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Zhang CX, Zhang LZ, Lin H, Man QW, Liu B. BRAF V600E mutation mediates invasive and growth features in ameloblastoma. Oral Dis 2024; 30:4426-4439. [PMID: 38424736 DOI: 10.1111/odi.14909] [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: 08/15/2023] [Revised: 12/16/2023] [Accepted: 02/14/2024] [Indexed: 03/02/2024]
Abstract
OBJECTIVES Ameloblastoma (AM), a locally aggressive tumor with extensive growth capacity, causes significant damage to the jaw and affects facial appearance. Although the high prevalence of BRAF V600E mutation in AM is known, its specific impacts on patients with AM remain unclear. Thus, the present study investigated the role of BRAF V600E mutation, thereby focusing on its impact on AM invasion and growth. MATERIALS AND METHODS Immunohistochemical analysis was used to compare BRAF V600E, MMP2, MMP9, and Ki-67 expressions in AM (n = 49), normal oral mucosa (NOM) (n = 10), and odontogenic keratocyst (OKC) (n = 15) tissues. AM was further classified according to the presence or absence of BRAF V600E. The relationship between BRAF V600E and invasion as well as growth was evaluated. In addition, correlation analysis was performed using immunohistochemistry and confirmed via double-labeling immunofluorescence. Finally, comparative analyses using mass spectrometry, immunohistochemistry, and immunofluorescence were performed to explore and identify underlying mechanisms. RESULTS AM exhibited a higher incidence of BRAF V600E mutation than NOM and OKC. BRAF V600E expression was positively correlated with the invasion-associated proteins MMP2 and MMP9 and the growth-related protein Ki-67. Proteomic data revealed that BRAF V600E primarily activates the MAPK signaling pathway in AM, particularly driving the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). CONCLUSIONS In summary, the findings suggested that the BRAF V600E mutation enhances the invasion and growth abilities of AM via the MAPK/ERK signaling pathway. Thus, targeting BRAF V600E or the MAPK/ERK pathway may be a potential AM therapy.
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Affiliation(s)
- Chen-Xi Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Lin-Zhou Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hao Lin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Qi-Wen Man
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral Maxillofacial Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral Maxillofacial Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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Riofrio Chung GL, Santos Tucto TL, Quispe-Salcedo A. [Molecular basis of ameloblastoma pathogenesis: A review]. REVISTA CIENTÍFICA ODONTOLÓGICA 2024; 12:e212. [PMID: 39444727 PMCID: PMC11495173 DOI: 10.21142/2523-2754-1203-2024-212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 08/04/2024] [Indexed: 10/25/2024] Open
Abstract
Ameloblastoma is the most common and highly invasive benign odontogenic tumor. Its pathogenesis is not yet fully understood. Objective To describe the most important molecular findings that promote the proliferative activity of ameloblastoma and the factors involved that encourage invasion into surrounding bone tissues. Methodology A search for scientific evidence was conducted through the following databases: Science Direct, Medline, Wiley, Web of Science, and Google Scholar. A total of 32 articles were reviewed, with inclusion criteria being articles published in English and Spanish; descriptive and analytical studies, narrative and systematic reviews published from January 2015 to June 2021. Letters to the editor were excluded. Results The biological molecular findings that allow ameloblastoma to invade surrounding tissues involve alterations in the RANK/RANKL/OPG pathways, transforming growth factor beta (TGF-β), Wnt/β-catenin pathway, and matrix metalloproteinases, as well as alterations in MAPK and SHH pathways that facilitate the proliferation and tumor development of ameloblastoma. Conclusions These findings are fundamental for a better understanding of the pathways involved in the pathogenesis of ameloblastoma.
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Affiliation(s)
- Grecia Lourdes Riofrio Chung
- Facultad de Odontología, Universidad Nacional Mayor de San Marcos. Lima, Perú. Universidad Nacional Mayor de San Marcos Facultad de Odontología Universidad Nacional Mayor de San Marcos Lima Peru
| | - Tania Lisseth Santos Tucto
- Facultad de Medicina, Universidad Científica del Sur. Lima, Perú. Universidad Científica del Sur Facultad de Medicina Universidad Científica del Sur Lima Peru
- Knowledge Community "Sustainable Innovation in Dentistry", Universidad Federico Villareal. Lima, Perú. Universidad Nacional Federico Villarreal Knowledge Community "Sustainable Innovation in Dentistry" Universidad Federico Villareal Lima Peru
| | - Angela Quispe-Salcedo
- Division of Anatomy and Cell Biology of the Hard Tissue. Niigata University Graduate School of Medical and Dental Science. Niigata, Niigata University Division of Anatomy and Cell Biology of the Hard Tissue Niigata University Graduate School of Medical and Dental Science Niigata Japan
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3
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Farah C, Mignion L, Jordan BF. Metabolic Profiling to Assess Response to Targeted and Immune Therapy in Melanoma. Int J Mol Sci 2024; 25:1725. [PMID: 38339003 PMCID: PMC10855758 DOI: 10.3390/ijms25031725] [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: 12/21/2023] [Revised: 01/26/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
There is currently no consensus to determine which advanced melanoma patients will benefit from targeted therapy, immunotherapy, or a combination of both, highlighting the critical need to identify early-response biomarkers to advanced melanoma therapy. The goal of this review is to provide scientific rationale to highlight the potential role of metabolic imaging to assess response to targeted and/or immune therapy in melanoma cancer. For that purpose, a brief overview of current melanoma treatments is provided. Then, current knowledge with respect to melanoma metabolism is described with an emphasis on major crosstalks between melanoma cell metabolism and signaling pathways involved in BRAF-targeted therapy as well as in immune checkpoint inhibition therapies. Finally, preclinical and clinical studies using metabolic imaging and/or profiling to assess response to melanoma treatment are summarized with a particular focus on PET (Positron Emission Tomography) imaging and 13C-MRS (Magnetic Resonance Spectroscopy) methods.
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Affiliation(s)
- Chantale Farah
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium;
| | - Lionel Mignion
- Nuclear and Electron Spin Technologies (NEST) Platform, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium;
| | - Bénédicte F. Jordan
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium;
- Nuclear and Electron Spin Technologies (NEST) Platform, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium;
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Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther 2023; 8:455. [PMID: 38105263 PMCID: PMC10725898 DOI: 10.1038/s41392-023-01705-z] [Citation(s) in RCA: 83] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/03/2023] [Accepted: 11/12/2023] [Indexed: 12/19/2023] Open
Abstract
Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF-mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.
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Affiliation(s)
- Md Entaz Bahar
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Deok Ryong Kim
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea.
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5
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Gunji D, Narumi R, Muraoka S, Isoyama J, Ikemoto N, Ishida M, Tomonaga T, Sakai Y, Obama K, Adachi J. Integrative analysis of cancer dependency data and comprehensive phosphoproteomics data revealed the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant colorectal cancer. Mol Omics 2023; 19:624-639. [PMID: 37232035 DOI: 10.1039/d3mo00042g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Colorectal cancer (CRC), a common malignant tumour of the gastrointestinal tract, is a life-threatening cancer worldwide. Mutations in KRAS and BRAF, the major driver mutation subtypes in CRC, activate the RAS pathway, contribute to tumorigenesis in CRC and are being investigated as potential therapeutic targets. Despite recent advances in clinical trials targeting KRASG12C or RAS downstream signalling molecules for KRAS-mutant CRC, there is a lack of effective therapeutic interventions. Therefore, understanding the unique molecular characteristics of KRAS-mutant CRC is essential for identifying molecular targets and developing novel therapeutic interventions. We obtained in-depth proteomics and phosphoproteomics quantitative data for over 7900 proteins and 38 700 phosphorylation sites in cells from 35 CRC cell lines and performed informatic analyses, including proteomics-based coexpression analysis and correlation analysis between phosphoproteomics data and cancer dependency scores of the corresponding phosphoproteins. Our results revealed novel dysregulated protein-protein associations enriched specifically in KRAS-mutant cells. Our phosphoproteomics analysis revealed activation of EPHA2 kinase and downstream tight junction signalling in KRAS-mutant cells. Furthermore, the results implicate the phosphorylation site Y378 in the tight junction protein PARD3 as a cancer vulnerability in KRAS-mutant cells. Together, our large-scale phosphoproteomics and proteomics data across 35 steady-state CRC cell lines represent a valuable resource for understanding the molecular characteristics of oncogenic mutations. Our approach to predicting cancer dependency from phosphoproteomics data identified the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant CRC.
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Affiliation(s)
- Daigo Gunji
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
- Department of Surgery, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, 606-8507, Japan
| | - Ryohei Narumi
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
| | - Satoshi Muraoka
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
- Laboratory of Clinical and Analytical Chemistry, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
| | - Junko Isoyama
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
| | - Narumi Ikemoto
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
| | - Mimiko Ishida
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
| | - Takeshi Tomonaga
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, 606-8507, Japan
| | - Kazutaka Obama
- Department of Surgery, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, 606-8507, Japan
| | - Jun Adachi
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
- Laboratory of Clinical and Analytical Chemistry, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
- Laboratory of Proteomics and Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
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Nakai C, Mimaki S, Matsushima K, Shinozaki E, Yamazaki K, Muro K, Yamaguchi K, Nishina T, Yuki S, Shitara K, Bando H, Suzuki Y, Akagi K, Nomura S, Fujii S, Sugiyama M, Nishida N, Mizokami M, Koh Y, Koshizaka T, Okada H, Abe Y, Ohtsu A, Yoshino T, Tsuchihara K. Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant. Int J Clin Oncol 2023; 28:654-663. [PMID: 36856908 PMCID: PMC10119053 DOI: 10.1007/s10147-023-02318-w] [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: 03/03/2022] [Accepted: 02/17/2023] [Indexed: 03/02/2023]
Abstract
BACKGROUND Oncogenic mutations in BRAF genes are found in approximately 5-10% of colorectal cancers. The majority of BRAF mutations are located within exons 11-15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation. METHODS HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis. RESULTS The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance. CONCLUSIONS We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.
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Affiliation(s)
- Chikako Nakai
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Sachiyo Mimaki
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Koutatsu Matsushima
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-0063, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimo-Nagakubo, Nagaizumi-Cho, Sunto, Shizuoka, 411-8777, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-0063, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Minamiumemotomachi, Matsuyama, Ehime, 791-0245, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Hideaki Bando
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
| | - Yutaka Suzuki
- Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Kiwamu Akagi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 818 Komuro, Inami-machi, Kitaadachi, Saitama, 362-0806, Japan
| | - Shogo Nomura
- Biostatistics Division, Center for Research and Administration and Support, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Satoshi Fujii
- Department of Molecular Pathology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Masaya Sugiyama
- Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Nao Nishida
- Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Yasuhiro Koh
- Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Takuya Koshizaka
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Hideki Okada
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Yukiko Abe
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Atsushi Ohtsu
- National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Katsuya Tsuchihara
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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Scalia P, Williams SJ, Fujita-Yamaguchi Y, Giordano A. Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation. Cell Cycle 2023; 22:1-37. [PMID: 36005738 PMCID: PMC9769454 DOI: 10.1080/15384101.2022.2108117] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.
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Affiliation(s)
- Pierluigi Scalia
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states,CONTACT Pierluigi Scalia ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA9102, USA
| | - Stephen J Williams
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states
| | - Yoko Fujita-Yamaguchi
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Antonio Giordano
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,School of Medical Biotechnology, University of Siena, Italy
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Parnell SC, Raman A, Zhang Y, Daniel EA, Dai Y, Khanna A, Reif GA, Vivian JL, Fields TA, Wallace DP. Expression of active B-Raf proto-oncogene in kidney collecting ducts induces cyst formation in normal mice and accelerates cyst growth in mice with polycystic kidney disease. Kidney Int 2022; 102:1103-1114. [PMID: 35760151 PMCID: PMC9588601 DOI: 10.1016/j.kint.2022.05.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 12/14/2022]
Abstract
Polycystic kidney disease (PKD) is characterized by the formation and progressive enlargement of fluid-filled cysts due to abnormal cell proliferation. Cyclic AMP agonists, including arginine vasopressin, stimulate ERK-dependent proliferation of cystic cells, but not normal kidney cells. Previously, B-Raf proto-oncogene (BRAF), a MAPK kinase kinase that activates MEK-ERK signaling, was shown to be a central intermediate in the cAMP mitogenic response. However, the role of BRAF on cyst formation and enlargement in vivo had not been demonstrated. To determine if active BRAF induces kidney cyst formation, we generated transgenic mice that conditionally express BRAFV600E, a common activating mutation, and bred them with Pkhd1-Cre mice to express active BRAF in the collecting ducts, a predominant site for cyst formation. Collecting duct expression of BRAFV600E (BRafCD) caused kidney cyst formation as early as three weeks of age. There were increased levels of phosphorylated ERK (p-ERK) and proliferating cell nuclear antigen, a marker for cell proliferation. BRafCD mice developed extensive kidney fibrosis and elevated blood urea nitrogen, indicating a decline in kidney function, by ten weeks of age. BRAFV600E transgenic mice were also bred to Pkd1RC/RC and pcy/pcy mice, well-characterized slowly progressive PKD models. Collecting duct expression of active BRAF markedly increased kidney weight/body weight, cyst number and size, and total cystic area. There were increased p-ERK levels and proliferating cells, immune cell infiltration, interstitial fibrosis, and a decline in kidney function in both these models. Thus, our findings demonstrate that active BRAF is sufficient to induce kidney cyst formation in normal mice and accelerate cystic disease in PKD mice.
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Affiliation(s)
- Stephen C Parnell
- Department of Biochemistry and Molecular Biology, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Archana Raman
- Department of Molecular and Integrative Physiology, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Yan Zhang
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Emily A Daniel
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Yuqiao Dai
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Aditi Khanna
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Gail A Reif
- Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Jay L Vivian
- Department of Pathology and Laboratory Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Timothy A Fields
- Department of Pathology and Laboratory Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Darren P Wallace
- Department of Molecular and Integrative Physiology, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA; Department of Internal Medicine, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
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BRAF and MEK Targeted Therapies in Pediatric Central Nervous System Tumors. Cancers (Basel) 2022; 14:cancers14174264. [PMID: 36077798 PMCID: PMC9454417 DOI: 10.3390/cancers14174264] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/21/2022] [Accepted: 08/25/2022] [Indexed: 11/18/2022] Open
Abstract
Simple Summary This review is divided into two parts. The first analyzes the mechanisms of two important cellular pathways that are involved in tumoral proliferation, differentiation, migration, and angiogenesis: RAS/RAF/MEK/MAPK and PI3K/AKT/mTOR. The second part focuses on the currently available experience regarding targeted therapies against the mitogen-activated protein kinase (MAPK) pathway in pediatric CNS tumors, with the hope of offering a practical guide for consultation. Abstract BRAF is a component of the MAPK and PI3K/AKT/mTOR pathways that play a crucial role in cellular proliferation, differentiation, migration, and angiogenesis. Pediatric central nervous system tumors very often show mutations of the MAPK pathway, as demonstrated by next-generation sequencing (NGS), which now has an increasing role in cancer diagnostics. The MAPK mutated pathway in pediatric CNS tumors is the target of numerous drugs, approved or under investigation in ongoing clinical trials. In this review, we describe the main aspects of MAPK and PI3K/AKT/mTOR signaling pathways, with a focus on the alterations commonly involved in tumorigenesis. Furthermore, we reported the main available data about current BRAF and MEK targeted therapies used in pediatric low-grade gliomas (pLLGs), pediatric high-grade gliomas (pHGGs), and other CNS tumors that often present BRAF or MEK mutations. Further molecular stratification and clinical trial design are required for the treatment of pediatric CNS tumors with BRAF and MEK inhibitors.
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Park HB, Baek KH. E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188736. [DOI: 10.1016/j.bbcan.2022.188736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/30/2022] [Accepted: 05/11/2022] [Indexed: 12/13/2022]
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Chang CH, Sung WW. Nevi, dysplastic nevi, and melanoma: Molecular and immune mechanisms involving the progression. Tzu Chi Med J 2022; 34:1-7. [PMID: 35233349 PMCID: PMC8830542 DOI: 10.4103/tcmj.tcmj_158_20] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/28/2020] [Accepted: 03/12/2021] [Indexed: 11/25/2022] Open
Abstract
Melanocytic nevi, dysplastic nevi, and melanoma are all derived from the pigment-producing cells, namely melanocytes. Concerning the clinical spectrum, cutaneous melanoma is the most aggressive skin cancer with a low survival rate, while nevi are the most common benign lesions in the general population, and dysplastic nevi place in between nevi and melanoma. Ultraviolet (UV) radiation is a well-recognized extrinsic risk factor for all three. BRAFV600E is a well-recognized driver mutation that activates the RAS-BRAF-mitogen-activated protein kinase (MAPK) signaling pathway among 40%–60% of melanoma cases. Interestingly, BRAFV600E mutation is detected even more in acquired nevi, approximately 80%. However, in nevi, several tumor suppressors such as p53 and phosphatase and tensin homolog (PTEN) are intact, and senescence factors, including p15INK4b, p16INK4a, p19, and senescence-associated acidic β-galactosidase, are expressed, leading to cell senescence and cell cycle arrest. Although loss of p53 function is rarely found in melanoma, decreased or loss of PTEN with an activated PI3k/Akt signaling pathway is common in nevi, which may abolish senescence status and allow further progression into dysplastic nevi or melanoma. At present, mouse models closely resembling human nevi are used for investigating these phenomena. Melanocortin 1 receptor deficiency, an intrinsic risk factor for melanomagenesis, is related to the production of procarcinogenic pheomelanin and the inhibition of PTEN function. Immune response escape via programmed cell death-1/programmed cell death ligand-1 interaction plays further roles in monitoring the spectrum. Here, we review the current literature on the molecular and immune mechanisms involving the transition from benign nevi to malignant melanoma.
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Fuchigami T, Ono Y, Kishida S, Nakamura N. Molecular biological findings of ameloblastoma. JAPANESE DENTAL SCIENCE REVIEW 2021; 57:27-32. [PMID: 33737992 PMCID: PMC7946346 DOI: 10.1016/j.jdsr.2020.12.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 11/17/2020] [Accepted: 12/13/2020] [Indexed: 01/10/2023] Open
Abstract
Ameloblastoma is benign odontogenic tumours that mainly occur in the jawbone. This tumour induces aggressive invasion into the surrounding bone and has a high recurrence rate after surgery. Therefore, mandibular resection is performed in many patients with this tumour, causing aesthetic and functional problems. It is necessary to develop a novel treatment strategy for ameloblastoma, but there are currently no innovative treatments. Although our understanding of the molecular biological mechanisms of ameloblastoma is still insufficient, there have been many recent reports of new molecular biological findings on ameloblastoma. Therefore, bioactive factors that have potential for novel therapeutic methods, such as molecular targeted therapy, have been discovered in ameloblastoma. In this review, we summarize the molecular biological findings of ameloblastoma reported over several decades, focusing on factors involved in invasion into surrounding tissues and disease-specific gene mutations. We also mention the effect of the interaction between tumour cells and stromal components in ameloblastoma on tumour development. Scientific field of dental Science: Oral surgery, Odontogenic tumor, Ameloblastoma.
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Affiliation(s)
- Takao Fuchigami
- Department of Oral and Maxillofacial Surgery, Field of Maxillofacial Rehabilitation Graduate School of Medical and Dental Sciences, Kagoshima University, Japan
| | - Yusuke Ono
- Department of Oral and Maxillofacial Surgery, Field of Maxillofacial Rehabilitation Graduate School of Medical and Dental Sciences, Kagoshima University, Japan
| | - Shosei Kishida
- Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Japan
| | - Norifumi Nakamura
- Department of Oral and Maxillofacial Surgery, Field of Maxillofacial Rehabilitation Graduate School of Medical and Dental Sciences, Kagoshima University, Japan
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Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy. Int J Mol Sci 2021; 22:ijms222111726. [PMID: 34769156 PMCID: PMC8584081 DOI: 10.3390/ijms222111726] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 10/26/2021] [Indexed: 12/25/2022] Open
Abstract
Metastatic melanoma accounts for the highest number of skin cancer-related deaths. Traditional treatments are ineffective due to their inability to induce tumor regression at a high rate. Newer treatments such as immune checkpoint inhibitors (ICI), targeted therapy (BRAFi and MEKi), and T cell receptor (TCR)-engineered T cells aim to increase the ability of the host immune system to recognize and eradicate tumors. ICIs inhibit negative regulatory mechanisms and boost the antitumor activity of the host’s immune system, while targeted therapy directed against aberrant signaling molecules (BRAF and MEK) will block the uncontrolled proliferation and expansion of melanomas. The basis of the TCR-engineered T cell strategy is to transduce host T cells with antigen-specific TCRα/β chains to produce high-affinity T cells for tumor-associated antigens. TCR-transgenic T cells are expanded and activated ex vivo and reinfused into patients to increase the targeting of cancer cells. While these treatments have had varyingly favorable results, their efficacy is limited due to inherent or acquired resistance. Various mechanisms explain melanoma immune-resistance, including the loss or downregulation of the MCH/peptide complex, aberrant activity of signaling pathways, and altered dynamics of apoptotic machinery. Collectively, these mechanisms confer melanoma resistance to apoptotic stimuli delivered by T cells despite a fully functional and effective antitumor immune response. Identification of biomarkers, combination treatment, and the use of CAR T cells are among the approaches that can potentially circumvent melanoma’s resistance to immunotherapy.
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Fujii S, Ishibashi T, Kokura M, Fujimoto T, Matsumoto S, Shidara S, Kurppa KJ, Pape J, Caton J, Morgan PR, Heikinheimo K, Kikuchi A, Jimi E, Kiyoshima T. RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation. J Pathol 2021; 256:119-133. [PMID: 34622442 DOI: 10.1002/path.5814] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 09/10/2021] [Accepted: 10/05/2021] [Indexed: 12/17/2022]
Abstract
Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAFV600E mutation with mitogen-activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAFV600E mutation in which patients were successfully treated with a BRAF inhibitor. Therefore, the MAPK pathway may be involved in the development of ameloblastoma; however, the precise mechanism by which it induces ameloblastoma is unclear. The expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C), induced by a combination of the EGF-MAPK pathway and Wnt/β-catenin signalling, has been shown to induce epithelial morphogenesis. It was also reported that the overexpression of ARL4C, due to alterations in the EGF/RAS-MAPK pathway and Wnt/β-catenin signalling, promotes tumourigenesis. However, the roles of ARL4C in ameloblastoma are unknown. We investigated the involvement of ARL4C in the development of ameloblastoma. In immunohistochemical analyses of tissue specimens obtained from 38 ameloblastoma patients, ARL4C was hardly detected in non-tumour regions but tumours frequently showed strong expression of ARL4C, along with the expression of both BRAFV600E and RAF1 (also known as C-RAF). Loss-of-function experiments using inhibitors or siRNAs revealed that ARL4C elevation depended on the RAF1-MEK/ERK pathway in ameloblastoma cells. It was also shown that the RAF1-ARL4C and BRAFV600E-MEK/ERK pathways promoted cell proliferation independently. ARL4C-depleted tumour cells (generated by knockdown or knockout) exhibited decreased proliferation and migration capabilities. Finally, when ameloblastoma cells were co-cultured with mouse bone marrow cells and primary osteoblasts, ameloblastoma cells induced osteoclast formation. ARL4C elevation in ameloblastoma further promoted its formation capabilities through the increased RANKL expression of mouse bone marrow cells and/or primary osteoblasts. These results suggest that the RAF1-MEK/ERK-ARL4C axis, which may function in cooperation with the BRAFV600E-MEK/ERK pathway, promotes ameloblastoma development. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Shinsuke Fujii
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Takuma Ishibashi
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Megumi Kokura
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Tatsufumi Fujimoto
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Shinji Matsumoto
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Japan
| | - Satsuki Shidara
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Kari J Kurppa
- Institute of Biomedicine and MediCity Research Laboratories, University of Turku, and Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Judith Pape
- Division of Surgery and Interventional Science, Department of Targeted Intervention, Centre for 3D Models of Health and Disease, University College London, London, UK
| | - Javier Caton
- Department of Anatomy and Embryology, Faculty of Medicine, University Complutense Madrid, Madrid, Spain
| | - Peter R Morgan
- Head & Neck Pathology, King's College London, Guy's Hospital, London, UK
| | - Kristiina Heikinheimo
- Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku and Turku University Hospital, Turku, Finland
| | - Akira Kikuchi
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Eijiro Jimi
- Oral Health/Brain Health/Total Health Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.,Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Tamotsu Kiyoshima
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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Shi Y, Li M, Yu Y, Zhou Y, Wang S. Whole exome sequencing and system biology analysis support the "two-hit" mechanism in the onset of Ameloblastoma. Med Oral Patol Oral Cir Bucal 2021; 26:e510-e517. [PMID: 33395399 PMCID: PMC8254878 DOI: 10.4317/medoral.24385] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/11/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Ameloblastoma is the most frequent odontogenic tumor. Various evidence has highlighted the role of somatic mutations, including recurrent mutation BRAF V600E, in the tumorigenesis of Ameloblastoma, but the intact genetic pathology remains unknown. MATERIAL AND METHODS We sequenced the whole exome of both tumor tissue and healthy bone tissue from four mandibular ameloblastoma patients. The identified somatic mutations were integrated into Weighted Gene Co-expression Network Analysis on publicly available expression data of odontoblast, ameloblast, and Ameloblastoma. RESULTS We identified a total of 70 rare and severe somatic mutations. We found BRAF V600E on all four patients, supporting previous discovery. HSAP4 was also hit by two missense mutations on two different patients. By applying Weighted Gene Co-expression Network Analysis on expression data of odontoblast, ameloblast, and Ameloblastoma, we found a proliferation-associated gene module that was significantly disrupted in tumor tissues. Each patient carried at least two rare, severe somatic mutations affecting genes within this module, including HSPA4, GNAS, CLTC, NES, and KMT2D. All these mutations had a ratio of variant-support reads lower than BRAF V600E, indicating that they occurred later than BRAF V600E. CONCLUSIONS We suggest that a severe somatic mutation on the gene network of cell proliferation other than BRAF V600E, namely second hit, may contribute to the tumorigenesis of Ameloblastoma.
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Affiliation(s)
- Y Shi
- Department of Oral Surgery Shanghai Ninth People's Hospital #639 Zhizaoju Road, Shanghai 200011, China
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Bondhopadhyay B, Sisodiya S, Kasherwal V, Nazir SU, Khan A, Tanwar P, Dil-Afroze, Singh N, Rasool I, Agrawal U, Rath G, Mehrotra R, Hussain S. The differential expression of Promyelocytic Leukemia (PML) and retinoblastoma (RB1) genes in breast cancer. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Bhuyan L, Nishat R, Behura SS, Mahapatra N, Kumar H. Insight into the molecular pathogenesis of odontogenic lesions. J Oral Biosci 2021; 63:35-44. [PMID: 33476705 DOI: 10.1016/j.job.2020.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Odontogenic tumors, derived from epithelial, ectomesenchymal, and/or mesenchymal elements of the tooth-forming apparatus, constitute a heterogeneous group of lesions, including hamartomas, benign and malignant neoplasms with metastatic capabilities. HIGHLIGHT This review provides a comprehensive overviewof the pathogenesis of odontogenic tumors and explains the associated molecular events in the context of hallmarks of cancer established by Hanahan D and Weinberg RA. Diagrammatic representations depicted in the article would facilitate easier understanding. CONCLUSION A better understanding of the pathogenesis of the lesions may assist in determining patient's prognosis and devising better targeted therapeutic treatment, thus, reducing the morbidity and mortalityof patients.
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Affiliation(s)
- Lipsa Bhuyan
- Department of Oral Pathology and Microbiology, Kalinga Institute of Dental Sciences, KIIT Deemed to Be University, Bhubaneswar, Odisha, 751024, India.
| | - Roquaiya Nishat
- Department of Dentistry, Nalanda Medical College Hospital, Patna, Bihar, 800007, India.
| | - Shyam Sundar Behura
- Department of Oral Pathology and Microbiology, Kalinga Institute of Dental Sciences, KIIT Deemed to Be University, Bhubaneswar, Odisha, 751024, India.
| | - Niva Mahapatra
- Department of Oral Pathology and Microbiology, Kalinga Institute of Dental Sciences, KIIT Deemed to Be University, Bhubaneswar, Odisha, 751024, India.
| | - Harish Kumar
- Department of Oral Pathology and Microbiology, Kalinga Institute of Dental Sciences, KIIT Deemed to Be University, Bhubaneswar, Odisha, 751024, India.
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Wang A, Liu L, Yuan M, Han S, You X, Zhang H, Lei F, Zhang Y. Role and mechanism of FLNa and UCP2 in the development of cervical cancer. Oncol Rep 2020; 44:2656-2668. [PMID: 33125133 PMCID: PMC7640370 DOI: 10.3892/or.2020.7819] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 09/11/2020] [Indexed: 01/15/2023] Open
Abstract
Recent studies have reported that filamin A (FLNa) and uncoupling protein 2 (UCP2) are highly expressed in various types of cancer, but little is currently known about their roles in cervical cancer (CC). In the present study, immunohistochemical staining of paraffin sections of cervical tissues was performed in order to compare the differential expression of FLNa, UCP2, p16 and Ki67 between CC and high-grade intraepithelial neoplasia (HSIL). UCP2 and FLNa were knocked down in CC cell lines to investigate the effects on cell proliferation, cell cycle arrest, apoptosis, migration and invasion. In addition, the present study investigated the expression of cell-associated proteins [extracellular signal-regulated kinase (ERK), phosphorylated (p) ERK, protein kinase B (AKT), p-AKT and B-cell lymphoma-2 (Bcl-2)] and the mRNA levels of cellular proteins such as Ras, matrix metalloproteinase (MMP)-2 and MMP-9. FLNa and UCP2 expression levels were significantly higher in CC tissues than in HSIL tissues, with no significant differential expression of p16 or Ki67. UCP2 expression was significantly different in patients with clinical stage II or higher or lymph node metastasis compared with in other patients with cervical cancer. FLNa or UCP2 knockdown slowed or decreased SiHa and HeLa cell proliferation, migration and invasion, with no significant change in apoptosis, and downregulated the protein levels of p-ERK1/2, and the mRNA levels of Ras, MMP-2 and MMP-9. UCP2 knockdown arrested the cell cycle at the G2 phase in SiHa and HeLa cells, while FLNa knockdown arrested the cell cycle at the G2 phase in HeLa cells. The results of the present study revealed that FLNa and UCP2 play roles in the development and progression of CC via the Ras/MAPK/ERK signalling pathway. FLNa and UCP2 are superior to p16 and Ki67 for early prediction of CC, indicating that FLNa and UCP2 may be used for the early diagnosis of CC. UCP2 may be used to predict the prognosis of CC.
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Affiliation(s)
- Aihong Wang
- Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Lu Liu
- Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Miao Yuan
- Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Sai Han
- Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xuewu You
- Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hui Zhang
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, Shandong 271000, P.R. China
| | - Fuhua Lei
- Department of Pathology, Feicheng Hospital Affiliated to Shandong First Medical University, Tai'an, Shandong 271600, P.R. China
| | - Youzhong Zhang
- Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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Kanat O, Ertas H, Caner B. Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations. World J Gastrointest Oncol 2020; 12:1080-1090. [PMID: 33133378 PMCID: PMC7579731 DOI: 10.4251/wjgo.v12.i10.1080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/07/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.
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Affiliation(s)
- Ozkan Kanat
- Department of Medical Oncology, Acıbadem Bursa Hospital, Bursa 16059, Turkey
| | - Hulya Ertas
- Department of Medical Oncology, Bursa City Hospital, Bursa 16059, Turkey
| | - Burcu Caner
- Department of Medical Oncoloy, Balıkesir Ataturk City Hospital, Bursa 16059, Turkey
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Rashid FA, Munkhdelger J, Fukuoka J, Bychkov A. Prevalence of BRAFV600E mutation in Asian series of papillary thyroid carcinoma-a contemporary systematic review. Gland Surg 2020; 9:1878-1900. [PMID: 33224863 PMCID: PMC7667088 DOI: 10.21037/gs-20-430] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/04/2020] [Indexed: 12/30/2022]
Abstract
Papillary thyroid carcinoma (PTC), the most common malignancy of the endocrine system, is frequently driven by BRAFV600E mutation, which was reported in 35-60% cases in Western series. Numerous studies have recently emerged from Asian countries and regions; however sufficient summary is lacking to date. BRAF mutation serves as a diagnostic and prognostic tool in thyroid cancer, therefore establishing a rate of BRAF on the national scale could be of practical significance. We performed systematic reviews of available literature to investigate the prevalence of BRAF mutation in series of PTC from various Asian countries and regions. Out of the total 3,966 reports identified via initial screening, 138 studies encompassing over 40,000 PTCs were included for the final analysis. A vast majority (90.2%) of PTCs with known BRAF status were from East Asia, including China, South Korea, and Japan, with BRAF mutation rates of 71.2%, 75.5%, and 70.6%, respectively. Less abundant Indian and Saudi Arabian series found 45.6% and 46.3% prevalence of BRAFV600E in PTC, respectively. Much limited evidence was available from Thailand, Iran, Kazakhstan, Taiwan, Singapore, Indonesia, Hong Kong, Philippines, Vietnam, Iraq, and Myanmar. No relevant publications were found from other highly populated countries, such as Pakistan, Bangladesh, and Malaysia. After grouping by geographic region, we found that the highest rate of BRAFV600E was reported in the PTC series from East Asia (76.4%). Much lower rate (45-48%) was seen in PTC cohorts from South Asia, Central Asia, and the Middle East while the Southeast Asian series were in between (57%). Further subgroup analysis revealed that studies employing fresh frozen tissue and fine-needle aspirates showed higher rates of BRAF compared to those used formalin-fixed paraffin-embedded tissues. We found that the PTC series enrolled patients' cohorts after 2010 demonstrated a higher rate of BRAF compared to the earlier series. Finally, pediatric PTCs had lower BRAF prevalence compared to the baseline rate for the country. In conclusion, despite considerable among and within countries heterogeneity, the Asian PTC series showed a higher prevalence of BRAFV600E mutation than that in Western series. Causes of geographic heterogeneity, whether genuine (etiology, genetics) or methodology-related should be further investigated.
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Affiliation(s)
- Faiza Abdul Rashid
- Department of Biological Sciences, Faculty of Basic and Applied Sciences, International Islamic University, Islamabad, Pakistan
| | | | - Junya Fukuoka
- Department of Pathology, Kameda Medical Center, Kamogawa, Chiba, Japan
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Andrey Bychkov
- Department of Pathology, Kameda Medical Center, Kamogawa, Chiba, Japan
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Shi HA, Ng CWB, Kwa CT, Sim QXC. Ameloblastoma: A succinct review of the classification, genetic understanding and novel molecular targeted therapies. Surgeon 2020; 19:238-243. [PMID: 32712102 DOI: 10.1016/j.surge.2020.06.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 06/15/2020] [Indexed: 12/30/2022]
Abstract
Ameloblastomas are benign but locally invasive neoplasms which may grow to massive proportions and cause significant morbidity. Although some types of ameloblastoma can be treated predictably with aggressive surgical treatment, recurrent ameloblastoma and metastasising ameloblastoma are still difficult to treat. Recent studies have identified recurrent somatic and activating mutations in the mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH) signalling pathways in ameloblastoma. This development provided a possibility that molecular targeted therapies can be used as neoadjuvant treatment. In this review, we provide a summary of the latest WHO classification of ameloblastoma, the current understanding of genetic mutations and novel molecular targeted therapies arising from the recent developments.
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Affiliation(s)
- Hongyi Adrian Shi
- Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore.
| | - Chee Wee Benjamin Ng
- Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore
| | - Chong Teck Kwa
- Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore
| | - Qiu Xia Chelsia Sim
- Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore
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Vollmer S, Cunoosamy D, Lv H, Feng H, Li X, Nan Z, Yang W, Perry MWD. Design, Synthesis, and Biological Evaluation of MEK PROTACs. J Med Chem 2019; 63:157-162. [PMID: 31804822 DOI: 10.1021/acs.jmedchem.9b00810] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PROteolysis TArgeting Chimeras (PROTACs) targeting the degradation of MEK have been designed based on allosteric MEK inhibitors. Inhibition of the phosphorylation of ERK1/2 was less effective with the PROTACs than a small-molecule inhibitor; the best PROTACs, however, were more effective in inhibiting proliferation of A375 cells than an inhibitor.
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Affiliation(s)
| | | | - Huafei Lv
- Pharmaron Beijing Company, Limited , No. 6 Taihe Road, BDA , Beijing 100176 , P.R. China
| | - Huanxi Feng
- Pharmaron Beijing Company, Limited , No. 6 Taihe Road, BDA , Beijing 100176 , P.R. China
| | - Xia Li
- Pharmaron Beijing Company, Limited , No. 6 Taihe Road, BDA , Beijing 100176 , P.R. China
| | - Ziyang Nan
- Pharmaron Beijing Company, Limited , No. 6 Taihe Road, BDA , Beijing 100176 , P.R. China
| | - Wenzhen Yang
- Pharmaron Beijing Company, Limited , No. 6 Taihe Road, BDA , Beijing 100176 , P.R. China
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23
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Paredes SR, Chan C, Rickard MJFX. Immunohistochemistry in screening for heritable colorectal cancer: what to do with an abnormal result. ANZ J Surg 2019; 90:702-707. [PMID: 31828933 DOI: 10.1111/ans.15586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 10/28/2019] [Accepted: 11/03/2019] [Indexed: 02/06/2023]
Abstract
Recent developments in our understanding of molecular genetics have transformed screening and diagnostic practices for Lynch syndrome. The current standard involves universal tumour analysis of resected colorectal cancer (and ideally polypectomy) specimens using immunohistochemistry and molecular techniques. Patients with abnormal immunohistochemical findings are subsequently referred for definitive mutational testing. This review relates the molecular pathogenesis of Lynch syndrome to current immunohistochemistry-based screening strategies and discusses the interpretation and clinical implications of screening results.
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Affiliation(s)
- Steven R Paredes
- Discipline of Surgery, School of Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Concord Clinical School, School of Medicine, The University of Sydney, Sydney, New South Wales, Australia
| | - Charles Chan
- Concord Clinical School, School of Medicine, The University of Sydney, Sydney, New South Wales, Australia.,Anatomical Pathology Department, Concord Repatriation General Hospital, Sydney, New South Wales, Australia
| | - Matthew J F X Rickard
- Discipline of Surgery, School of Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Division of Colorectal Surgery, Department of Surgery, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.,Division of Colorectal Surgery, Department of Surgery, Macquarie University Hospital, Macquarie University, Sydney, New South Wales, Australia
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24
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Sharma R, Koruth R, Kanters S, Druyts E, Tarhini A. Comparative efficacy and safety of dabrafenib in combination with trametinib versus competing adjuvant therapies for high-risk melanoma. J Comp Eff Res 2019; 8:1349-1363. [PMID: 31778073 DOI: 10.2217/cer-2019-0061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim To conduct a systematic literature review of high-risk resectable cutaneous melanoma adjuvant therapeutics and compare safety and efficacy. Methods: The systematic literature review included randomized controlled trials investigating: dabrafenib plus trametinib (DAB + TRAM), nivolumab, pembrolizumab, ipilimumab, vemurafenib, chemotherapy and interferons. Outcomes included overall survival (OS), relapse-free survival, distant metastasis-free survival and safety. All outcomes were synthesized using Bayesian network meta-analysis. Results: Across relapse-free survival, distant metastasis-free survival and OS, DAB + TRAM had the lowest estimated hazards of respective events relative to all other treatments (exception relative to nivolumab in OS). Differences were significant relative to placebo, chemotherapy, interferons and ipilimumab. Conclusion: DAB + TRAM has improved efficacy over historical treatment options (ipilimumab, interferons and chemotherapy) and comparable efficacy with other targeted and immune checkpoint inhibitors.
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Affiliation(s)
- Rohini Sharma
- Precision Xtract, Vancouver, British Columbia, V6H 3Y4, Canada
| | - Roy Koruth
- Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA
| | - Steve Kanters
- Precision Xtract, Vancouver, British Columbia, V6H 3Y4, Canada
| | - Eric Druyts
- Precision Xtract, Vancouver, British Columbia, V6H 3Y4, Canada.,Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.,Moffitt Comprehensive Cancer Center, Tampa, FL 33612, USA
| | - Ahmad Tarhini
- Moffitt Comprehensive Cancer Center, Tampa, FL 33612, USA
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25
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Mohammadi Kian M, Haghi A, Salami M, Chahardouli B, Rostami SH, Malekzadeh K, Kamranzadeh Foumani H, Mohammadi S, Nikbakht M. Arsenic Trioxide and Thalidomide Combination Induces Autophagy Along with Apoptosis in Acute Myeloid Cell Lines. CELL JOURNAL 2019; 22:193-202. [PMID: 31721534 PMCID: PMC6874786 DOI: 10.22074/cellj.2020.6469] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 02/20/2019] [Indexed: 11/04/2022]
Abstract
Objective Autophagy and apoptosis play key roles in cancer survival and pathogenesis and are governed by specific genes which have a dual role in both cell death and survival. Arsenic trioxide (ATO) and thalidomide (THAL) are used for treatment of many types of hematologic malignancies. ATO prevents the proliferation of cells and induces apoptosis in some cancer cells. Moreover, THAL has immunomodulatory and antiangiogenic effects in malignant cells. The aim of present study was to examine the effects of ATO and THAL on U937 and KG-1 cells, and evaluation of mRNA expression level of VEGFs genes, PI3K genes and some of autophagy genes. Materials and Methods In this in vitro experimental study, U937 and KG-1 cells were treated by ATO (0.4-5 μM) and THAL (5-100 μM) for 24, 48 and 72 hours. Cell viability was measured by MTT assay. The apoptosis rate and cell cycle arrest were evaluated by flow cytometry (Annexin/PI) and cell cycle flow cytometry analysis, respectively. The effect of ATO/THAL on mRNAs expression was evaluated by real-time polymerase chain reaction (PCR). Results ATO/THAL combination enhanced cell apoptosis in a dose-dependent manner. Also, ATO/THAL induced SubG1/ G1 phase arrest. mRNA expression levels of VEGFC (contrary to other VEGFs isoform), PI3K, AKT, mTOR, MEK1, PTEN, IL6, LC3 and P62 genes were upregulated in acute myeloid leukemia (AML) cells following treatment with ATO/THAL. Conclusion Combined treatment with ATO and THAL can inhibit proliferation and invasion of AML cells by down-regulating ULK1 and BECLIN1 and up-regulating PTEN and IL6, and this effect was more marked than the effects of ATO and THAL alone.
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Affiliation(s)
- Mahnaz Mohammadi Kian
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Atousa Haghi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Young Researchers and Elite Club, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Mahdieh Salami
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahram Chahardouli
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - S Hahrbanoo Rostami
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Kianoosh Malekzadeh
- Molecular Medicine Research Center (MMRC), Hormozgan University of Medical Science (HUMS), Bandar Abbass, Iran
| | - Hosein Kamranzadeh Foumani
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Mohammadi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.Electronic Address:.,Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Nikbakht
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic Address:.,Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran
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26
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Zhang XY, Guo H, Huang Y, Hao PQ, Yang Y, Liu Y, Guo XX, Hao Q, An S, Xu TR. Comparative interactome analysis reveals distinct and overlapping properties of Raf family kinases. Biochem Biophys Res Commun 2019; 514:1217-1223. [DOI: 10.1016/j.bbrc.2019.05.089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 05/12/2019] [Indexed: 12/31/2022]
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27
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Reyes R, Mayo-de-las-Casas C, Teixidó C, Cabrera C, Marín E, Vollmer I, Jares P, Garzón M, Molina-Vila MÁ, Reguart N. Clinical Benefit From BRAF/MEK Inhibition in a Double Non-V600E BRAF Mutant Lung Adenocarcinoma: A Case Report. Clin Lung Cancer 2019; 20:e219-e223. [DOI: 10.1016/j.cllc.2019.02.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/11/2019] [Accepted: 02/21/2019] [Indexed: 02/09/2023]
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28
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Structural snapshots of RAF kinase interactions. Biochem Soc Trans 2018; 46:1393-1406. [PMID: 30381334 DOI: 10.1042/bst20170528] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 07/25/2018] [Accepted: 07/30/2018] [Indexed: 02/07/2023]
Abstract
RAF (rapidly accelerated fibrosarcoma) Ser/Thr kinases (ARAF, BRAF, and CRAF) link the RAS (rat sarcoma) protein family with the MAPK (mitogen-activated protein kinase) pathway and control cell growth, differentiation, development, aging, and tumorigenesis. Their activity is specifically modulated by protein-protein interactions, post-translational modifications, and conformational changes in specific spatiotemporal patterns via various upstream regulators, including the kinases, phosphatase, GTPases, and scaffold and modulator proteins. Dephosphorylation of Ser-259 (CRAF numbering) and dissociation of 14-3-3 release the RAF regulatory domains RAS-binding domain and cysteine-rich domain for interaction with RAS-GTP and membrane lipids. This, in turn, results in RAF phosphorylation at Ser-621 and 14-3-3 reassociation, followed by its dimerization and ultimately substrate binding and phosphorylation. This review focuses on structural understanding of how distinct binding partners trigger a cascade of molecular events that induces RAF kinase activation.
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29
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Luke GA, Ryan MD. "Therapeutic applications of the 'NPGP' family of viral 2As". Rev Med Virol 2018; 28:e2001. [PMID: 30094875 DOI: 10.1002/rmv.2001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 06/29/2018] [Accepted: 07/01/2018] [Indexed: 12/15/2022]
Abstract
Oligopeptide "2A" and "2A-like" sequences ("2As"; 18-25aa) are found in a range of RNA virus genomes controlling protein biogenesis through "recoding" of the host-cell translational apparatus. Insertion of multiple 2As within a single open reading frame (ORF) produces multiple proteins; hence, 2As have been used in a very wide range of biotechnological and biomedical applications. During translation, these 2A peptide sequences mediate a eukaryote-specific, self-"cleaving" event, termed "ribosome skipping" with very high efficiency. A particular advantage of using 2As is the ability to simultaneously translate a number of proteins at an equal level in all eukaryotic systems although, naturally, final steady-state levels depend upon other factors-notably protein stability. By contrast, the use of internal ribosome entry site elements for co-expression results in an unbalanced expression due to the relative inefficiency of internal initiation. For example, a 1:1 ratio is of particular importance for the biosynthesis of the heavy-chain and light-chain components of antibodies: highly valuable as therapeutic proteins. Furthermore, each component of these "artificial polyprotein" systems can be independently targeted to different sub-cellular sites. The potential of this system was vividly demonstrated by concatenating multiple gene sequences, linked via 2A sequences, into a single, long, ORF-a polycistronic construct. Here, ORFs comprising the biosynthetic pathways for violacein (five gene sequences) and β-carotene (four gene sequences) were concatenated into a single cistron such that all components were co-expressed in the yeast Pichia pastoris. In this review, we provide useful information on 2As to serve as a guide for future utilities of this co-expression technology in basic research, biotechnology, and clinical applications.
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Affiliation(s)
- Garry A Luke
- Centre for Biomolecular Sciences, School of Biology, University of St Andrews, St Andrews, UK
| | - Martin D Ryan
- Centre for Biomolecular Sciences, School of Biology, University of St Andrews, St Andrews, UK
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30
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Torres-Collado AX, Knott J, Jazirehi AR. Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAF V600E-Specific Inhibitor). Cancers (Basel) 2018; 10:cancers10060157. [PMID: 29795041 PMCID: PMC6025215 DOI: 10.3390/cancers10060157] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 05/14/2018] [Accepted: 05/23/2018] [Indexed: 12/19/2022] Open
Abstract
Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAFV600E mutation that causes constitutive activation of the MAPK pathway leading to drug-, immune-resistance, apoptosis evasion, proliferation, survival, and metastasis of melanomas. The ATP competitive BRAFV600E selective inhibitor, vemurafenib, has shown dramatic success in clinical trials; promoting tumor regression and an increase in overall survival of patients with metastatic melanoma. Regrettably, vemurafenib-resistance develops over an average of six months, which renders melanomas resistant to other therapeutic strategies. Elucidation of the underlying mechanism(s) of acquisition of vemurafenib-resistance and design of novel approaches to override resistance is the subject of intense clinical and basic research. In this review, we summarize recent developments in therapeutic approaches and clinical investigations on melanomas with BRAFV600E mutation to establish a new platform for the treatment of melanoma.
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Affiliation(s)
- Antoni Xavier Torres-Collado
- Department of Surgery, Division of Surgical Oncology, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA.
| | - Jeffrey Knott
- Department of Surgery, Division of Surgical Oncology, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA.
| | - Ali R Jazirehi
- Department of Surgery, Division of Surgical Oncology, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA.
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31
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Nakhaei-Rad S, Haghighi F, Nouri P, Rezaei Adariani S, Lissy J, Kazemein Jasemi NS, Dvorsky R, Ahmadian MR. Structural fingerprints, interactions, and signaling networks of RAS family proteins beyond RAS isoforms. Crit Rev Biochem Mol Biol 2018; 53:130-156. [PMID: 29457927 DOI: 10.1080/10409238.2018.1431605] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Saeideh Nakhaei-Rad
- a Institute of Biochemistry and Molecular Biology II, Medical Faculty , Heinrich-Heine University , Düsseldorf , Germany
| | - Fereshteh Haghighi
- a Institute of Biochemistry and Molecular Biology II, Medical Faculty , Heinrich-Heine University , Düsseldorf , Germany
| | - Parivash Nouri
- a Institute of Biochemistry and Molecular Biology II, Medical Faculty , Heinrich-Heine University , Düsseldorf , Germany
| | - Soheila Rezaei Adariani
- a Institute of Biochemistry and Molecular Biology II, Medical Faculty , Heinrich-Heine University , Düsseldorf , Germany
| | - Jana Lissy
- a Institute of Biochemistry and Molecular Biology II, Medical Faculty , Heinrich-Heine University , Düsseldorf , Germany
| | - Neda S Kazemein Jasemi
- a Institute of Biochemistry and Molecular Biology II, Medical Faculty , Heinrich-Heine University , Düsseldorf , Germany
| | - Radovan Dvorsky
- a Institute of Biochemistry and Molecular Biology II, Medical Faculty , Heinrich-Heine University , Düsseldorf , Germany
| | - Mohammad Reza Ahmadian
- a Institute of Biochemistry and Molecular Biology II, Medical Faculty , Heinrich-Heine University , Düsseldorf , Germany
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32
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Sanclemente M, Francoz S, Esteban-Burgos L, Bousquet-Mur E, Djurec M, Lopez-Casas PP, Hidalgo M, Guerra C, Drosten M, Musteanu M, Barbacid M. c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling. Cancer Cell 2018; 33:217-228.e4. [PMID: 29395869 DOI: 10.1016/j.ccell.2017.12.014] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 10/24/2017] [Accepted: 12/21/2017] [Indexed: 02/07/2023]
Abstract
A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.
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Affiliation(s)
- Manuel Sanclemente
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Sarah Francoz
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Laura Esteban-Burgos
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Emilie Bousquet-Mur
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Magdolna Djurec
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Pedro P Lopez-Casas
- Clinical Research Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Manuel Hidalgo
- Clinical Research Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Carmen Guerra
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Matthias Drosten
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Monica Musteanu
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
| | - Mariano Barbacid
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
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33
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BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy. Int J Mol Sci 2018; 19:ijms19010289. [PMID: 29346301 PMCID: PMC5796234 DOI: 10.3390/ijms19010289] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 01/12/2018] [Accepted: 01/17/2018] [Indexed: 12/19/2022] Open
Abstract
BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs. vemurafenib (Vem) and cobimetinib (Cobi) on the activation and functionality of chimeric antigen receptor (CAR)-transfected T cells. We co-cultured CAR-transfected CD8⁺ T cells and target cells with clinically relevant concentrations of the inhibitors and determined the antigen-induced cytokine secretion. All BRAFi/MEKi reduced this release as single agents, with Dabra having the mildest inhibitory effect, and Dabra + Tram having a clearly milder inhibitory effect than Vem + Cobi. A similar picture was observed for the upregulation of the activation markers CD25 and CD69 on CAR-transfected T cells after antigen-specific stimulation. Most importantly, the cytolytic capacity of the CAR-T cells was significantly inhibited by Cobi and Vem + Cobi, whereas the other kinase inhibitors showed no effect. Therefore, the combination Dabra + Tram would be more suitable for combining with T-cell-based immunotherapy than Vem + Cobi.
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34
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Ma L, Xu Z, Wang J, Zhu Z, Lin G, Jiang L, Lu X, Zou C. Matrine inhibits BCR/ABL mediated ERK/MAPK pathway in human leukemia cells. Oncotarget 2017; 8:108880-108889. [PMID: 29312576 PMCID: PMC5752489 DOI: 10.18632/oncotarget.22353] [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: 08/20/2016] [Accepted: 06/30/2017] [Indexed: 12/22/2022] Open
Abstract
The BCR/ABL fusion gene and its downstream signaling pathways such as Ras/Raf/MAPK, JAK/STAT3, and PI3K/AKT pathways play important roles in malignant transformation of leukemia, especially chronic myelogenous leukemia (CML). Our previous study showed that matrine, an alkaloid extracted from a Chinese herb radix sophorae, significantly inhibited the proliferation of human CML K562cells, induced cell cycle arrest in G0/G1, and promoted cell apoptosis. In the present study, we investigated the molecular mechanism of matrine in the growth inhibition of leukemia cells using K562 and HL-60 cell lines. RT-PCR and Western blot assay demonstrated that the expression of BCR/ABL in K562 and HL-60 cells was significantly inhibited by matrine treatment. Phosphorylation of MEK1, ERK1/2, and their upstream adaptor molecules Shc and SHP2 were significantly downregulated. The protein and mRNA expression of components of the ERK/MAPK signal pathway, and Bcl-xL, Cyclin D1, and c-Myc, were dramatically reduced. Conversely, the expression of p27, a negative regulator of cell cycle progression, increased after matrine treatment. These results indicated that the inhibition of ERK/MAPK and BCR/ABL signaling pathway was associated with matrine's suppressive effects on the growth of K562 and HL-60 cells. In in vivo study, matrine significantly decreased the mortality rate of tumor-baring mice and suggested that matrine could exert its anti-leukemia effect in vivo.
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Affiliation(s)
- Lingdi Ma
- Laboratory Center, The Third People's Hospital of Huizhou, Affiliated Hospital of Guangzhou Medical University, Huizhou 516002, China
| | - Zhenyu Xu
- Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - Jian Wang
- Laboratory Center, The Third People's Hospital of Huizhou, Affiliated Hospital of Guangzhou Medical University, Huizhou 516002, China
| | - Zhichao Zhu
- Laboratory Center, The Second People's Hospital of Changzhou, Affiliated Hospital of Nanjing Medical University, Changzhou 213000, China
| | - Guibin Lin
- Laboratory Center, The Third People's Hospital of Huizhou, Affiliated Hospital of Guangzhou Medical University, Huizhou 516002, China
| | - Lijia Jiang
- Laboratory Center, The Second People's Hospital of Changzhou, Affiliated Hospital of Nanjing Medical University, Changzhou 213000, China
| | - Xuzhang Lu
- Department of Hematology, The Second People's Hospital of Changzhou, Affiliated Hospital of Nanjing Medical University, Changzhou 213000, China
| | - Chang Zou
- Clinical Medical Research Center, The Second Clinical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
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35
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Gao M, Guo KM, Wei YM, Ma MM, Cai JR, Xia TT, Ye QJ. Aspirin inhibits the proliferation of human uterine leiomyoma cells by downregulation of K‑Ras‑p110α interaction. Oncol Rep 2017; 38:2507-2517. [PMID: 28849118 DOI: 10.3892/or.2017.5915] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 08/14/2017] [Indexed: 11/06/2022] Open
Abstract
Aspirin has been confirmed as an effective antitumor drug in various cancers. However, the relationship between aspirin and uterine leiomyoma is still underexplored. Here, we explored the effects of aspirin on human uterine leiomyoma cells and provide insights into the underlying mechanisms. Cell Counting Kit-8 (CCK-8) and flow cytometry analysis showed that aspirin treatment inhibited cell proliferation and promoted cell cycle arrest at G0/G1 phase in a dose- and time‑dependent manner of human uterine leiomyoma cells. Further studies revealed that aspirin blocked the interaction between K-Ras and p110α by co-immunoprecipitation and immunofluorescence. Western blotting demonstrated K‑Ras‑p110α interaction was required for the effects of aspirin‑induced inhibition on cell growth and cell cycle transition via cell cycle regulators, including cyclin D1 and cyclin-dependent kinase 2 (CDK2). PI3K/Akt/caspase signaling pathway was involved in human uterine leiomyoma cell growth under aspirin treatment. Taken together, these results suggest that aspirin inhibited human uterine leiomyoma cell growth by regulating K‑Ras‑p110α interaction. Aspirin which targeting on interaction between K-Ras and p110α may serve as a new therapeutic drug for uterine leiomyoma treatment.
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Affiliation(s)
- Min Gao
- Department of Pharmacy, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Kai-Min Guo
- Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, P.R. China
| | - Ying-Mei Wei
- Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Ming-Ming Ma
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jia-Rong Cai
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ting-Ting Xia
- Department of Infertility, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Qing-Jian Ye
- Department of Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China
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36
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Hong SP, Ahn SK. Discovery of a novel pan-RAF inhibitor with potent anti-tumor activity in preclinical models of BRAF V600E mutant cancer. Life Sci 2017. [DOI: 10.1016/j.lfs.2017.06.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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37
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Liu LJ, Wang W, Huang SY, Hong Y, Li G, Lin S, Tian J, Cai Z, Wang HMD, Ma DL, Leung CH. Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(iii) metal-based compound. Chem Sci 2017; 8:4756-4763. [PMID: 28959398 PMCID: PMC5603957 DOI: 10.1039/c7sc00311k] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 05/08/2017] [Indexed: 01/09/2023] Open
Abstract
Targeting protein-protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI interfaces with organic small molecules has been found to be exceptionally challenging, and few candidates have been successfully developed into clinical drugs. Meanwhile, the striking array of distinctive properties exhibited by metal compounds renders them attractive scaffolds for the development of bioactive leads. Here, we report the identification of iridium(iii) compounds as inhibitors of the H-Ras/Raf-1 PPI. The lead iridium(iii) compound 1 exhibited potent inhibitory activity against the H-Ras/Raf-1 interaction and its signaling pathway in vitro and in vivo, and also directly engaged both H-Ras and Raf-1-RBD in cell lysates. Moreover, 1 repressed tumor growth in a mouse renal xenograft tumor model. Intriguingly, the Δ-enantiomer of 1 showed superior potency in the biological assays compared to Λ-1 or racemic 1. These compounds could potentially be used as starting scaffolds for the development of more potent Ras/Raf PPI inhibitors for the treatment of kidney cancer or other proliferative diseases.
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Affiliation(s)
- Li-Juan Liu
- State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences , University of Macau , Macao , China .
| | - Wanhe Wang
- Department of Chemistry , Hong Kong Baptist University , Kowloon Tong , Hong Kong , China .
| | - Shi-Ying Huang
- College of Oceanology and Food Science , Quanzhou Normal University , Quanzhou 362000 , China
- Key Laboratory for the Development of Bioactive Material from Marine Algae , Quanzhou 362000 , China
| | - Yanjun Hong
- Partner State Key Laboratory of Environmental and Biological Analysis , Department of Chemistry , Hong Kong Baptist University , 224 Waterloo Road , Kowloon Tong , Hong Kong SAR , P. R. China .
| | - Guodong Li
- State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences , University of Macau , Macao , China .
| | - Sheng Lin
- Department of Chemistry , Hong Kong Baptist University , Kowloon Tong , Hong Kong , China .
| | - Jinglin Tian
- Partner State Key Laboratory of Environmental and Biological Analysis , Department of Chemistry , Hong Kong Baptist University , 224 Waterloo Road , Kowloon Tong , Hong Kong SAR , P. R. China .
| | - Zongwei Cai
- Partner State Key Laboratory of Environmental and Biological Analysis , Department of Chemistry , Hong Kong Baptist University , 224 Waterloo Road , Kowloon Tong , Hong Kong SAR , P. R. China .
| | - Hui-Min David Wang
- Graduate Institute of Biomedical Engineering , National Chung Hsing University , Taichung 402 , Taiwan .
| | - Dik-Lung Ma
- Department of Chemistry , Hong Kong Baptist University , Kowloon Tong , Hong Kong , China .
| | - Chung-Hang Leung
- State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences , University of Macau , Macao , China .
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38
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Rekhi B, Kosemehmetoglu K, Tezel GG, Dervisoglu S. Clinicopathologic features and immunohistochemical spectrum of 11 cases of epithelioid malignant peripheral nerve sheath tumors, including INI1/SMARCB1 results and BRAF V600E
analysis. APMIS 2017; 125:679-689. [DOI: 10.1111/apm.12702] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 03/03/2017] [Indexed: 11/28/2022]
Affiliation(s)
- Bharat Rekhi
- Department of Surgical Pathology; Tata Memorial Hospital; Mumbai India
| | | | - Gaye Guler Tezel
- Department of Pathology; Hacettepe University School of Medicine; Ankara Turkey
| | - Sergulen Dervisoglu
- Department of Pathology; Istanbul University; Capa School of Medicine; Istanbul Turkey
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39
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Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours. Oncogene 2017; 36:4778-4789. [PMID: 28414306 DOI: 10.1038/onc.2017.93] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 02/27/2017] [Accepted: 02/28/2017] [Indexed: 12/25/2022]
Abstract
KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancers (NSCLCs). RAS proteins trigger multiple effector signalling pathways including the highly conserved RAF-MAPK pathway. CRAF, a direct RAS effector protein, is required for KRAS-mediated tumourigenesis. Thus, the molecular mechanisms driving the activation of CRAF are intensively studied. Prohibitin 1 (PHB1) is an evolutionarily conserved adaptor protein and interaction of CRAF with PHB1 at the plasma membrane is essential for CRAF activation. Here, we demonstrate that PHB1 is highly expressed in NSCLC patients and correlates with poor survival. Targeting of PHB1 with two chemical ligands (rocaglamide and fluorizoline) inhibits epidermal growth factor (EGF)/RAS-induced CRAF activation. Consistently, treatment with rocaglamide inhibited proliferation, migration and anchorage-independent growth of KRAS-mutated lung carcinoma cell lines. Surprisingly, rocaglamide treatment inhibited Ras-GTP loading in KRAS-mutated cells as well as in EGF-stimulated cells. Rocaglamide treatment further prevented the oncogenic growth of KRAS-driven lung cancer allografts and xenografts in mouse models. Our results suggest rocaglamide as a RAS inhibitor and that targeting plasma membrane-associated PHB1 with chemical ligands would be a viable therapeutic strategy to combat KRAS-mediated NSCLCs.
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Effiom OA, Ogundana OM, Akinshipo AO, Akintoye SO. Ameloblastoma: current etiopathological concepts and management. Oral Dis 2017; 24:307-316. [PMID: 28142213 DOI: 10.1111/odi.12646] [Citation(s) in RCA: 149] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 01/20/2017] [Indexed: 02/06/2023]
Abstract
Ameloblastoma is a benign odontogenic tumor of epithelial origin. It is locally aggressive with unlimited growth capacity and has a high potential for malignant transformation as well as metastasis. Ameloblastoma has no established preventive measures although majority of patients are between ages 30 and 60 years. Molecular and genetic factors that promote oncogenic transformation of odontogenic epithelium to ameloblastoma are strongly linked to dysregulation of multiple genes associated with mitogen-activated protein kinase, sonic hedgehog, and WNT/β-catenin signaling pathways. Treatment of ameloblastoma is focused on surgical resection with a wide margin of normal tissue because of its high propensity for locoregional invasion; but this is often associated with significant patient morbidity. The relatively high recurrence rate of ameloblastoma is influenced by the type of molecular etiological factors, the management approach, and how early the patient presents for treatment. It is expected that further elucidation of molecular factors that orchestrate pathogenesis and recurrence of ameloblastoma will lead to new diagnostic markers and targeted drug therapies for ameloblastoma.
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Affiliation(s)
- O A Effiom
- Department of Oral and Maxillofacial Pathology/Biology, Faculty of Dental Sciences, University of Lagos, Lagos, Nigeria
| | - O M Ogundana
- Department of Oral and Maxillofacial Pathology/Biology, Faculty of Dental Sciences, University of Lagos, Lagos, Nigeria
| | - A O Akinshipo
- Department of Oral and Maxillofacial Pathology/Biology, Faculty of Dental Sciences, University of Lagos, Lagos, Nigeria
| | - S O Akintoye
- Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
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41
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Obaid NM, Bedard K, Huang WY. Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations. Int J Mol Sci 2017; 18:ijms18030585. [PMID: 28282860 PMCID: PMC5372601 DOI: 10.3390/ijms18030585] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 02/07/2017] [Accepted: 02/23/2017] [Indexed: 12/19/2022] Open
Abstract
The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of the BRAF gene. Since the initial identification of the BRAF mutation in 2002, a series of small molecular inhibitors that target the BRAFV600E have been developed, but intrinsic and acquired resistance to these drugs has presented an ongoing challenge. More recently, improvements in therapy have been achieved by combining the use of BRAF inhibitors with other drugs, such as inhibitors of the downstream effector mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) kinase (MEK). Despite improved success in response rates and in delaying resistance using combination therapy, ultimately, the acquisition of resistance remains a concern. Recent research articles have shed light on some of the underlying mechanisms of this resistance and have proposed numerous strategies that might be employed to overcome or avoid resistance to targeted therapies. This review will explore some of the resistance mechanisms, compare what is known in melanoma cancer to colorectal cancer, and discuss strategies under development to manage the development of resistance.
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Affiliation(s)
| | - Karen Bedard
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
| | - Weei-Yuarn Huang
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
- Department of Pathology, Nova Scotia Health Authority, Halifax, NS B3H 1V8, Canada.
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42
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Dorard C, Vucak G, Baccarini M. Deciphering the RAS/ERK pathway in vivo. Biochem Soc Trans 2017; 45:27-36. [PMID: 28202657 DOI: 10.1042/bst20160135] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 11/03/2016] [Accepted: 11/07/2016] [Indexed: 12/19/2022]
Abstract
The RAS/ERK pathway has been intensely studied for about three decades, not least because of its role in human pathologies. ERK activation is observed in the majority of human cancers; in about one-third of them, it is driven by mutational activation of pathway components. The pathway is arguably one of the best targets for molecule-based pharmacological intervention, and several small-molecule inhibitors are in clinical use. Genetically engineered mouse models have greatly contributed to our understanding of signaling pathways in development, tissue homeostasis, and disease. In the specific case of the RAS/ERK pathway, they have revealed unique biological roles of structurally and functionally similar proteins, new kinase-independent effectors, and unsuspected relationships with other cascades. This short review summarizes the contribution of mouse models to our current understanding of the pathway.
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Affiliation(s)
- Coralie Dorard
- Max F. Perutz Laboratories, Center for Molecular Biology, University of Vienna, Vienna 1030, Austria
| | - Georg Vucak
- Max F. Perutz Laboratories, Center for Molecular Biology, University of Vienna, Vienna 1030, Austria
| | - Manuela Baccarini
- Max F. Perutz Laboratories, Center for Molecular Biology, University of Vienna, Vienna 1030, Austria
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43
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Wu X, Fu Y, Wang Y, Wan S, Zhang J. Computational investigation on inhibition mechanism of BRAFV600E by Vemurafenib (PLX4032) and its analogue PLX4720. Med Chem Res 2016. [DOI: 10.1007/s00044-016-1757-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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44
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Abstract
The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1-6 and Sav1/WW45. Early studies emphasized the potent ability of MST1/MST2 to induce apoptosis upon being overexpressed, as well as the conversion of the endogenous MST1/MST2 polypeptides to constitutively active, caspase-cleaved catalytic fragments during apoptosis initiated by any stimulus. Later, the cleaved, constitutively active form of MST1 was identified in nonapoptotic, quiescent adult hepatocytes as well as in cells undergoing terminal differentiation, where its presence is necessary to maintain those cellular states. The physiologic regulation of full length MST1/MST2 is controlled by the availability of its noncatalytic SARAH domain partners. Interaction with Sav1/WW45 recruits MST1/MST2 into a tumor suppressor pathway, wherein it phosphorylates and activates the Sav1-bound protein kinases Lats1/Lats2, potent inhibitors of the Yap1 and TAZ oncogenic transcriptional regulators. A constitutive interaction with the Rap1-GTP binding protein RASSF5B (Nore1B/RAPL) in T cells recruits MST1 (especially) and MST2 as an effector of Rap1's control of T cell adhesion and migration, a program crucial to immune surveillance and response; loss of function mutation in human MST1 results in profound immunodeficiency. MST1 and MST2 are also regulated by other protein kinases, positively by TAO1 and negatively by Par1, SIK2/3, Akt, and cRaf1. The growing list of candidate MST1/MST2 substrates suggests that the full range of MST1/MST2's physiologic programs and contributions to pathophysiology remains to be elucidated.
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Affiliation(s)
- Jacob A. Galan
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Diabetes Unit and Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Joseph Avruch
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Diabetes Unit and Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
- Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States
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45
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Noeparast A, Teugels E, Giron P, Verschelden G, De Brakeleer S, Decoster L, De Grève J. Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and Dabrafenib. Oncotarget 2016; 8:60094-60108. [PMID: 28947956 PMCID: PMC5601124 DOI: 10.18632/oncotarget.11635] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 06/09/2016] [Indexed: 12/12/2022] Open
Abstract
Approximately half of BRAF-mutated Non-small cell lung cancers (NSCLCs) harbor a non-V600 BRAF mutation, accounting for ∼40,000 annual deaths worldwide. Recent studies have revealed the benefits of combined targeted therapy with a RAF-inhibitor (Dabrafenib) and a MEK-inhibitor (Trametinib) in treating V600 BRAF mutant cancers, including NSCLC. In contrast, sensitivity of non-V600 BRAF mutations to these inhibitors is not documented. Non-V600 mutations can either increase or impair BRAF kinase activity. However, impaired BRAF kinases can still activate the ERK pathway in a CRAF-dependent manner. Herein, beyond describing a cohort of BRAF mutant NSCLC patients and functionally analyzing 13 tumor-derived BRAF mutations, we demonstrate that both types of non-V600 BRAF mutations can be sensitive to clinically relevant doses of Dabrafenib and Trametinib in HEK293T cells, in lung epithelial cellular model (BEAS-2B) and in human cancer cell lines harboring non-V600 BRAF mutations. ERK activity induced by both types of these mutations is further reduced by combinatorial drug treatment. Moreover, the combination leads to more prolonged ERK inhibition and has anti-proliferative and pro-apoptotic effects in cells harboring both types of non-V600 BRAF mutations. This study provides a basis for the clinical exploration of non-V600 BRAF mutant lung cancers upon treatment with Trametinib and Dabrafenib.
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Affiliation(s)
- Amir Noeparast
- Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Erik Teugels
- Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Philippe Giron
- Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Gil Verschelden
- Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sylvia De Brakeleer
- Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Lore Decoster
- Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jacques De Grève
- Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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46
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Groesser L, Peterhof E, Evert M, Landthaler M, Berneburg M, Hafner C. BRAF and RAS Mutations in Sporadic and Secondary Pyogenic Granuloma. J Invest Dermatol 2016; 136:481-6. [PMID: 26802240 DOI: 10.1038/jid.2015.376] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 09/07/2015] [Accepted: 09/11/2015] [Indexed: 01/13/2023]
Abstract
Pyogenic granuloma (PG) is a common benign vascular skin lesion presenting as a rapidly growing angiomatous papule. The pathogenesis of most sporadic PGs and PGs associated with port wine stains (PWSs) remains elusive. We report that of 10 PGs secondarily arisen on a PWS, 8 showed a BRAF c.1799T>A (p.(Val600Glu)) and 1 a NRAS c.182A>G (p.(Gln61Arg)) mutation. The GNAQ c.548G>A mutation was identified in the PG and in the respective underlying PWS, indicating that PGs originate from cells of the PWS. In contrast to PG, 12 papulonodular lesions, which had developed in the PWSs of seven patients, showed a RAS and BRAF wild-type status. In sporadic PG we identified the BRAF c.1799T>A mutation in 3 of 25, a BRAF c.1391G>A mutation in 1 of 25, and a KRAS c.37G>C mutation in 1 of 25. Mutation-specific immunohistochemical detection of BRAF p.(Val600Glu) confirmed endothelial cells as carriers of the mutation in secondary and sporadic PG. Our study identifies the BRAF c.1799T>A mutation as a major driver mutation in the pathogenesis of, particularly, secondary PG. These data shed light on the hitherto undetermined genetic basis of PG and classify PG as a benign neoplasm.
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Affiliation(s)
- Leopold Groesser
- Department of Dermatology, University of Regensburg, Regensburg, Germany.
| | - Eva Peterhof
- Department of Dermatology, University of Regensburg, Regensburg, Germany
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Michael Landthaler
- Department of Dermatology, University of Regensburg, Regensburg, Germany
| | - Mark Berneburg
- Department of Dermatology, University of Regensburg, Regensburg, Germany
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47
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Areses Manrique MC, Iglesias Rey L, Cubiella J. [The long road from molecular biology to clinical practice in colorectal cancer]. GASTROENTEROLOGIA Y HEPATOLOGIA 2016; 39:429-32. [PMID: 26847767 DOI: 10.1016/j.gastrohep.2015.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/03/2015] [Accepted: 11/09/2015] [Indexed: 11/27/2022]
Affiliation(s)
| | - Leticia Iglesias Rey
- Servicio de Oncología Médica, Complexo Hospitalario Universitario de Ourense, Ourense, España
| | - Joaquín Cubiella
- Servicio de Aparato Digestivo, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Biomédica Ourense, Pontevedra y Vigo, Ourense, España.
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48
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Zhang X, Wang Y, Wang J, Sun F. Protein-protein interactions among signaling pathways may become new therapeutic targets in liver cancer (Review). Oncol Rep 2015; 35:625-38. [PMID: 26717966 DOI: 10.3892/or.2015.4464] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 07/06/2015] [Indexed: 11/05/2022] Open
Abstract
Numerous signaling pathways have been shown to be dysregulated in liver cancer. In addition, some protein-protein interactions are prerequisite for the uncontrolled activation or inhibition of these signaling pathways. For instance, in the PI3K/AKT signaling pathway, protein AKT binds with a number of proteins such as mTOR, FOXO1 and MDM2 to play an oncogenic role in liver cancer. The aim of the present review was to focus on a series of important protein-protein interactions that can serve as potential therapeutic targets in liver cancer among certain important pro-carcinogenic signaling pathways. The strategies of how to investigate and analyze the protein-protein interactions are also included in this review. A survey of these protein interactions may provide alternative therapeutic targets in liver cancer.
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Affiliation(s)
- Xiao Zhang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
| | - Yulan Wang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
| | - Jiayi Wang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
| | - Fenyong Sun
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
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49
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Brown NA, Betz BL. Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries. BIOMARKERS IN CANCER 2015; 7:19-24. [PMID: 26483612 PMCID: PMC4597444 DOI: 10.4137/bic.s29329] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/13/2015] [Accepted: 07/14/2015] [Indexed: 12/30/2022]
Abstract
Ameloblastoma is an odontogenic neoplasm whose molecular pathogenesis has only recently been elucidated. The discovery of recurrent activating mutations in FGFR2, BRAF, and RAS in a large majority of ameloblastomas has implicated dysregulation of MAPK pathway signaling as a critical step in the pathogenesis of this tumor. Some degree of controversy exists regarding the role of mutations affecting the sonic hedgehog (SHH) pathway, specifically Smoothened (SMO), which have been postulated to serve as either an alternative pathogenetic mechanism or secondary mutations. Here, we review recent advances in our understanding of the molecular pathogenesis of ameloblastoma as well as the diagnostic, prognostic, and therapeutic implications of these discoveries.
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Affiliation(s)
- Noah A Brown
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Bryan L Betz
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
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50
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Truncated RAF kinases drive resistance to MET inhibition in MET-addicted cancer cells. Oncotarget 2015; 6:221-33. [PMID: 25473895 PMCID: PMC4381590 DOI: 10.18632/oncotarget.2771] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 11/14/2014] [Indexed: 01/06/2023] Open
Abstract
Constitutively active receptor tyrosine kinases (RTKs) are known oncogenic drivers and provide valuable therapeutic targets in many cancer types. However, clinical efficacy of RTK inhibitors is limited by intrinsic and acquired resistance. To identify genes conferring resistance to inhibition of the MET RTK, we conducted a forward genetics screen in the GTL-16 gastric cancer cell line, carrying MET amplification and exquisitely sensitive to MET inhibition. Cells were transduced with three different retroviral cDNA expression libraries and selected for growth in the presence of the MET inhibitor PHA-665752. Selected cells displayed robust and reproducible enrichment of library-derived cDNAs encoding truncated forms of RAF1 and BRAF proteins, whose silencing reversed the resistant phenotype. Transduction of naïve GTL-16 cells with truncated, but not full length, RAF1 and BRAF conferred in vitro and in vivo resistance to MET inhibitors, which could be reversed by MEK inhibition. Induction of resistance by truncated RAFs was confirmed in other MET-addicted cell lines, and further extended to EGFR-addicted cells. These data show that truncated RAF1 and BRAF proteins, recently described as products of genomic rearrangements in gastric cancer and other malignancies, have the ability to render neoplastic cells resistant to RTK-targeted therapy.
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