages of FNCs. Further, the applications of various FNCs, such as liposomes, polymeric NCs, albumin nanoparticles, inorganic NCs, liquid crystalline nanoparticles, and nanogels, have been elaborated for melanoma therapy. Likewise, the potential of FNCs in immunotherapy, photodynamic therapy, chemotherapy, gene therapy, photothermal therapy, and tumor imaging has been exhaustively discussed. Furthermore, translational hurdles and potential solutions are discussed in detail. The present review is expected to give thoughtful ideas to researchers, industry stakeholders, and formulation scientists for the efficacious development of FNCs.
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Affiliation(s)
- Prajakta Sahane
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
| | - Niharika Puri
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
| | - Pooja Khairnar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
| | - Vivek Phatale
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
| | - Shalini Shukla
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
| | - Abhipsa Priyadarshinee
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
| | - Saurabh Srivastava
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
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2
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Tayebi Z, Ali S, Patterson M. TCellR2Vec: efficient feature selection for TCR sequences for cancer classification. PeerJ Comput Sci 2024; 10:e2239. [PMID: 39650499 PMCID: PMC11622898 DOI: 10.7717/peerj-cs.2239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 07/14/2024] [Indexed: 12/11/2024]
Abstract
Cancer remains one of the leading causes of death globally. New immunotherapies that harness the patient's immune system to fight cancer show promise, but their development requires analyzing the diversity of immune cells called T-cells. T-cells have receptors that recognize and bind to cancer cells. Sequencing these T-cell receptors allows to provide insights into their immune response, but extracting useful information is challenging. In this study, we propose a new computational method, TCellR2Vec, to select key features from T-cell receptor sequences for classifying different cancer types. We extracted features like amino acid composition, charge, and diversity measures and combined them with other sequence embedding techniques. For our experiments, we used a dataset of over 50,000 T-cell receptor sequences from five cancer types, which showed that TCellR2Vec improved classification accuracy and efficiency over baseline methods. These results demonstrate TCellR2Vec's ability to capture informative aspects of complex T-cell receptor sequences. By improving computational analysis of the immune response, TCellR2Vec could aid the development of personalized immunotherapies tailored to each patient's T-cells. This has important implications for creating more effective cancer treatments based on the individual's immune system.
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Affiliation(s)
- Zahra Tayebi
- Computer Science, Georgia State University, Atlanta, GA, United States of America
| | - Sarwan Ali
- Computer Science, Georgia State University, Atlanta, GA, United States of America
| | - Murray Patterson
- Computer Science, Georgia State University, Atlanta, GA, United States of America
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3
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Boudreault J, Canaff L, Ghozlan M, Wang N, Guarnieri V, Salcuni AS, Scillitani A, Goltzman D, Ali S, Lebrun JJ. Multiple Endocrine Neoplasia Type 1 Regulates TGFβ-Mediated Suppression of Tumor Formation and Metastasis in Melanoma. Cells 2024; 13:973. [PMID: 38891107 PMCID: PMC11172218 DOI: 10.3390/cells13110973] [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: 03/11/2024] [Revised: 05/27/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Over the past few decades, the worldwide incidence of cutaneous melanoma, a malignant neoplasm arising from melanocytes, has been increasing markedly, leading to the highest rate of skin cancer-related deaths. While localized tumors are easily removed by excision surgery, late-stage metastatic melanomas are refractory to treatment and exhibit a poor prognosis. Consequently, unraveling the molecular mechanisms underlying melanoma tumorigenesis and metastasis is crucial for developing novel targeted therapies. We found that the multiple endocrine neoplasia type 1 (MEN1) gene product Menin is required for the transforming growth factor beta (TGFβ) signaling pathway to induce cell growth arrest and apoptosis in vitro and prevent tumorigenesis in vivo in preclinical xenograft models of melanoma. We further identified point mutations in two MEN1 family members affected by melanoma that led to proteasomal degradation of the MEN1 gene product and to a loss of TGFβ signaling. Interestingly, blocking the proteasome degradation pathway using an FDA-approved drug and RNAi targeting could efficiently restore MEN1 expression and TGFβ transcriptional responses. Together, these results provide new potential therapeutic strategies and patient stratification for the treatment of cutaneous melanoma.
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Affiliation(s)
- Julien Boudreault
- Cancer Research Program, Department of Medicine, Research Institute of McGill University Health Center, Montreal, QC H4A 3J1, Canada; (J.B.); (L.C.); (M.G.); (N.W.); (D.G.); (S.A.)
| | - Lucie Canaff
- Cancer Research Program, Department of Medicine, Research Institute of McGill University Health Center, Montreal, QC H4A 3J1, Canada; (J.B.); (L.C.); (M.G.); (N.W.); (D.G.); (S.A.)
| | - Mostafa Ghozlan
- Cancer Research Program, Department of Medicine, Research Institute of McGill University Health Center, Montreal, QC H4A 3J1, Canada; (J.B.); (L.C.); (M.G.); (N.W.); (D.G.); (S.A.)
| | - Ni Wang
- Cancer Research Program, Department of Medicine, Research Institute of McGill University Health Center, Montreal, QC H4A 3J1, Canada; (J.B.); (L.C.); (M.G.); (N.W.); (D.G.); (S.A.)
| | - Vito Guarnieri
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Antonio Stefano Salcuni
- Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia, 33100 Udine, Italy;
| | - Alfredo Scillitani
- Endocrinology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - David Goltzman
- Cancer Research Program, Department of Medicine, Research Institute of McGill University Health Center, Montreal, QC H4A 3J1, Canada; (J.B.); (L.C.); (M.G.); (N.W.); (D.G.); (S.A.)
| | - Suhad Ali
- Cancer Research Program, Department of Medicine, Research Institute of McGill University Health Center, Montreal, QC H4A 3J1, Canada; (J.B.); (L.C.); (M.G.); (N.W.); (D.G.); (S.A.)
| | - Jean-Jacques Lebrun
- Cancer Research Program, Department of Medicine, Research Institute of McGill University Health Center, Montreal, QC H4A 3J1, Canada; (J.B.); (L.C.); (M.G.); (N.W.); (D.G.); (S.A.)
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Papaccio F, Caputo S, Iorio A, De Simone P, Ottaviani M, Del Brocco A, Frascione P, Bellei B. Persistent β-Hexachlorocyclohexane Exposure Impacts Cellular Metabolism with a Specific Signature in Normal Human Melanocytes. Cells 2024; 13:374. [PMID: 38474338 PMCID: PMC10930995 DOI: 10.3390/cells13050374] [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: 12/22/2023] [Revised: 01/27/2024] [Accepted: 02/18/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Cutaneous melanoma arises from skin melanocytes and has a high risk of metastatic spread. Despite better prevention, earlier detection, and the development of innovative therapies, melanoma incidence and mortality increase annually. Major clinical risk factors for melanoma include fair skin, an increased number of nevi, the presence of dysplastic nevi, and a family history of melanoma. However, several external inducers seem to be associated with melanoma susceptibility such as environmental exposure, primarily unprotected sun experience, alcohol consumption, and heavy metals. In recent years, epidemiological studies have highlighted a potential risk of β-hexachlorocyclohexane (β-HCH), the most studied organochlorine pesticide, causing cancer induction including melanoma. METHODS We evaluated in vitro the impact of this pollutant on epidermal and dermal cells, attempting to describe mechanisms that could render cutaneous cells more prone to oncogenic transformation. RESULTS We demonstrated that β-HCH impacts melanocyte biology with a highly cell-type specific signature that involves perturbation of AKT/mTOR and Wnt/β-catenin signaling, and AMPK activation, resulting in lowering energy reserve, cell proliferation, and pigment production. CONCLUSIONS In conclusion, long-term exposure to persistent organic pollutants damages melanocyte metabolism in its function of melanin production with a consequent reduction of melanogenesis indicating a potential augmented skin cancer risk.
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Affiliation(s)
- Federica Papaccio
- Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (F.P.); (S.C.); (M.O.)
| | - Silvia Caputo
- Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (F.P.); (S.C.); (M.O.)
| | - Alessandra Iorio
- Oncologic and Preventative Dermatology, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (A.I.); (P.D.S.); (P.F.)
| | - Paola De Simone
- Oncologic and Preventative Dermatology, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (A.I.); (P.D.S.); (P.F.)
| | - Monica Ottaviani
- Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (F.P.); (S.C.); (M.O.)
| | - Antonella Del Brocco
- Laboratory Clinimed, Clinical and Microbiological Analyses Laboratory, 03023 Ceccano, Italy;
| | - Pasquale Frascione
- Oncologic and Preventative Dermatology, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (A.I.); (P.D.S.); (P.F.)
| | - Barbara Bellei
- Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (F.P.); (S.C.); (M.O.)
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Taheri A, Khandaker MU, Moradi F, Bradley DA. A simulation study on the radiosensitization properties of gold nanorods. Phys Med Biol 2024; 69:045029. [PMID: 38286017 DOI: 10.1088/1361-6560/ad2380] [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: 09/14/2023] [Accepted: 01/29/2024] [Indexed: 01/31/2024]
Abstract
Objective. Gold nanorods (GNRs) have emerged as versatile nanoparticles with unique properties, holding promise in various modalities of cancer treatment through drug delivery and photothermal therapy. In the rapidly evolving field of nanoparticle radiosensitization (NPRS) for cancer therapy, this study assessed the potential of gold nanorods as radiosensitizing agents by quantifying the key features of NPRS, such as secondary electron emission and dose enhancement, using Monte Carlo simulations.Approach. Employing the TOPAS track structure code, we conducted a comprehensive evaluation of the radiosensitization behavior of spherical gold nanoparticles and gold nanorods. We systematically explored the impact of nanorod geometry (in particular size and aspect ratio) and orientation on secondary electron emission and deposited energy ratio, providing validated results against previously published simulations.Main results. Our findings demonstrate that gold nanorods exhibit comparable secondary electron emission to their spherical counterparts. Notably, nanorods with smaller surface-area-to-volume ratios (SA:V) and alignment with the incident photon beam proved to be more efficient radiosensitizing agents, showing superiority in emitted electron fluence. However, in the microscale, the deposited energy ratio (DER) was not markedly influenced by the SA:V of the nanorod. Additionally, our findings revealed that the geometry of gold nanoparticles has a more significant impact on the emission of M-shell Auger electrons (with energies below 3.5 keV) than on higher-energy electrons.Significance. This research investigated the radiosensitization properties of gold nanorods, positioning them as promising alternatives to the more conventionally studied spherical gold nanoparticles in the context of cancer research. With increasing interest in multimodal cancer therapy, our findings have the potential to contribute valuable insights into the perspective of gold nanorods as effective multipurpose agents for synergistic photothermal therapy and radiotherapy. Future directions may involve exploring alternative metallic nanorods as well as further optimizing the geometry and coating materials, opening new possibilities for more effective cancer treatments.
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Affiliation(s)
- Ali Taheri
- Applied Physics and Radiation Technologies Group, CCDCU, School of Engineering and Technology, Sunway University, 47500 Bandar Sunway, Selangor, Malaysia
| | - Mayeen Uddin Khandaker
- Applied Physics and Radiation Technologies Group, CCDCU, School of Engineering and Technology, Sunway University, 47500 Bandar Sunway, Selangor, Malaysia
- Faculty of Graduate Studies, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Farhad Moradi
- Fibre Optics Research Centre, Faculty of Engineering, Multimedia University, Jalan Multimedia 63100, Cyberjaya, Malaysia
| | - David Andrew Bradley
- Applied Physics and Radiation Technologies Group, CCDCU, School of Engineering and Technology, Sunway University, 47500 Bandar Sunway, Selangor, Malaysia
- School of Mathematics and Physics, University of Surrey, Guildford, GU2 7XH, United Kingdom
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ALMatrafi TA, Mohammedsaleh ZM, Moawadh MS, Bassfar Z, Jalal MM, Badahdah FA, Alghamdi YS, Almasoudi HH, Hakami MA, Binshaya AS, Almohaimeed HM, Soliman MH. Identification of potential biomarkers for melanoma cancer (black tumor) using bioinformatics strategy: a study based on GEO and SRA datasets. J Appl Genet 2024; 65:83-93. [PMID: 37875608 DOI: 10.1007/s13353-023-00794-4] [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: 09/10/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/26/2023]
Abstract
Melanoma, a highly invasive type of skin cancer that penetrates the entire dermis layer, is associated with increased mortality rates. Excessive exposure of the skin to sunlight, specifically ultraviolet radiation, is the underlying cause of this malignant condition. The appearance of unique skin moles represents a visible clue, referred to as the "ugly duckling" sign, indicating the presence of melanoma and its association with cellular DNA damage. This research aims to explore potential biomarkers derived from microarray data, employing bioinformatics techniques and methodologies, for a thorough investigation of melanoma skin cancer. The microarray dataset for melanoma skin cancer was obtained from the GEO database, and thorough data analysis and quality control measures were performed to identify differentially expressed genes (DEGs). The top 14 highly expressed DEGs were identified, and their gene information and protein sequences were retrieved from the NCBI gene and protein database. These proteins were further analyzed for domain identification and network analysis. Gene expression analysis was conducted to visualize the upregulated and downregulated genes. Additionally, gene metabolite network analysis was carried out to understand the interactions between highly interconnected genes and regulatory transcripts. Molecular docking was employed to investigate the ligand-binding sites and visualize the three-dimensional structure of proteins. Our research unveiled a collection of genes with varying expression levels, some elevated and others reduced, which could function as promising biomarkers closely linked to the development and advancement of melanoma skin cancer. Through molecular docking analysis of the GINS2 protein, we identified two natural compounds (PubChem-156021169 and PubChem-60700) with potential as inhibitors against melanoma. This research has implications for early detection, treatment, and understanding the molecular basis of melanoma.
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Affiliation(s)
| | - Zuhair M Mohammedsaleh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491, Tabuk, Saudi Arabia
| | - Mamdoh S Moawadh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491, Tabuk, Saudi Arabia
| | - Zaid Bassfar
- Faculty of Computing and Information Technology, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammed M Jalal
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491, Tabuk, Saudi Arabia
| | - Fatima Ahmed Badahdah
- Surgical Department, Prince Sultan Military Medical City, PSMMC, Riyadh, Saudi Arabia
| | - Youssef S Alghamdi
- Department of Biology, Turabah University College, Taif University, 21995, Taif, Saudi Arabia
| | - Hassan Hussain Almasoudi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran, Saudi Arabia
| | - Mohammed Ageeli Hakami
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Al-Quwayiyah, Shaqra University, Riyadh, Saudi Arabia
| | - Abdulkarim S Binshaya
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, 11942, AlKharj, Saudi Arabia
| | - Hailah M Almohaimeed
- Department of Basic Science, College of Medicine, Princess Nourah bint Abdulrahman, University, P.O. Box 84428, 11671, Riyadh, Saudi Arabia
| | - Mona H Soliman
- Botany and Microbiology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt.
- Biology Department, Faculty of Science, Taibah University, Al-Sharm, Yanbu El-Bahr, Yanbu, 46429, Saudi Arabia.
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7
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Singh A, Sonawane P, Kumar A, Singh H, Naumovich V, Pathak P, Grishina M, Khalilullah H, Jaremko M, Emwas AH, Verma A, Kumar P. Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022. ACS OMEGA 2023; 8:27819-27844. [PMID: 37576670 PMCID: PMC10413849 DOI: 10.1021/acsomega.3c00332] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 02/27/2023] [Indexed: 08/15/2023]
Abstract
Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.
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Affiliation(s)
- Ankit
Kumar Singh
- Department
of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Pankaj Sonawane
- Department
of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Adarsh Kumar
- Department
of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Harshwardhan Singh
- Department
of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Vladislav Naumovich
- Laboratory
of Computational Modeling of Drugs, Higher Medical and Biological
School, South Ural State University, Chelyabinsk 454008, Russia
| | - Prateek Pathak
- Laboratory
of Computational Modeling of Drugs, Higher Medical and Biological
School, South Ural State University, Chelyabinsk 454008, Russia
| | - Maria Grishina
- Laboratory
of Computational Modeling of Drugs, Higher Medical and Biological
School, South Ural State University, Chelyabinsk 454008, Russia
| | - Habibullah Khalilullah
- Department
of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of
Pharmacy, Qassim University, Unayzah 51911, Saudi Arabia
| | - Mariusz Jaremko
- Smart-Health
Initiative and Red Sea Research Center, Division of Biological and
Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
| | - Abdul-Hamid Emwas
- Core
Laboratories, King Abdullah University of
Science and Technology, Thuwal 23955-6900, Saudi
Arabia
| | - Amita Verma
- Bioorganic
and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical
Sciences, Sam Higginbottom University of
Agriculture, Technology and Sciences, Prayagraj 211007, India
| | - Pradeep Kumar
- Department
of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
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8
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Antonova E, Hambikova A, Shcherbakov D, Sukhov V, Vysochanskaya S, Fadeeva I, Gorshenin D, Sidorova E, Kashutina M, Zhdanova A, Mitrokhin O, Avvakumova N, Zhernov Y. Determination of Common microRNA Biomarker Candidates in Stage IV Melanoma Patients and a Human Melanoma Cell Line: A Potential Anti-Melanoma Agent Screening Model. Int J Mol Sci 2023; 24:ijms24119160. [PMID: 37298110 DOI: 10.3390/ijms24119160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that play an important role in regulating gene expression. Dysregulation of miRNA expression is commonly observed in cancer, and it can contribute to malignant cell growth. Melanoma is the most fatal type of skin malignant neoplasia. Some microRNAs can be prospective biomarkers for melanoma in stage IV (advanced) at higher risk of relapses and require validation for diagnostic purposes. This work aimed to (1) determine the most significant microRNA biomarker candidates in melanoma using content analysis of the scientific literature, (2) to show microRNA biomarker candidates' diagnostic efficacy between melanoma patients and healthy control groups in a small-scale preliminary study by blood plasma PCR analysis, (3) to determine significant microRNA markers of the MelCher human melanoma cell line, which are also detected in patients with melanoma, that can be used as markers of drug anti-melanoma activity, and (4) test anti-melanoma activity of humic substances and chitosan by their ability to reduce level of marker microRNAs. The content analysis of the scientific literature showed that hsa-miR-149-3p, hsa-miR-150-5p, hsa-miR-193a-3p, hsa-miR-21-5p, and hsa-miR-155-5p are promising microRNA biomarker candidates for diagnosing melanoma. Estimating microRNA in plasma samples showed that hsa-miR-150-5p and hsa-miR-155-5p may have a diagnostic value for melanoma in stage IV (advanced). When comparing ΔCt hsa-miR-150-5p and ΔCt hsa-miR-155-5p levels in melanoma patients and healthy donors, statistically significant differences were found (p = 0.001 and p = 0.001 respectively). Rates ΔCt were significantly higher among melanoma patients (medians concerning the reference gene miR-320a were 1.63 (1.435; 2.975) and 6.345 (4.45; 6.98), respectively). Therefore, they persist only in plasma from the melanoma patients group but not in the healthy donors group. In human wild-type stage IV melanoma (MelCher) cell culture, the presence of hsa-miR-150-5p and hsa-miR-155-5p in supernatant was detected. The ability of humic substance fractions and chitosan to reduce levels of hsa-miR-150-5p and hsa-miR-155-5p was tested on MelCher cultures, which is associated with anti-melanoma activity. It was found that the hymatomelanic acid (HMA) fraction and its subfraction UPLC-HMA statistically significantly reduced the expression of miR-150-5p and miR-155-5p (p ≤ 0.05). For the humic acid (HA) fraction, this activity was determined only to reduce miR-155-5p (p ≤ 0.05). Ability to reduce miR-150-5p and miR-155-5p expression on MelCher cultures was not determined for chitosan fractions with a molecular weight of 10 kDa, 120 kDa, or 500 kDa. Anti-melanoma activity was also determined in the MTT test on MelCher cultures for explored substances. The median toxic concentration (TC50) was determined for HA, HMA and UPLC-HMA (39.3, 39.7 and 52.0 μg/mL, respectively). For 10 kDa, 120 kDa, or 500 kDa chitosan fractions TC50 was much higher compared to humic substances (508.9, 6615.9, 11352.3 μg/mL, respectively). Thus, our pilot study identified significant microRNAs for testing the in vitro anti-melanoma activity of promising drugs and melanoma diagnostics in patients. Using human melanoma cell cultures gives opportunities to test new drugs on a culture that has a microRNA profile similar to that of patients with melanoma, unlike, for example, murine melanoma cell cultures. It is necessary to conduct further studies with a large number of volunteers, which will make it possible to correlate the profile of individual microRNAs with specific patient data, including the correlation of the microRNA profile with the stage of melanoma.
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Affiliation(s)
- Elena Antonova
- Research Center for Fundamental and Applied Problems of Bioecology and Biotechnology, I.N. Ulyanov Ulyanovsk State Pedagogical University, 432700 Ulyanovsk, Russia
| | - Anastasia Hambikova
- Research Center for Fundamental and Applied Problems of Bioecology and Biotechnology, I.N. Ulyanov Ulyanovsk State Pedagogical University, 432700 Ulyanovsk, Russia
| | - Denis Shcherbakov
- Department of General Hygiene, F. Erismann Institute of Public Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Vitaly Sukhov
- Department of General Hygiene, F. Erismann Institute of Public Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Sonya Vysochanskaya
- Department of General Hygiene, F. Erismann Institute of Public Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Inna Fadeeva
- Department of English Language, Institute of World Economy, Diplomatic Academy of the Russian Foreign Ministry, 119992 Moscow, Russia
| | - Denis Gorshenin
- Laboratory of Innate Immunity, National Research Center-Institute of Immunology FMBA of Russia, 115522 Moscow, Russia
| | - Ekaterina Sidorova
- Department of General Hygiene, F. Erismann Institute of Public Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Maria Kashutina
- Loginov Moscow Clinical Scientific and Practical Center, 111123 Moscow, Russia
- Department of Public Health Promotion, National Research Centre for Therapy and Preventive Medicine, 101990 Moscow, Russia
- Department of Therapy, Clinical Pharmacology and Emergency Medicine, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia
| | - Alina Zhdanova
- Department of Medical Chemistry, Samara State Medical University, 443099 Samara, Russia
| | - Oleg Mitrokhin
- Department of General Hygiene, F. Erismann Institute of Public Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Nadezhda Avvakumova
- Department of Medical Chemistry, Samara State Medical University, 443099 Samara, Russia
| | - Yury Zhernov
- Department of General Hygiene, F. Erismann Institute of Public Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
- Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia
- Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia
- Center for Medical Anthropology, N.N. Miklukho-Maclay Institute of Ethnology and Anthropology of the Russian Academy of Sciences, 119017 Moscow, Russia
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9
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Wang ZX, Zhang GJ, Yang XF, Feng SJ, Ji SS, Qi YB. miRNA-633 and KAI1 as Potential Biomarkers of Malignant Melanoma with Gastric Cancer. Comb Chem High Throughput Screen 2023; 26:1001-1014. [PMID: 35713138 DOI: 10.2174/1386207325666220616125608] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/07/2022] [Accepted: 03/08/2022] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Malignant melanoma with gastric cancer is one of the most malignant tumors. However, there have been no reports on the effects of KAI1 and miRNA-633 on the survival and prognosis of patients with malignant melanoma with gastric cancer. METHODS Fifty patients with malignant melanoma and gastric cancer were collected from October 2017 to December 2019. The clinical parameters included clinical information, such as sex, age, tumor size, and tumor staging. RT-qPCR was used to detect the expression of KAI1 and miRNA- 633. The role of KAI1 and miRNA-633 on the overall survival of melanoma was explored by the Pearson chi-square test, Spearman-rho correlation test, Univariate and multivariate cox regression analyses, and Kaplan-Meier method. Furthermore, the bioinformatic analysis was used to verify the role of KAI1 and miRNA-633 on malignant melanoma with gastric cancer. RESULTS The expression of KAI1 and miRNA-633 was significantly related with the tumor size and staging of tumor (p<0.05) based on the Pearson chi-square test. Spearman's correlation coefficient displayed that KAI1 was significantly correlated with the miRNA-633 (ρ=-0.439, p=0.001). The result of multivariate cox proportional regression analysis showed that KAI1 (HR =0.109, 95% CI: 0.031-0.375, p< 0.001), and miRNA-633 (HR = 13.315, 95% CI: 3.844-46.119, p<0.001) were significantly associated with overall survival. CONCLUSION The low expression level of KAI1 and high expression of miRNA-633 are significantly correlated with the poor overall survival prognosis of malignant melanoma with gastric cancer, to provide a basis for KAI1 and miRNA-633 to become novel molecular targets for malignant melanoma with gastric cancer.
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Affiliation(s)
- Zheng-Xiang Wang
- Department of Dermatology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou, 061000 Hebei Province, P.R. China
| | - Guang-Jing Zhang
- Department of Dermatology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou, 061000 Hebei Province, P.R. China
| | - Xiu-Fang Yang
- Department of Dermatology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou, 061000 Hebei Province, P.R. China
| | - Shi-Jun Feng
- Department of Dermatology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou, 061000 Hebei Province, P.R. China
| | - Shan-Shan Ji
- Department of Dermatology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou, 061000 Hebei Province, P.R. China
| | - Ya-Bin Qi
- Department of Dermatology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou, 061000 Hebei Province, P.R. China
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10
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Perota G, Zahraie N, Vais RD, Zare M, Sattarahmady N. Au/TiO2 nanocomposite as a triple-sensitizer for 808 and 650 nm phototherapy and sonotherapy: Synergistic therapy of melanoma cancer in vitro. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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11
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A Review with Updated Perspectives on Nutritional and Therapeutic Benefits of Apricot and the Industrial Application of Its Underutilized Parts. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27155016. [PMID: 35956966 PMCID: PMC9370680 DOI: 10.3390/molecules27155016] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 11/16/2022]
Abstract
Fruits maintain the image as the richest sources of vitamins. Focusing on apricots, utilization of apricot species for many applications is possible due to its various benefits. Many research studies demonstrated different perspectives of apricot, especially in medical used as it can act as antioxidant, anti-inflammatory, and antimicrobial agents. Moreover, in the industrial sectors, apricots can be used in the production of biofuels and batteries. All components of the apricot fruit, including seeds and kernels have been found to possess significant interest. This review is to breach the knowledge gap regarding the key nutrients and chemicals of apricot fruit, contributing to its health-promoting properties to emphasize the noble importance of this fruit in the diet and in the management of several diseases. We also cover the application of apricots in the industry that could be developed as a promising and sustainable source.
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12
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Yue Z, Cao M, Hong A, Zhang Q, Zhang G, Jin Z, Zhao L, Wang Q, Fang F, Wang Y, Sun J. m 6A Methyltransferase METTL3 Promotes the Progression of Primary Acral Melanoma via Mediating TXNDC5 Methylation. Front Oncol 2022; 11:770325. [PMID: 35117988 PMCID: PMC8804213 DOI: 10.3389/fonc.2021.770325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/15/2021] [Indexed: 11/13/2022] Open
Abstract
m6A modification is one of the most important post-transcriptional modifications in RNA and plays an important role in promoting translation or decay of RNAs. The role of m6A modifications has been highlighted by increasing evidence in various cancers, which, however, is rarely explored in acral melanoma. Here, we demonstrated that m6A level was highly elevated in acral melanoma tissues, along with the expression of METTL3, one of the most important m6A methyltransferase. Besides, higher expression of METTL3 messenger RNA (mRNA) correlated with a higher stage in primary acral melanoma patients. Knockdown of METTL3 decreased global m6A level in melanoma cells. Furthermore, METTL3 knockdown suppressed the proliferation, migration, and invasion of melanoma cells. In METTL3 knockdown xenograft mouse models, we observed decreased volumes and weights of melanoma tissues. Mechanistically, we found that METTL3 regulates certain m6A-methylated transcripts, thioredoxin domain containing protein 5 (TXNDC5), with the confirmation of RNA-seq, MeRIP-seq, and Western blot. These data suggest that METTL3 may play a key role in the progression of acral melanoma, and targeting the m6A dependent-METTL3 signaling pathway may serve as a promising therapeutic strategy for management of patients of acral melanomas.
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Affiliation(s)
- Zhanghui Yue
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Meng Cao
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Anlan Hong
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Qian Zhang
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Guoqiang Zhang
- Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhibin Jin
- Department of Ultrasound, Nanjing Drum Tower Hospital, Nanjing, China
| | - Liang Zhao
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Qiang Wang
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Fang Fang
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Yan Wang
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Jianfang Sun
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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13
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Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers. Cancers (Basel) 2021; 13:cancers13246180. [PMID: 34944799 PMCID: PMC8699560 DOI: 10.3390/cancers13246180] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/30/2021] [Accepted: 12/03/2021] [Indexed: 12/25/2022] Open
Abstract
Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma's susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.
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14
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Fan Y, Liang X, Yu D. Low expression of endoplasmic reticulum stress-related gene SERP1 is associated with poor prognosis and immune infiltration in skin cutaneous melanoma. Aging (Albany NY) 2021; 13:23036-23071. [PMID: 34613934 PMCID: PMC8544316 DOI: 10.18632/aging.203594] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/20/2021] [Indexed: 02/05/2023]
Abstract
Stress-associated endoplasmic reticulum protein 1 (SERP1) is a gene induced by endoplasmic reticulum (ER) stress and a major contributor to multiple tumor types. Skin cutaneous melanoma (SKCM) is a highly aggressive and fatal cancer with poor treatment outcomes after progression. In this study, we evaluated SERP1's role in tumorigenesis, prognosis, and immune infiltration in SKCM. Patients with SKCM had low SERP1 expression. We identified differentially expressed genes between high- and low-SERP1 expression groups and conducted functional, pathway, and gene enrichment analyses. Protein-protein (PPI) and gene-gene interaction (GGI) networks were constructed via STRING and GeneMANIA, respectively. SERP1 mutation information was obtained through cBioPortal; location in the skin was identified through the Human Protein Atlas. Kaplan-Meier analysis revealed an association between low SERP1 expression and overall survival (OS), disease-specific survival (DSS), progress-free interval (PFI) rates, and worse prognosis in patients with multiple clinicopathological features. Cox regression analysis and nomograms further presented SERP1 level as an independent prognostic factor for patients with SKCM. Furthermore, there were significant correlations between SERP1 expression and immune infiltrates; thus, low SERP1 expression is associated with immune cell infiltration and can be considered a poor prognostic biomarker in patients with SKCM. Stress-associated endoplasmic reticulum protein 1 (SERP1) is a gene induced by endoplasmic reticulum (ER) stress and a major contributor to multiple tumor types. Skin cutaneous melanoma (SKCM) is a highly aggressive and fatal cancer with poor treatment outcomes after progression. In this study, we evaluated SERP1's role in tumorigenesis, prognosis, and immune infiltration in SKCM. Patients with SKCM had low SERP1 expression. We identified differentially expressed genes between high- and low-SERP1 expression groups and conducted functional, pathway, and gene enrichment analyses. Protein-protein (PPI) and gene-gene interaction (GGI) networks were constructed via STRING and GeneMANIA, respectively. SERP1 mutation information was obtained through cBioPortal; location in the skin were identified through the Human Protein Atlas. Kaplan-Meier analysis revealed an association between low SERP1 expression and overall survival (OS), disease-specific survival (DSS), progress-free interval (PFI) rates, and worse prognosis in patients with multiple clinicopathological features. Cox regression analysis and nomograms further presented SERP1 level as an independent prognostic factor for patients with SKCM. Furthermore, there were significant correlations between SERP1 expression and immune infiltrates; thus, low SERP1 expression is associated with immune cell infiltration and can be considered a poor prognostic biomarker in patients with SKCM.
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Affiliation(s)
- Yuchao Fan
- Department of Anesthesiology, Sichuan Cancer Center, Sichuan Cancer Hospital and Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Xiao Liang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Deshui Yu
- Department of Anesthesiology, The Second People’s Hospital of Yibin, Yibin, Sichuan Province, China
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15
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Guo Y, Zhang X, Wang L, Li M, Shen M, Zhou Z, Zhu S, Li K, Fang Z, Yan B, Zhao S, Su J, Chen X, Peng C. The plasma exosomal miR-1180-3p serves as a novel potential diagnostic marker for cutaneous melanoma. Cancer Cell Int 2021; 21:487. [PMID: 34544412 PMCID: PMC8454000 DOI: 10.1186/s12935-021-02164-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 08/19/2021] [Indexed: 02/08/2023] Open
Abstract
Background Exosomes are a promising tool in disease detection because they are noninvasive, cost-effective, sensitive and stable in body fluids. MicroRNAs (miRNAs) are the main exosomal component and participate in tumor development. However, the exosomal miRNA profile among Asian melanoma patients remains unclear. Methods Exosomal miRNAs from the plasma of melanoma patients (n = 20) and healthy individuals (n = 20) were isolated and subjected to small RNA sequencing. Real-time PCR was performed to identify the differential miRNAs and to determine the diagnostic efficiency. Proliferation, scratch and Transwell assays were performed to detect the biological behavior of melanoma cells. Results Exosomal miRNA profiling revealed decreased miR-1180-3p expression as a potential diagnostic marker of melanoma. The validation group of melanoma patients (n = 28) and controls (n = 28) confirmed the diagnostic efficiency of miR-1180-3p. The level of miR-1180-3p in melanoma cells was lower than that in melanocytes. Accordingly, the level of miR-1180-3p was negatively associated with the proliferation, migration and invasion of melanoma cells. Functional analysis and target gene prediction found that ST3GAL4 was a potential target and highly expressed in melanoma tissues and was negatively regulated by miR-1180-3p. Knockdown of ST3GAL4 hindered the malignant phenotype of melanoma cells. Conclusions This study indicates that reduced exosomal miR-1180-3p in melanoma patient plasma is a promising diagnostic marker and provides novel insight into melanoma development. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02164-8.
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Affiliation(s)
- Yeye Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Xu Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Linconghua Wang
- Hunan Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha, 410083, China
| | - Min Li
- Hunan Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha, 410083, China
| | - Minxue Shen
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhe Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Susi Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Keke Li
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhiqin Fang
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Bei Yan
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Shuang Zhao
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road #87, Changsha, 410008, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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16
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Kalil LL, Prado EHM, Resende RVU, Pimenta MRC, Wainstein AJA, Drummond-Lage AP. Melanoma Awareness Among Medical Students. JOURNAL OF CANCER EDUCATION : THE OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER EDUCATION 2021; 36:677-681. [PMID: 31902090 DOI: 10.1007/s13187-019-01685-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Melanoma is the most aggressive skin cancer. Since diagnosis is visual, it is critical to evaluate if students acquire enough knowledge for early detection during medical school. To assess the melanoma knowledge of first-year (freshman) and sixth-year (senior) medical students, in a Brazilian Institution. It was a transversal and quantitative study. A questionnaire with sociodemographic data, knowledge about melanoma, and the habit of skin self-exam was filled out by medical students. A total of 128 first-year and 122 seniors students were included. All the sixth-year students knew melanoma as a skin cancer compared with 46.09% of the first-year students. Melanoma clinical characteristics were known by 30.51% of the freshman and 97.54% of seniors. However, they did not know the most usual site of melanoma occurrence (79.66% of first-year students and 24.59% of senior). About the skin self-exam, only 50% of first-year students and 53.28% of senior had the habit of doing it sometimes. Medical school was effective in providing knowledge about melanoma and its features. However, this was not reflected in an increase in the number of students that did the skin self-exam, which indicates the need for new approaches in teaching.
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Affiliation(s)
- L L Kalil
- Medical Sciences Faculty, School of Medicine, Alameda Ezequiel Dias 275-Centro, Belo Horizonte, 30130-110, Brazil
| | - E H M Prado
- Medical Sciences Faculty, School of Medicine, Alameda Ezequiel Dias 275-Centro, Belo Horizonte, 30130-110, Brazil
| | - R V U Resende
- Medical Sciences Faculty, School of Medicine, Alameda Ezequiel Dias 275-Centro, Belo Horizonte, 30130-110, Brazil
| | - M R C Pimenta
- Medical Sciences Faculty, School of Medicine, Alameda Ezequiel Dias 275-Centro, Belo Horizonte, 30130-110, Brazil
| | - A J A Wainstein
- Medical Sciences Faculty, School of Medicine, Alameda Ezequiel Dias 275-Centro, Belo Horizonte, 30130-110, Brazil
| | - A P Drummond-Lage
- Medical Sciences Faculty, School of Medicine, Alameda Ezequiel Dias 275-Centro, Belo Horizonte, 30130-110, Brazil.
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17
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Marley AR, Li M, Champion VL, Song Y, Han J, Li X. The association between citrus consumption and melanoma risk in the UK Biobank. Br J Dermatol 2021; 185:353-362. [PMID: 33782946 PMCID: PMC8373643 DOI: 10.1111/bjd.19896] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Melanoma incidence has been dramatically increasing worldwide. Psoralen, a known photocarcinogen, is naturally abundant in citrus products, leading to the hypothesis that high citrus consumption may increase melanoma risk. OBJECTIVES To investigate the association between total citrus consumption and melanoma risk, and the association between individual citrus products and melanoma risk, and to test for interactions between total citrus intake and established melanoma risk factors. METHODS Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between citrus consumption and melanoma risk among 1592 cases and 197 372 controls from the UK Biobank cohort. Citrus consumption data were collected via five rounds of 24-h recall questionnaires. International Classification of Diseases codes were used to determine melanoma outcome. RESULTS After adjusting for potential confounders, participants in the highest category of total citrus intake (> 2 servings per day) had a significantly increased risk of melanoma (OR 1·63, 95% CI 1·24-2·12) relative to those with no consumption. For individual citrus products, participants with the most orange and orange juice consumption (> 1 serving per day) had a significantly increased melanoma risk relative to those with no consumption (OR 1·79, 95% CI 1·07-2·78 and OR 1·54, 95% CI 1·10-2·10, respectively). Fair- or very fair-skinned participants with high citrus consumption had an even greater melanoma risk (OR 1·75, 95% CI 1·31-2·29). CONCLUSIONS High citrus consumption was associated with an increased risk of melanoma in a large, prospective, population-based cohort. Further validation of these findings could lead to improved melanoma prevention strategies.
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Affiliation(s)
- A R Marley
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA
| | - M Li
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health, Bloomington, IN, USA
| | - V L Champion
- Department of Community Health Systems, Indiana University School of Nursing, Indianapolis, IN, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Y Song
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA
| | - J Han
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - X Li
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
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18
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Papaccio F, Kovacs D, Bellei B, Caputo S, Migliano E, Cota C, Picardo M. Profiling Cancer-Associated Fibroblasts in Melanoma. Int J Mol Sci 2021; 22:7255. [PMID: 34298873 PMCID: PMC8306538 DOI: 10.3390/ijms22147255] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/18/2021] [Accepted: 06/25/2021] [Indexed: 11/18/2022] Open
Abstract
Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma-fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF-melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread.
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Affiliation(s)
- Federica Papaccio
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (D.K.); (B.B.); (S.C.); (M.P.)
| | - Daniela Kovacs
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (D.K.); (B.B.); (S.C.); (M.P.)
| | - Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (D.K.); (B.B.); (S.C.); (M.P.)
| | - Silvia Caputo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (D.K.); (B.B.); (S.C.); (M.P.)
| | - Emilia Migliano
- Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
| | - Carlo Cota
- Genetic Research, Molecular Biology and Dermatopathology Unit, San Gallicano Dermatological Institute IRCCS, 00144 Rome, Italy;
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; (D.K.); (B.B.); (S.C.); (M.P.)
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Abstract
Melanoma accounts for approximately 1% of all skin cancers but contributes to almost all skin cancer deaths. The developing picture suggests that melanoma phenotypes are driven by epigenetic mechanisms that reflect a complex interplay between genotype and environment. Furthermore, the growing consensus is that current classification standards, notwithstanding pertinent clinical history and appropriate biopsy, fall short of capturing the vast complexity of the disease. This article summarizes the current understanding of the clinical picture of melanoma, with a focus on the tremendous breakthroughs in molecular classification and therapeutics.
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Affiliation(s)
- Sarem Rashid
- Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02466, USA; Boston University School of Medicine, Boston, MA, USA
| | - Hensin Tsao
- Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02466, USA.
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20
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Lu JW, Lin SH, Yeh CM, Yeh KT, Huang LR, Chen CY, Lin YM. Cytoplasmic CK1ε Protein Expression Is Correlated With Distant Metastasis and Survival in Patients With Melanoma. In Vivo 2021; 34:2905-2911. [PMID: 32871831 DOI: 10.21873/invivo.12119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIM Casein kinase 1 epsilon (CK1ε) is a member of the casein kinase 1 family, which includes highly conserved and ubiquitous serine/threonine protein kinases. Recent research has revealed that CK1ε plays an important role in a variety of human cancer types; however, its role in human melanoma remains unclear. The aim of this study was to elucidate the clinical role of CK1ε in patients with melanoma. PATIENTS AND METHODS Samples from 34 patients with melanoma were analyzed by immunohistochemical staining. Formalin-fixed paraffin-embedded tissue microarrays were also examined by two histopathologists to assess CK1ε protein expression in humans. RESULTS Cytoplasmic CK1ε protein expression was significantly lower in tumor tissue than in normal tissue. Lack of cytoplasmic CK1ε protein was significantly correlated with distant metastasis (p=0.022) and poorer survival (p=0.030). However, Kaplan-Meier survival analysis revealed that elevated expression of cytoplasmic CK1ε protein was not significantly associated with the overall survival of patients with melanoma. Univariate and multivariate analyses demonstrated that lack of cytoplasmic CK1ε protein expression was related to distant metastasis (p<0.001 and p=0.004), showing that CK1ε was a prognostic factor. CONCLUSION CK1ε protein expression might serve as a prognostic indicator in the treatment of patients with melanoma.
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Affiliation(s)
- Jeng-Wei Lu
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Shu-Hui Lin
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.,Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C
| | - Chung-Min Yeh
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.,Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan, R.O.C
| | - Kun-Tu Yeh
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Lan-Ru Huang
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C
| | - Chia-Yu Chen
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C
| | - Yueh-Min Lin
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C. .,School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
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21
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McKenna S, García-Gutiérrez L. Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing? Int J Mol Sci 2021; 22:5115. [PMID: 34066022 PMCID: PMC8150731 DOI: 10.3390/ijms22105115] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/26/2021] [Accepted: 05/06/2021] [Indexed: 12/20/2022] Open
Abstract
Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.
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Affiliation(s)
| | - Lucía García-Gutiérrez
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland;
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22
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Du Y, Yang J, Su T, Shen Z, Li J. Lipid mediator lipoxin A4 and its analog BML-111 exert antitumor effects in melanoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:802. [PMID: 34268415 PMCID: PMC8246158 DOI: 10.21037/atm-21-1873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/08/2021] [Indexed: 11/15/2022]
Abstract
Background LipoxinA4 (LXA4) is an anti-inflammatory lipid mediator which was recently proposed to have antitumor potential. However, the therapeutic effect of LXA4 in melanoma is still unclear. This work aimed to investigate the function of LXA4 and its analog in melanoma invasion through in vivo and in vitro experiments. Methods The expression of the LXA4 receptor (ALXR) was detected in melanoma tissues and A375 human melanoma cells, using benign melanocytic nevi tissues and human melanocytes as negative controls, respectively. The invasive and apoptotic abilities of A375 cells in the presence or absence of LXA4 were examined by cell invasion assay and flow cytometric analysis. Finally, mice melanoma models were established, and the antitumor effects of BML-111 [5(S), 6(R)-7-trihydroxymethyl heptanoate], an agonist of ALXR, were examined in vivo. Results ALXR was abundantly expressed in human melanoma tissues. The ALXR messenger RNA (mRNA) and protein expression levels were higher in A375 melanoma cells than in the controls (P<0.05). LXA4 could significantly attenuate the invasion ability of A375 cells (P<0.05). This trend was further enhanced by BML-111, which tended to control the tumor development in A375 melanoma models. Conclusions LXA4 and its analog BML-111 exert antitumor effects in vivo and in vitro, and may be potential therapeutic options for patients with invasive melanoma.
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Affiliation(s)
- Yu Du
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jianing Yang
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.,Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic and Technology of China, Chengdu, China
| | - Tangfeng Su
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhu Shen
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.,Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic and Technology of China, Chengdu, China
| | - Juan Li
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.,Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic and Technology of China, Chengdu, China
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23
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Netanely D, Leibou S, Parikh R, Stern N, Vaknine H, Brenner R, Amar S, Factor RH, Perluk T, Frand J, Nizri E, Hershkovitz D, Zemser-Werner V, Levy C, Shamir R. Classification of node-positive melanomas into prognostic subgroups using keratin, immune, and melanogenesis expression patterns. Oncogene 2021; 40:1792-1805. [PMID: 33564068 PMCID: PMC7946641 DOI: 10.1038/s41388-021-01665-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 11/08/2020] [Accepted: 01/18/2021] [Indexed: 01/30/2023]
Abstract
Cutaneous melanoma tumors are heterogeneous and show diverse responses to treatment. Identification of robust molecular biomarkers for classifying melanoma tumors into clinically distinct and homogenous subtypes is crucial for improving the diagnosis and treatment of the disease. In this study, we present a classification of melanoma tumors into four subtypes with different survival profiles based on three distinct gene expression signatures: keratin, immune, and melanogenesis. The melanogenesis expression pattern includes several genes that are characteristic of the melanosome organelle and correlates with worse survival, suggesting the involvement of melanosomes in melanoma aggression. We experimentally validated the secretion of melanosomes into surrounding tissues by melanoma tumors, which potentially affects the lethality of metastasis. We propose a simple molecular decision tree classifier for predicting a tumor's subtype based on representative genes from the three identified signatures. Key predictor genes were experimentally validated on melanoma samples taken from patients with varying survival outcomes. Our three-pattern approach for classifying melanoma tumors can contribute to advancing the understanding of melanoma variability and promote accurate diagnosis, prognostication, and treatment.
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Affiliation(s)
- Dvir Netanely
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
| | - Stav Leibou
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Roma Parikh
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Neta Stern
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
| | - Hananya Vaknine
- Department of Oncology, Edith Wolfson Medical Center, Holon, Israel
| | - Ronen Brenner
- Department of Oncology, Edith Wolfson Medical Center, Holon, Israel
| | - Sarah Amar
- Department of Oncology, Edith Wolfson Medical Center, Holon, Israel
| | - Rivi Haiat Factor
- Department of Plastic and Reconstructive Surgery, Edith Wolfson Medical Center, Holon, Israel
| | - Tomer Perluk
- Department of Plastic and Reconstructive Surgery, Edith Wolfson Medical Center, Holon, Israel
| | - Jacob Frand
- Department of Plastic and Reconstructive Surgery, Edith Wolfson Medical Center, Holon, Israel
| | - Eran Nizri
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Surgery A, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Dov Hershkovitz
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | | | - Carmit Levy
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ron Shamir
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
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24
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Dash G, Pradhan S, Naik S. Unusual Morphological Presentation of Cutaneous Malignant Melanoma: A Rare Case Report. Indian Dermatol Online J 2021; 12:139-141. [PMID: 33768036 PMCID: PMC7982043 DOI: 10.4103/idoj.idoj_387_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/10/2020] [Accepted: 09/20/2020] [Indexed: 11/04/2022] Open
Abstract
Cutaneous malignant melanoma is a rapidly progressing skin tumor accounting for most deaths from skin malignancies. Four morphological variants (nodular, superficial spreading, lentigo maligna, and acral lentiginous) are described in the literature. Here we are reporting malignant melanoma in a 35-year-old male who presented with depigmented plaques with few hyperpigmented areas and extensive overlying scaling. The patient progressed to the nodular stage within 2 weeks and succumbed to death during chemotherapy. We are reporting such rare presentation of malignant melanoma to create awareness among dermatologists to avoid misdiagnosis and delayed treatment which can lead to rapid progression and fatal outcome.
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Affiliation(s)
- Gaurav Dash
- Department of Dermatology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Swetalina Pradhan
- Department of Dermatology, All India Institute of Medical Sciences, Patna, Bihar, India
| | - Subhasini Naik
- Department of Pathology, Prolife Diagnostics, Bhubaneswar, Odisha, India
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25
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Yu L, Peng F, Dong X, Chen Y, Sun D, Jiang S, Deng C. Sex-Determining Region Y Chromosome-Related High-Mobility-Group Box 10 in Cancer: A Potential Therapeutic Target. Front Cell Dev Biol 2020; 8:564740. [PMID: 33344444 PMCID: PMC7744619 DOI: 10.3389/fcell.2020.564740] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 11/17/2020] [Indexed: 01/20/2023] Open
Abstract
Sex-determining region Y-related high mobility group-box 10 (SOX10), a member of the SOX family, has recently been highlighted as an essential transcriptional factor involved in developmental biology. Recently, the functionality of SOX 10 has been increasingly revealed by researchers worldwide. It has been reported that SOX10 significantly regulates the proliferation, migration, and apoptosis of tumors and is closely associated with the progression of cancer. In this review, we first introduce the basic background of the SOX family and SOX10 and then discuss the pathophysiological roles of SOX10 in cancer. Besides, we enumerate the application of SOX10 in the pathological diagnosis and therapeutic potential of cancer. Eventually, we summarize the potential directions and perspectives of SOX10 in neoplastic theranostics. The information compiled herein may assist in additional studies and increase the potential of SOX10 as a therapeutic target for cancer.
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Affiliation(s)
- Liming Yu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, China
| | - Fan Peng
- Department of Cardiology, Xijing Hopspital, The Airforce Military Medical University, Xi'an, China
| | - Xue Dong
- Outpatient Department of Liaoning Military Region, General Hospital of Northern Theater Command, Shenyang, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Dongdong Sun
- Department of Cardiology, Xijing Hopspital, The Airforce Military Medical University, Xi'an, China
| | - Shuai Jiang
- Department of Cardiology, Xijing Hopspital, The Airforce Military Medical University, Xi'an, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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26
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Bellei B, Migliano E, Picardo M. A Framework of Major Tumor-Promoting Signal Transduction Pathways Implicated in Melanoma-Fibroblast Dialogue. Cancers (Basel) 2020; 12:cancers12113400. [PMID: 33212834 PMCID: PMC7697272 DOI: 10.3390/cancers12113400] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Melanoma cells reside in a complex stromal microenvironment, which is a critical component of disease onset and progression. Mesenchymal or fibroblastic cell type are the most abundant cellular element of tumor stroma. Factors secreted by melanoma cells can activate non-malignant associated fibroblasts to become melanoma associate fibroblasts (MAFs). MAFs promote tumorigenic features by remodeling the extracellular matrix, supporting tumor cells proliferation, neo-angiogenesis and drug resistance. Additionally, environmental factors may contribute to the acquisition of pro-tumorigenic phenotype of fibroblasts. Overall, in melanoma, perturbed tissue homeostasis contributes to modulation of major oncogenic intracellular signaling pathways not only in tumor cells but also in neighboring cells. Thus, targeted molecular therapies need to be considered from the reciprocal point of view of melanoma and stromal cells. Abstract The development of a modified stromal microenvironment in response to neoplastic onset is a common feature of many tumors including cutaneous melanoma. At all stages, melanoma cells are embedded in a complex tissue composed by extracellular matrix components and several different cell populations. Thus, melanomagenesis is not only driven by malignant melanocytes, but also by the altered communication between melanocytes and non-malignant cell populations, including fibroblasts, endothelial and immune cells. In particular, cancer-associated fibroblasts (CAFs), also referred as melanoma-associated fibroblasts (MAFs) in the case of melanoma, are the most abundant stromal cells and play a significant contextual role in melanoma initiation, progression and metastasis. As a result of dynamic intercellular molecular dialogue between tumor and the stroma, non-neoplastic cells gain specific phenotypes and functions that are pro-tumorigenic. Targeting MAFs is thus considered a promising avenue to improve melanoma therapy. Growing evidence demonstrates that aberrant regulation of oncogenic signaling is not restricted to transformed cells but also occurs in MAFs. However, in some cases, signaling pathways present opposite regulation in melanoma and surrounding area, suggesting that therapeutic strategies need to carefully consider the tumor–stroma equilibrium. In this novel review, we analyze four major signaling pathways implicated in melanomagenesis, TGF-β, MAPK, Wnt/β-catenin and Hyppo signaling, from the complementary point of view of tumor cells and the microenvironment.
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Affiliation(s)
- Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
- Correspondence: ; Tel.: +39-0652666246
| | - Emilia Migliano
- Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
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Wang S, Zheng H, Zhou L, Cheng F, Liu Z, Zhang H, Zhang Q. Injectable redox and light responsive MnO2 hybrid hydrogel for simultaneous melanoma therapy and multidrug-resistant bacteria-infected wound healing. Biomaterials 2020; 260:120314. [DOI: 10.1016/j.biomaterials.2020.120314] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 08/09/2020] [Accepted: 08/10/2020] [Indexed: 12/15/2022]
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28
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Rahmati M, Ebrahim S, Hashemi S, Motamedi M, Moosavi MA. New insights on the role of autophagy in the pathogenesis and treatment of melanoma. Mol Biol Rep 2020; 47:9021-9032. [DOI: 10.1007/s11033-020-05886-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023]
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29
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Tang L, Peng C, Zhu SS, Zhou Z, Liu H, Cheng Q, Chen X, Chen XP. Tre2-Bub2-Cdc16 Family Proteins Based Nomogram Serve as a Promising Prognosis Predicting Model for Melanoma. Front Oncol 2020; 10:579625. [PMID: 33194704 PMCID: PMC7656061 DOI: 10.3389/fonc.2020.579625] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 10/05/2020] [Indexed: 12/21/2022] Open
Abstract
Tre2-Bub2-Cdc16 (TBC) proteins are conserved in eukaryotic organisms and function as negative feedback dominating the GAPs for Rab GTPases, while the function of TBC proteins in melanoma remains unclear. In this study, we observed the differential expression of 33 TBC genes in TCGA datasets classified by clinical features. Seven prognostic-associated TBC genes were identified by LASSO Cox regression analysis. Mutation analysis revealed distinctive frequency alteration in the seven prognostic-associated TBCs between cases with high and low scores. High-risk score and cluster 1 based on LASSO Cox regression and consensus clustering analysis were relevant to clinical features and unfavorable prognosis. GSVA analysis showed that prognostic-associated TBCs were related to metabolism and protein transport signaling pathway. Correlation analysis indicated the relationship between the prognostic-associated TBCs with RAB family members, invasion-related genes and immune cells. The prognostic nomogram model was well established to predict survival in melanoma. What's more, interference of one of the seven TBC proteins TBC1D7 was confirmed to inhibit the proliferation, migration and invasion of melanoma cells in vitro. In summary, we preliminarily investigated the impact of TBCs on melanoma through multiple bioinformatics analysis and experimental validation, which is helpful for clarifying the mechanism of melanoma and the development of anti-tumor drugs.
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Affiliation(s)
- Ling Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Cong Peng
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.,Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
| | - Su-Si Zhu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
| | - Zhe Zhou
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.,Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
| | - Han Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
| | - Quan Cheng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.,Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xiang Chen
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.,Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
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30
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Shi K, Camilon PR, Roberts JM, Meier JD. Survival Differences Between Pediatric Head and Neck Versus Body Melanoma in the Surveillance, Epidemiology, and End Results Program. Laryngoscope 2020; 131:E635-E641. [PMID: 32364637 DOI: 10.1002/lary.28711] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 03/28/2020] [Accepted: 04/08/2020] [Indexed: 01/13/2023]
Abstract
OBJECTIVES/HYPOTHESIS To review the demographics, treatment, and survival of pediatric melanoma of the head and neck and to determine if melanoma of the head and neck has worse survival than melanoma of other body sites. STUDY DESIGN Retrospective database review. METHODS Pediatric patients from 0 to 21 years in the Surveillance, Epidemiology, and End Results 18 registries database were included from 1975 to 2016 based on a diagnosis of melanoma of the skin using the primary site International Classification of Diseases for Oncology, Third Edition codes from C44.0-C44.9.skin of lip, C44.1-eyelid, C44.2-external ear, C44.3-skin other/unspecified parts of face, C44.4-skin of scalp and neck, C44.5-skin of trunk, C44.6-skin of upper limb and shoulder, C44.7-skin of lower limb and hip, C44.8-overlapping lesion of skin, and C44.9-skin, NOS (not otherwise specified). RESULTS A total of 4,561 pediatric melanomas of the skin were identified. There were 854 (18.7%) cases of melanoma of the head and neck (MHN) and 3,707 (81.3%) cases of melanoma of the body (MOB). The hazard ratio for MHN versus MOB was 1.6 (95% confidence interval: 1.3-2.1) after accounting for sex, race, and age. Of MHN sites, the hazard ratio for melanoma of the scalp and neck was 2.2 (1.1-4.7). The 2- and 5-year Kaplan-Meier overall survival for MHN were 94.6% and 90.7%, respectively, compared with 96.6% and 94.7%, respectively, for MOB (P < .01). CONCLUSIONS Survival outcomes of pediatric melanoma are notably related to anatomic site. Children with melanoma of the scalp and neck have the worst survival of all sites. Additionally, children who are older/white/male are at greater risk for worse survival outcomes. LEVEL OF EVIDENCE 3 Laryngoscope, 131:E635-E641, 2021.
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Affiliation(s)
- Kevin Shi
- Department of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, Utah, U.S.A
| | - P Ryan Camilon
- Department of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, Utah, U.S.A
| | - Jared M Roberts
- Department of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, Utah, U.S.A
| | - Jeremy D Meier
- Department of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, Utah, U.S.A
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31
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Abstract
Ultraviolet (UV) irradiation causes various types of DNA damage, which leads to specific mutations and the emergence of skin cancer in humans, often decades after initial exposure. Different UV wavelengths cause the formation of prominent UV-induced DNA lesions. Most of these lesions are removed by the nucleotide excision repair pathway, which is defective in rare genetic skin disorders referred to as xeroderma pigmentosum. A major role in inducing sunlight-dependent skin cancer mutations is assigned to the cyclobutane pyrimidine dimers (CPDs). In this review, we discuss the mechanisms of UV damage induction, the genomic distribution of this damage, relevant DNA repair mechanisms, the proposed mechanisms of how UV-induced CPDs bring about DNA replication-dependent mutagenicity in mammalian cells, and the strong signature of UV damage and mutagenesis found in skin cancer genomes.
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32
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Zhang ED, Zhang M, Li G, Zhang CL, Li Z, Zang G, Su Z, Zhang M, Xiang D, Zhao L, Zhu J. Mutation spectrum in GNAQ and GNA11 in Chinese uveal melanoma. PRECISION CLINICAL MEDICINE 2019; 2:213-220. [PMID: 35693877 PMCID: PMC8985776 DOI: 10.1093/pcmedi/pbz021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Uveal melanoma is the most common intraocular cancer in the adult eye. R183 and Q209 were found to be mutational hotspots in exon 4 and exon 5 of GNAQ and GNA11 in Caucasians. However, only a few studies have reported somatic mutations in GNAQ or GNA11 in uveal melanoma in Chinese. We extracted somatic DNA from paraffin-embedded biopsies of 63 Chinese uveal melanoma samples and sequenced the entire coding regions of exons 4 and 5 in GNAQ and GNA11. The results showed that 33% of Chinese uveal melanoma samples carried Q209 mutations while none had R183 mutation in GNAQ or GNA11. In addition, seven novel missense somatic mutations in GNAQ (Y192C, F194L, P170S, D236N, L232F, V230A, and M227I) and four novel missense somatic mutations in GNA11 (R166C, I200T, S225F, and V206M) were found in our study. The high mutation frequency of Q209 and the novel missense mutations detected in this study suggest that GNAQ and GNA11 are common targets for somatic mutations in Chinese uveal melanoma.
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Affiliation(s)
- Edward D Zhang
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510530, China
| | - Meixia Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Gen Li
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Charlotte L Zhang
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510530, China
| | - Zhihuan Li
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510530, China
| | - Guangxi Zang
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510530, China
| | - Zhiguang Su
- Molecular Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ming Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Daoman Xiang
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Ling Zhao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Jie Zhu
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
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Payandeh Z, Yarahmadi M, Nariman-Saleh-Fam Z, Tarhriz V, Islami M, Aghdam AM, Eyvazi S. Immune therapy of melanoma: Overview of therapeutic vaccines. J Cell Physiol 2019; 234:14612-14621. [PMID: 30706472 DOI: 10.1002/jcp.28181] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 01/10/2019] [Indexed: 01/24/2023]
Abstract
Melanoma is the most serious type of skin cancer which develops from the occurrence of genetic mutations in the melanocytes. Based on the features of melanoma tumors such as location, genetic profile and stage, there are several therapeutic strategies including surgery, chemotherapy, and radiotherapy. However, because of the appearance resistance mechanisms, the efficiency of these treatments strategies may be reduced. It has been demonstrated that therapeutic monoclonal antibodies can improve the efficiency of melanoma therapies. Recently, several mAbs, such as nivolumab, pembrolizumab, and ipilimumab, were approved for the immunotherapy of melanoma. The antibodies inhibit immune checkpoint receptors such as CTL4 and pd-1. Another therapeutic strategy for the treatment of melanoma is cancer vaccines, which improve clinical outcomes in patients. The combination therapy using antibodies and gene vaccine give us a new perspective in the treatment of melanoma patients. Herein, we present the recent progressions in the melanoma immunotherapy, especially dendritic cells mRNA vaccines by reviewing recent literature.
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Affiliation(s)
- Zahra Payandeh
- Immunology Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maral Yarahmadi
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ziba Nariman-Saleh-Fam
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Islami
- Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Shirin Eyvazi
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Biotechnology Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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35
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Nunes CJ, Otake AH, Bustos SO, Fazzi RB, Chammas R, Da Costa Ferreira AM. Unlike reactivity of mono- and binuclear imine-copper(II) complexes toward melanoma cells via a tyrosinase-dependent mechanism. Chem Biol Interact 2019; 311:108789. [PMID: 31401089 DOI: 10.1016/j.cbi.2019.108789] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 07/24/2019] [Accepted: 08/07/2019] [Indexed: 01/03/2023]
Abstract
The cytotoxicity of a dinuclear imine-copper (II) complex 2, and its analogous mononuclear complex 1, toward different melanoma cells, particularly human SKMEL-05 and SKMEL-147, was investigated. Complex 2, a tyrosinase mimic, showed much higher activity in comparison to complex 1, and its reactivity was verified to be remarkably activated by UVB-light, while the mononuclear compound showed a small or negligible effect. Further, a significant dependence on the melanin content in the tumor cells, both from intrinsic pigmentation or stimulated by irradiation, was observed in the case of complex 2. Similar tests with keratinocytes and melanocytes indicated a much lower sensitivity to both copper (II) complexes, even after exposition to UV light. Clonogenic assays attested that the fractions of melanoma cells survival were much lower under treatment with complex 2 compared to complex 1, both with or without previous irradiation of the cells. The process also involves generation of reactive oxygen species (ROS), as verified by EPR spectroscopy, and by using fluorescence indicators. Autophagic assays indicated a remarkable formation of cytoplasmic vacuoles in melanomas treated with complex 2, while this effect was not observed in similar treatment with complex 1. Monitoring of specific protein LC3 corroborated the simultaneous occurrence of autophagy. A balance interplay between different modes of cell death, apoptosis and autophagy, occurs when melanomas were treated with the dinuclear complex 2, in contrast to the mononuclear complex 1. These results pointed out to different mechanisms of action of such complexes, depending on its nuclearity.
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Affiliation(s)
- Cléia Justino Nunes
- Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, São Paulo, 05508-000, SP, Brazil
| | - Andréia Hanada Otake
- Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, 01246-000, SP, Brazil
| | - Silvina Odete Bustos
- Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, 01246-000, SP, Brazil
| | - Rodrigo Boni Fazzi
- Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, São Paulo, 05508-000, SP, Brazil
| | - Roger Chammas
- Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, 01246-000, SP, Brazil
| | - Ana Maria Da Costa Ferreira
- Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, São Paulo, 05508-000, SP, Brazil.
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36
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Laforgia M, Marech I, Nardulli P, Calabrò C, Gadaleta CD, Ranieri G. An evaluation of masitinib for treating systemic mastocytosis. Expert Opin Pharmacother 2019; 20:1539-1550. [PMID: 31381378 DOI: 10.1080/14656566.2019.1645121] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Systemic Mastocytosis (SM) is a complex family of rare diseases, against which pharmacological therapies are still very few. It is a c-kit driven disease, whose disregulation leads to uncontrolled activation and proliferation of mast cells (MCs) with consequent release of effector molecules which are responsible for its clinical manifestations. Areas covered: Masitinib is a relatively new potential drug against SM and its chemical structure strictly derives from imatinib, the first tyrosine kinase inhibitor which entered the pharmaceutical market about 15 years ago. In this review, the authors present masitinib in all its properties, from chemistry to pharmacology and toxicity to its potential clinical application in SM, focusing the discussion on the few clinical trials in which it has been involved, with a particular attention on the still open challenge to determine how to measure the response to therapy. Expert opinion: In spite of their similarity in chemistry and biological activity against submolecular targets, masitinib is much more selective towards c-kit receptors than other tyrosine kinases, such as Bcl-Abl. Furthermore, its ability to inhibit degranulation, cytokine production and MCs migration from bone marrow gives it a great chance to become an important therapeutic option for selected SM patients.
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Affiliation(s)
| | - Ilaria Marech
- Interventional and Medical Oncology Unit, IRCCS Istituto Tumori "G. Paolo II" , Bari , Italy
| | | | - Concetta Calabrò
- Pharmacy Unit, IRCCS Istituto Tumori "G. Paolo II" , Bari , Italy
| | - Cosimo Damiano Gadaleta
- Interventional and Medical Oncology Unit, IRCCS Istituto Tumori "G. Paolo II" , Bari , Italy
| | - Girolamo Ranieri
- Interventional and Medical Oncology Unit, IRCCS Istituto Tumori "G. Paolo II" , Bari , Italy
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37
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Ma FC, He RQ, Lin P, Zhong JC, Ma J, Yang H, Hu XH, Chen G. Profiling of prognostic alternative splicing in melanoma. Oncol Lett 2019; 18:1081-1088. [PMID: 31423168 PMCID: PMC6607279 DOI: 10.3892/ol.2019.10453] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 04/12/2019] [Indexed: 12/18/2022] Open
Abstract
Alternative splicing can lead to the coding of proteins that act as promoters of cancer, which is associated with the progression of cancer. However, to the best of our knowledge, no systematic survival analysis of alternative splicing in melanoma has previously been reported. The present study conducted an in-depth analysis of integrated alternative splicing events detected in 96 patients with melanoma using data obtained from The Cancer Genome Atlas. Prognostic models and an alternative splicing correlation network were built for patients with melanoma. A total of 41,446 mRNA splicing events were detected in 9,780 genes and 2,348 alternative splicing events were identified to be significantly associated with overall survival of patients with melanoma. Of all the events used in the prognostic model, the model with alternate terminator alternative splicing events exhibited the highest efficiency for evaluating the outcome of patients with melanoma, with an area under the curve of 0.902. The present study identified prognostic predictors for melanoma and revealed alternative splicing networks in melanoma that could indicate underlying mechanisms.
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Affiliation(s)
- Fu-Chao Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Peng Lin
- Ultrasonics Division of Radiology Department, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jin-Cai Zhong
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jie Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Hong Yang
- Ultrasonics Division of Radiology Department, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiao-Hua Hu
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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38
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Couto GK, Segatto NV, Oliveira TL, Seixas FK, Schachtschneider KM, Collares T. The Melding of Drug Screening Platforms for Melanoma. Front Oncol 2019; 9:512. [PMID: 31293965 PMCID: PMC6601395 DOI: 10.3389/fonc.2019.00512] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/28/2019] [Indexed: 12/30/2022] Open
Abstract
The global incidence of cancer is rising rapidly and continues to be one of the leading causes of death in the world. Melanoma deserves special attention since it represents one of the fastest growing types of cancer, with advanced metastatic forms presenting high mortality rates due to the development of drug resistance. The aim of this review is to evaluate how the screening of drugs and compounds for melanoma has been performed over the last seven decades. Thus, we performed literature searches to identify melanoma drug screening methods commonly used by research groups during this timeframe. In vitro and in vivo tests are essential for the development of new drugs; however, incorporation of in silico analyses increases the possibility of finding more suitable candidates for subsequent tests. In silico techniques, such as molecular docking, represent an important and necessary first step in the screening process. However, these techniques have not been widely used by research groups to date. Our research has shown that the vast majority of research groups still perform in vitro and in vivo tests, with emphasis on the use of in vitro enzymatic tests on melanoma cell lines such as SKMEL and in vivo tests using the B16 mouse model. We believe that the union of these three approaches (in silico, in vitro, and in vivo) is essential for improving the discovery and development of new molecules with potential antimelanoma action. This workflow would provide greater confidence and safety for preclinical trials, which will translate to more successful clinical trials and improve the translatability of new melanoma treatments into clinical practice while minimizing the unnecessary use of laboratory animals under the principles of the 3R's.
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Affiliation(s)
- Gabriela Klein Couto
- Research Group in Molecular and Cellular Oncology, Postgraduate Program in Biochemistry and Bioprospecting, Cancer Biotechnology Laboratory, Center for Technological Development, Federal University of Pelotas, Pelotas, Brazil
| | - Natália Vieira Segatto
- Biotechnology Graduate Program, Molecular and Cellular Oncology Research Group, Laboratory of Cancer Biotechnology, Technology Development Center, Federal University of Pelotas, Pelotas, Brazil
| | - Thaís Larré Oliveira
- Biotechnology Graduate Program, Molecular and Cellular Oncology Research Group, Laboratory of Cancer Biotechnology, Technology Development Center, Federal University of Pelotas, Pelotas, Brazil
| | - Fabiana Kömmling Seixas
- Biotechnology Graduate Program, Molecular and Cellular Oncology Research Group, Laboratory of Cancer Biotechnology, Technology Development Center, Federal University of Pelotas, Pelotas, Brazil
| | - Kyle M Schachtschneider
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States.,Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago, Chicago, IL, United States.,National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Tiago Collares
- Biotechnology Graduate Program, Molecular and Cellular Oncology Research Group, Laboratory of Cancer Biotechnology, Technology Development Center, Federal University of Pelotas, Pelotas, Brazil
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39
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Li K, Xiao G, Richardson JJ, Tardy BL, Ejima H, Huang W, Guo J, Liao X, Shi B. Targeted Therapy against Metastatic Melanoma Based on Self-Assembled Metal-Phenolic Nanocomplexes Comprised of Green Tea Catechin. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1801688. [PMID: 30886799 PMCID: PMC6402403 DOI: 10.1002/advs.201801688] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/09/2018] [Indexed: 02/05/2023]
Abstract
The targeted therapy of metastatic melanoma is an important yet challenging goal that has received only limited attention to date. Herein, green tea polyphenols, (-)-epigallocatechin-3-gallate (EGCG), and lanthanide metal ions (Sm3+) are used as building blocks to engineer self-assembled SmIII-EGCG nanocomplexes with synergistically enhanced tumor inhibitory properties. These nanocomplexes have negligible systemic toxic effects on healthy cells but cause a significant reduction in the viability of melanoma cells by efficiently regulating their metabolic pathways. Moreover, the wound-induced migration of melanoma cells can be efficiently inhibited by SmIII-EGCG, which is a key criterion for metastatic melanoma therapy. In a mouse melanoma tumor model, SmIII-EGCG is directly compared with a clinical anticancer drug, 5-fluorouracil and shows remarkable tumor inhibition. Moreover, the targeted therapy of SmIII-EGCG is shown to prevent metastatic lung melanoma from spreading to main organs with no adverse side effects on the body weight or organs. These in vivo results demonstrate significant advantages of SmIII-EGCG over its clinical counterpart. The results suggest that these green tea-based, self-assembled nanocomplexes possess all of the key traits of a clinically promising candidate to address the challenges associated with the treatment of advanced stage metastatic melanoma.
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Affiliation(s)
- Ke Li
- Department of Biomass Chemistry and EngineeringSichuan UniversityChengdu610065China
- Laboratory of EthnopharmacologyRegenerative Medicine Research CenterWest China HospitalSichuan UniversityChengduSichuan610041China
| | - Gao Xiao
- Wyss Institute for Biologically Inspired EngineeringJohn A. Paulson School of Engineering and Applied SciencesHarvard UniversityBostonMA02115USA
- Department of Environmental Science and EngineeringCollege of Environment and ResourcesFuzhou UniversityFuzhou350108China
| | - Joseph J. Richardson
- ARC Centre of Excellence in Convergent Bio‐Nano Science and Technology and Department of Chemical and Biomolecular EngineeringThe University of MelbourneParkvilleVictoria3010Australia
| | - Blaise L. Tardy
- Department of Bioproducts and BiosystemsSchool of Chemical EngineeringAalto UniversityP. O. Box 1630000076Finland
| | - Hirotaka Ejima
- Department of Materials EngineeringThe University of Tokyo7‐3‐1 HongoBunkyo‐kuTokyo113‐8656Japan
| | - Wen Huang
- Laboratory of EthnopharmacologyRegenerative Medicine Research CenterWest China HospitalSichuan UniversityChengduSichuan610041China
| | - Junling Guo
- Department of Biomass Chemistry and EngineeringSichuan UniversityChengdu610065China
- Wyss Institute for Biologically Inspired EngineeringJohn A. Paulson School of Engineering and Applied SciencesHarvard UniversityBostonMA02115USA
- National Engineering Laboratory for Clean Technology of Leather ManufactureSichuan UniversityChengduSichuan610065China
| | - Xuepin Liao
- Department of Biomass Chemistry and EngineeringSichuan UniversityChengdu610065China
| | - Bi Shi
- Department of Biomass Chemistry and EngineeringSichuan UniversityChengdu610065China
- National Engineering Laboratory for Clean Technology of Leather ManufactureSichuan UniversityChengduSichuan610065China
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40
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Salama Y, Lin SY, Dhahri D, Hattori K, Heissig B. The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis. FASEB J 2018; 33:3465-3480. [PMID: 30458112 DOI: 10.1096/fj.201801339rrr] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The multifunctional endocytic receptor low-density lipoprotein receptor-related protein (LRP)1 has recently been identified as a hub within a biomarker network for multicancer clinical outcome prediction. The mechanism how LRP1 modulates cancer progression is poorly understood. In this study we found that LRP1 and one of its ligands, tissue plasminogen activator (tPA), are expressed in melanoma cells and control melanoma growth and lung metastasis in vivo. Mechanistic studies were performed on 2 melanoma cancer cell lines, B16F10 and the B16F1 cells, both of which form primary melanoma tumors, but only B16F10 cells metastasize to the lungs. Tumor-, but not niche cell-derived tPA, enhanced melanoma cell proliferation in tPA-/- mice. Gain-of-function experiments revealed that melanoma LRP1 is critical for tumor growth, recruitment of mesenchymal stem cells into the tumor bed, and metastasis. Melanoma LRP1 was found to enhance ERK activation, resulting in increased matrix metalloproteinase (MMP)-9 RNA, protein, and secreted activity, a well-known modulator of melanoma metastasis. Restoration of LRP1 and tPA in the less aggressive, poorly metastatic B16F1 tumor cells enhanced tumor cell proliferation and led to massive lung metastasis in murine tumor models. Antimelanoma drug treatment induced tPA and LRP1 expression. tPA or LRP1 knockdown enhanced chemosensitivity in melanoma cells. Our results identify the tPA-LRP1 pathway as a key switch that drives melanoma progression, in part by modulating the cellular composition and proteolytic makeup of the tumor niche. Targeting this pathway may be a novel treatment strategy in combination treatments for melanoma.-Salama, Y., Lin, S.-Y., Dhahri, D., Hattori, K., Heissig, B. The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis.
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Affiliation(s)
- Yousef Salama
- Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
| | - Shiou-Yuh Lin
- Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Douaa Dhahri
- Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Koichi Hattori
- Center for Genome and Regenerative Medicine Juntendo University School of Medicine, Tokyo, Japan; and
| | - Beate Heissig
- Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Atopy (Allergy) Center, Juntendo University School of Medicine, Tokyo, Japan
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41
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Chen X, Liu X, Deng B, Martinka M, Zhou Y, Lan X, Cheng Y. Cytoplasmic Pin1 expression is increased in human cutaneous melanoma and predicts poor prognosis. Sci Rep 2018; 8:16867. [PMID: 30442923 PMCID: PMC6238011 DOI: 10.1038/s41598-018-34906-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 10/26/2018] [Indexed: 01/25/2023] Open
Abstract
The prolyl isomerase Pin1 is widely over-expressed or over-activated in cancers and promotes tumorigenesis. The authors investigated the expression level of Pin1 and analyzed the prognostic value of Pin1 expression using a large-scale melanoma tissue microarray study. Two independent sets of tissue microarrays were employed, including 114 melanoma cases in the discovery set and 424 in the validation set (538 cases in total), 32 normal nevi and 86 dysplastic nevi 118 cases of nevi. The subcellular Pin1 expression in different stages of melanocytic lesions and its prognostic significance were studied. High expression (IRS 0-8) of cytoplasmic Pin1 was observed in 3.13%, 8.33%, 16.49% and 22.76% of the biopsies in normal nevi, dysplastic nevi, primary melanoma and metastatic melanoma, respectively. Significant differences for cytoplasmic Pin1 staining were observed between normal nevi and metastatic melanoma (P = 0.011, χ2 test), between dysplastic nevi and primary melanoma (P = 0.046, χ2 test) and between dysplastic nevi and metastatic melanoma (P = 0.016, χ2 test). Kaplan-Meier survival analysis showed that increased cytoplasmic Pin1 expression was associated with a worse 5-year melanoma-specific survival of melanoma (P < 0.001) and metastatic melanoma patients (P = 0.004). Multivariate Cox regression analysis showed that cytoplasmic Pin1 expression is an independent prognostic factor in melanoma. Our data indicate that cytoplasmic Pin1 plays an important role in melanoma pathogenesis and progression, and serve as a potential prognostic marker for melanoma.
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Affiliation(s)
- Xin Chen
- Institute for laboratory Medicine, Fuzhou General Hospital, PLA, Fuzhou, Fujian, China
- Department of General Dentistry, The 174th Hospital of Chinese PLA (Chenggong Hospital affiliated to Medical School of Xiamen University), Xiamen, Fujian, China
| | - Xiaosong Liu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research and Center for Stress Signaling Networks, Xiamen University, Xiamen, Fujian, China
| | - Bin Deng
- Department of Anesthesiology, Xiang'an Hospital of Xiamen University, Fujian, China
| | - Magdalena Martinka
- Department of Pathology, Vancouver General Hospital, Vancouver, BC, Canada
| | - Youwen Zhou
- Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Xiaopeng Lan
- Institute for laboratory Medicine, Fuzhou General Hospital, PLA, Fuzhou, Fujian, China.
| | - Yabin Cheng
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research and Center for Stress Signaling Networks, Xiamen University, Xiamen, Fujian, China.
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42
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Saha B, Pai GB, Subramanian M, Gupta P, Tyagi M, Patro BS, Chattopadhyay S. Resveratrol analogue, trans-4,4'-dihydroxystilbene (DHS), inhibits melanoma tumor growth and suppresses its metastatic colonization in lungs. Biomed Pharmacother 2018; 107:1104-1114. [PMID: 30257322 DOI: 10.1016/j.biopha.2018.08.085] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 08/14/2018] [Accepted: 08/15/2018] [Indexed: 12/29/2022] Open
Abstract
The prevalence of melanoma and the lack of effective therapy for metastatic melanoma warrant extensive and systematic evaluations of small molecules in cellular and pre-clinical models. We investigated, herein, the antitumor and anti-metastatic effects of trans-4,4'-dihydroxystilbene (DHS), a natural product present in bark of Yucca periculosa, using in vitro and in vivo melanoma murine models. DHS showed potent melanoma cytotoxicity, as determined by MTT and clonogenic assay. Further, DHS induced cytotoxicity was mediated through apoptosis, which was assessed by annexin V-FITC/PI, sub-G1 and caspase activation assays. In addition, DHS inhibited cell proliferation by inducing robust cell cycle arrest in G1-phase. Imperatively, these inhibitory effects led to a significant reduction of melanoma tumor in pre-clinical murine model. DHS also inhibited cell migration and invasion of melanoma cells, which were examined using wound healing and Transwell migration/invasion assays. Mechanistically, DHS modulated the expressions of several key metastasis regulating proteins e.g., MMP-2/9, N-cadherin, E-cadherin and survivin. We also showed the anti-metastatic effect of DHS in a melanoma mediated lung metastasis model in vivo. DHS significantly reduced large melanoma nodule formation in the parenchyma of lungs. Therefore, DHS may represent a promising natural drug in the repertoire of treatment against melanoma tumor growth and metastasis.
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Affiliation(s)
- Bhaskar Saha
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, 400085, India
| | - Ganesh B Pai
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, 400085, India
| | - Mahesh Subramanian
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, 400085, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400094, India
| | - Pooja Gupta
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, 400085, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400094, India
| | - Mrityunjay Tyagi
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, 400085, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400094, India
| | - Birija Sankar Patro
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, 400085, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400094, India.
| | - Subrata Chattopadhyay
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, 400085, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400094, India.
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Novel Immunotherapeutic Approaches for Neuroblastoma and Malignant Melanoma. J Immunol Res 2018; 2018:8097398. [PMID: 30510968 PMCID: PMC6232800 DOI: 10.1155/2018/8097398] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 08/15/2018] [Indexed: 01/24/2023] Open
Abstract
Neuroblastoma (NB) and malignant melanoma (MM), tumors of pediatric age and adulthood, respectively, share a common origin, both of them deriving from the neural crest cells. Although NB and MM have a different behavior, in respect to age of onset, primary tissue involvement and metastatic spread, the prognosis for high stage-affected patients is still poor, in spite of aggressive treatment strategies and the huge amount of new discovered biological knowledge. For these reasons researchers are continuously attempting to find out new treatment options, which in a near future could be translated to the clinical practice. In the last two decades, a strong effort has been spent in the field of translational research of immunotherapy which led to satisfactory results. Indeed, several immunotherapeutic clinical trials have been performed and some of them also resulted beneficial. Here, we summarize preclinical studies based on immunotherapeutic approaches applied in models of both NB and MM.
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Zhang D, Lin J, Chao Y, Zhang L, Jin L, Li N, He R, Ma B, Zhao W, Han C. Regulation of the adaptation to ER stress by KLF4 facilitates melanoma cell metastasis via upregulating NUCB2 expression. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:176. [PMID: 30055641 PMCID: PMC6064624 DOI: 10.1186/s13046-018-0842-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 07/13/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Adaptation to ER stress has been indicated to play an important role in resistance to therapy in human melanoma. However, the relationship between adaptation to ER stress and cell metastasis in human melanoma remains unclear. METHODS The relationship of adaptation to ER stress and cell metastasis was investigated using transwell and mouse metastasis assays. The potential molecular mechanism of KLF4 in regulating the adaptation to ER stress and cell metastasis was investigated using RNA sequencing analysis, q-RT-PCR and western blot assays. The transcriptional regulation of nucleobindin 2 (NUCB2) by KLF4 was identified using bioinformatic analysis, luciferase assay, and chromatin immunoprecipitation (ChIP). The clinical significance of KLF4 and NUCB2 was based on human tissue microarray (TMA) analysis. RESULTS Here, we demonstrated that KLF4 was induced by ER stress in melanoma cells, and increased KLF4 inhibited cell apoptosis and promoted cell metastasis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of NUCB2, facilitating its transcription. Additionally, an increase in KLF4 promoted melanoma ER stress resistance, tumour growth and cell metastasis by regulating NCUB2 expression in vitro and in vivo. Elevated KLF4 was found in human melanoma tissues, which was associated with NUCB2 expression. CONCLUSION Our data revealed that the promotion of ER stress resistance via the KLF4-NUCB2 axis is essential for melanoma cell metastasis, and KLF4 may be a promising specific target for melanoma therapy.
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Affiliation(s)
- Dongmei Zhang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.,Department of Physiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Jingrong Lin
- Department of Dermatology, the First Affiliated Hospital, Dalian Medical University, Liaoning, 116027, China
| | - Yulin Chao
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Lu Zhang
- Department of Orthopedics, Second Affiliated Hospital, Dalian Medical University, Dalian, 116044, China
| | - Lei Jin
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Na Li
- Department of Physiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ruiping He
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Binbin Ma
- Department of Orthopedics, Second Affiliated Hospital, Dalian Medical University, Dalian, 116044, China
| | - Wenzhi Zhao
- Department of Orthopedics, Second Affiliated Hospital, Dalian Medical University, Dalian, 116044, China.
| | - Chuanchun Han
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.
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45
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Liu Q, Das M, Liu Y, Huang L. Targeted drug delivery to melanoma. Adv Drug Deliv Rev 2018; 127:208-221. [PMID: 28939379 DOI: 10.1016/j.addr.2017.09.016] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 08/29/2017] [Accepted: 09/14/2017] [Indexed: 12/21/2022]
Abstract
Melanoma derived from melanocytes is the most aggressive genre of skin cancer. Although the considerable advancement in the study of human cancer biology and drug discovery, most advanced melanoma patients are inevitably unable to be cured. With the emergence of nanotechnology, the use of nano-carriers is widely expected to alter the landscape of melanoma treatment. In this review, we will discuss melanoma biology, current treatment options, mechanisms behind drug resistance, and nano-based solutions for effective anti-cancer therapy, followed by challenges and perspectives in both pre-clinical and clinical settings.
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Affiliation(s)
- Qi Liu
- Division of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC & NCSU Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Manisit Das
- Division of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yun Liu
- Division of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Leaf Huang
- Division of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC & NCSU Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Lin J, Zhang D, Fan Y, Chao Y, Chang J, Li N, Han L, Han C. Regulation of Cancer Stem Cell Self-Renewal by HOXB9 Antagonizes Endoplasmic Reticulum Stress-Induced Melanoma Cell Apoptosis via the miR-765-FOXA2 Axis. J Invest Dermatol 2018; 138:1609-1619. [PMID: 29408459 DOI: 10.1016/j.jid.2018.01.023] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 01/13/2018] [Accepted: 01/15/2018] [Indexed: 01/13/2023]
Abstract
Adaptation to endoplasmic reticulum (ER) stress has been indicated as a driver of malignancy and resistance to therapy in human melanoma. However, the relationship between cancer stem cells and adaptation to ER stress remains unclear. Here, we show that the ratio of cancer stem cells is increased in ER stress-resistant melanoma cells, which inhibit ER stress-induced apoptosis and promote tumorigenesis. Further mechanistic studies showed that HOXB9 triggered by ER stress favors cancer stem cell self-renewal and enhances ER stress resistance. HOXB9 directly binds to the promoter of microRNA-765 and facilitates its transcription, which in turn targets FOXA2, resulting in a FOXA2 decrease and cancer stem cell increase. Additionally, an increase in HOXB9 promotes melanoma growth and inhibits cell apoptosis in a mouse xenograft model. Elevated HOXB9 is found in human melanoma tissues, which is associated with microRNA-765 up-regulation and FOXA2 decreases. Thus, our data showed that the HOXB9-dependent, microRNA-765-mediated FOXA2 pathway contributes to the survival of melanoma under ER stress by maintaining the properties of cancer stem cells.
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Affiliation(s)
- Jingrong Lin
- Institute of Cancer Stem Cell and Department of Dermatology of the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China
| | - Dongmei Zhang
- Department of Physiology of College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, China
| | - Yongsheng Fan
- Institute of Cancer Stem Cell and Department of Dermatology of the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China
| | - Yulin Chao
- Institute of Cancer Stem Cell and Department of Dermatology of the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China
| | - Jinming Chang
- Institute of Cancer Stem Cell and Department of Dermatology of the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China
| | - Na Li
- Department of Physiology of College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, China
| | - Linlin Han
- Physical Examination Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Chuanchun Han
- Institute of Cancer Stem Cell and Department of Dermatology of the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China.
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Liu X, Si W, Liu X, He L, Ren J, Yang Z, Yang J, Li W, Liu S, Pei F, Yang X, Sun L. JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component. Mol Cancer 2017; 16:175. [PMID: 29187213 PMCID: PMC5708181 DOI: 10.1186/s12943-017-0744-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 11/21/2017] [Indexed: 12/11/2022] Open
Abstract
Background Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. Methods We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis. We used human melanoma A375, 451Lu and SK-MEL-1 cell lines for in vitro proliferation and invasion experiments, and xenograft transplanted mice using murine melanoma B16F10 cells by bioluminescence imaging for in vivo tumor growth and pulmonary metastasis assessments. Endothelial tube formation assay, chicken yolk sac membrane assay and matrigel plug assay were performed to test the effect of JMJD6 on the angiogenic potential in vitro and in vivo. Results Here we report that the jumonji C domain-containing demethylase/hydroxylase JMJD6 is markedly up-regulated in melanoma. We found that high expression of JMJD6 is closely correlated with advanced clinicopathologic stage, aggressiveness, and poor prognosis of melanoma. RNA-seq showed that knockdown of JMJD6 affects the alternative splicing of a panel of transcripts including that encoding for PAK1, a key component in MAPK signaling pathway. We demonstrated that JMJD6 enhances the MAPK signaling and promotes multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. Interestingly, JMJD6 is transcriptionally activated by c-Jun, generating a feedforward loop to drive the development and progression of melanoma. Conclusions Our results indicate that JMJD6 is critically involved in melanoma carcinogenesis, supporting the pursuit of JMJD6 as a potential biomarker for melanoma aggressiveness and a target for melanoma intervention. Electronic supplementary material The online version of this article (10.1186/s12943-017-0744-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xujun Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Wenzhe Si
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.,Department of Laboratory Medicine, Peking University Third Hospital, Beijing, 100191, China
| | - Xinhua Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Lin He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Jie Ren
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Ziran Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Jianguo Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Wanjin Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Shumeng Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Fei Pei
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Xiaohan Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Luyang Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. .,Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
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Bakshi HA, Hakkim FL, Sam S, Javid F, Rashan L. Dietary Crocin Reverses Melanoma Metastasis. J Biomed Res 2017; 32:39. [PMID: 29219852 PMCID: PMC5956257 DOI: 10.7555/jbr.31.20160120] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 06/02/2017] [Indexed: 01/18/2023] Open
Abstract
Crocus sativus and its bioactive constituent crocin are well known for anti-tumor potential in different models. However, the efficacy of crocin on in-vivo melanoma metastasis is not yet reported. In this study, melanoma metastatic model was developed by tail vein injection of B16F-10 cells in to C57BL/6 mice. Metastatic mice treated with two different doses of crocin (250 and 500 µg/kg of bodyweight) for 10 days and parameters such as lung metastasis inhibition, mean survival time, lung hydroxyproline, uronic acid and hexosamine levels were analyzed after 21 days of treatment. Then blood was collected and serum gamma glutamyl transpeptidase (g-GGT), sialic acid, tumor necrosis factor alpha (TNF-a), interleukin 10 (IL-10), IL-6, IL-2, and TIMP-1 levels were measured. Further, a lung histological examination was done in crocin treated metastatic mice. Subsequently hallmark metastatic parameters such as matrix metalloproteases (MMPs), extracellular regulated kinase 2 (ERK2), vascular endothelial growth factor (VEGF), and K-ras gene expression were investigated in the lungs of crocin treated metastatic mice. Further, in-vitro adhesion, invasion and migration of B16F-10 cells were examined after 24 h of crocin (5 and 10 µg/mL) treatment. Administration of crocin to tumor bearing C57BL/6 mice reduced the lung metastasis by 85%. Elevated levels of hydroxyproline, uronic acid, hexosamine, serum sialic acid andg-GGT in metastatic control were found to be significantly reduced in crocin treated mice. Crocin also inhibited expression of MMP-2, MMP-9, ERK-2, K-ras, and VEGF. Crocin reduced the ability of B16F-10 cells invasion (p<0.05), migration (p<0.05) and adhesion by upregulating E-cadherin expression. In conclusion, crocin elicited marked anti-metastatic potential by regulating the metastasis induced biomarkers.
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Affiliation(s)
- Hamid A Bakshi
- . Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD13DH, United Kingdom
- . Department of Research, Jawaharlal Nehru Cancer Hospital and Research, Idgah Hills, Bhopal 462001 MP, India
| | | | - Smitha Sam
- . Department of Research, Jawaharlal Nehru Cancer Hospital and Research, Idgah Hills, Bhopal 462001 MP, India
| | - Farideh Javid
- . Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield HD13DH, United Kingdom
| | - Luay Rashan
- . Frankincense Biodiversity Lab, Research center, Dhofar University, Salalah 211, Oman
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Simultaneous Presentation of Cerebellopontine Angle Pleomorphic Xanthoastrocytoma and Malignant Melanoma in a Known Case of Neurofibromatosis 1; Probable Role of BRAF Gene: A Case Report and Review of Literature. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2017. [DOI: 10.5812/ijcm.7211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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50
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Ma X, Wu Y, Zhang T, Song H, Jv H, Guo W, Ren G. The clinical significance of c-Kit mutations in metastatic oral mucosal melanoma in China. Oncotarget 2017; 8:82661-82673. [PMID: 29137292 PMCID: PMC5669918 DOI: 10.18632/oncotarget.19746] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 06/20/2017] [Indexed: 01/14/2023] Open
Abstract
c-Kit mutations are frequently detected in mucosal melanomas, but their clinical significance in metastatic oral mucosal melanomas (OMM) remains unclear. The main purpose of this study was to investigate the clinical and pathological features of metastatic OMMs with c-Kit mutations and the efficiency of the tyrosine kinase inhibitor imatinib in treating metastatic OMMs. We found thatresidual primary lesion and neck lymph nodes could act as independent prognostic factors in metastatic OMM patients. c-Kit mutations were detected in 22 out of 139 (15.8%) metastatic OMM patients. Under chemotherapy, the overall survival (OS) of c-Kit mutant patients was significantly shorter than that of wild-type patients. The Ki67 expression was significantly higher in c-Kit mutant patients than in wild-type patients. In distant metastatic OMM patients with c-Kit mutations, the treatment with c-Kit inhibitor resulted in a better OS. In conclusion, residual primary lesion, cervical lymph nodes and c-Kit mutations act as adverse prognostic factors of metastatic OMMs. The Kit inhibitor imatinib could benefit metastatic OMM patients with c-Kit mutations.
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Affiliation(s)
- Xuhui Ma
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Yunteng Wu
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Tian Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Hao Song
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Houyu Jv
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Wei Guo
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Guoxin Ren
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
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