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Zhu JK, Wang J. Cytochrome P450 3A gene family in gastric cancer: Unveiling diagnostic biomarkers and therapeutic targets for personalized treatment. World J Clin Oncol 2025; 16:101548. [DOI: 10.5306/wjco.v16.i4.101548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 01/12/2025] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
The cytochrome P450 3A (CYP3A) gene family’s role in early progression of gastric cancer was comprehensively investigated. Its potential as a therapeutic target was evaluated. Upon literature review, aberrant expression of the CYP3A gene family has a strong correlation with gastric cancer onset, although the precise underlying mechanisms remain unclear. To assess its potential as a biomarker for early diagnosis and a therapeutic target, we have provided a comprehensive review of the regulatory mechanisms governing CYP3A gene family expression in gastric cancer, as well as its relation with early tumor progression and the tumor microenvironment. The CYP3A gene family is crucial in the proliferation, migration, and invasion of gastric cancer cells and promotes cancer progression by modulating inflammatory responses and oxidative stress within the tumor microenvironment. Furthermore, genetic polymorphisms in CYP3Aenzymes highlight its potential value in personalized medicine. Based on these findings, this paper explores the feasibility of developing inhibitors and activators targeting CYP3A enzymes and discusses potential applications in gene therapy. This research provides crucial theoretical support for the CYP3A gene family as an early diagnostic marker and therapeutic target for gastric cancer. In the future, multi-omics studies and large-scale clinical trials will be essential to advance clinical translation of these findings.
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Affiliation(s)
- Jun-Kun Zhu
- Department of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jing Wang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
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Crispim D, Ramos C, Esteves F, Kranendonk M. The Adaptation of MCF-7 Breast Cancer Spheroids to the Chemotherapeutic Doxorubicin: The Dynamic Role of Phase I Drug Metabolizing Enzymes. Metabolites 2025; 15:136. [PMID: 39997761 PMCID: PMC11857127 DOI: 10.3390/metabo15020136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/05/2025] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
Background/Objectives: Drug resistance (DR) is a major challenge in cancer therapy, contributing to approximately 90% of cancer-related deaths. While alterations in drug metabolism are known to be key drivers of DR, their role-particularly in the early stages of acquired chemoresistance-remains understudied. Phase I drug-metabolizing enzymes (DMEs), especially cytochrome P450s (CYPs), significantly influence the metabolic fate of chemotherapeutic agents, directly affecting drug response. This study aimed to investigate the role of Phase I DMEs in the early metabolic adaptation of breast cancer (BC) MCF-7 cells to doxorubicin (DOX). Methods: Four types of spheroids were generated from MCF-7 cells that were either DOX-sensitive (DOXS) or adapted to low concentrations of the chemotherapeutic agent (DOXA 25, 35, and 45 nM). The expression levels of 92 Phase I DMEs and the activities of specific CYP isoforms were assessed in both DOXS and DOXA spheroids. Results: A total of twenty-four DMEs, including fifteen CYPs and nine oxidoreductases, were found to be differentially expressed in DOXA spheroids. Pathway analysis identified key roles for the differentially expressed DMEs in physiologically relevant pathways, including the metabolism of drugs, arachidonic acid, retinoic acid, and vitamin D. Conclusions: The deconvolution of these pathways highlights a highly dynamic process driving early-stage DOX resistance, with a prominent role of CYP3A-dependent metabolism in DOX adaptation. Our findings provide valuable insights into the underlying molecular mechanisms driving the early adaptation of MCF-7 cells to DOX exposure.
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Affiliation(s)
- Daniel Crispim
- Comprehensive Health Research Centre (CHRC) NOVA Medical School | Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal; (D.C.); (C.R.); (F.E.)
| | - Carolina Ramos
- Comprehensive Health Research Centre (CHRC) NOVA Medical School | Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal; (D.C.); (C.R.); (F.E.)
| | - Francisco Esteves
- Comprehensive Health Research Centre (CHRC) NOVA Medical School | Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal; (D.C.); (C.R.); (F.E.)
- Instituto Politécnico de Setúbal (IPS), Escola Superior de Saúde (ESS), Departamento de Ciências Biomédicas, Estefanilha, 2910-761 Setúbal, Portugal
| | - Michel Kranendonk
- Comprehensive Health Research Centre (CHRC) NOVA Medical School | Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal; (D.C.); (C.R.); (F.E.)
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Guimarães GM, Tesser-Gamba F, Petrilli AS, Alves MTS, Garcia-Filho RJ, Oliveira R, Toledo SRC. IGFBP5 in osteosarcoma tumorigenesis: Gene expression profile among metastatic and non-metastatic patients. Gene 2025; 934:149026. [PMID: 39442824 DOI: 10.1016/j.gene.2024.149026] [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: 02/16/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
Osteosarcoma (OS) is the most frequent primary malignant bone tumor among children and adolescents, with a peak of incidence in the second decade of life. The presence of metastasis at diagnosis in OS patients significantly decreases the chances of survival and new therapy approaches are needed. The IGFBP5 gene is related to osteoblasts metabolism and some studies have pointed out a role of its low expressions in OS development and metastasis. In this study, we aimed to establish an IGFBP5 gene expression profile among metastatic and non-metastatic OS patients throughout the treatment and development of the disease. Fresh-frozen tumor samples were obtained from 40 patients admitted to treatment at the Pediatric Oncology Institute (IOP/GRAACC/UNIFESP) and divided by clinical status: metastatic or non-metastatic disease. For each patient, samples before and after chemotherapy treatment were obtained, as well as metastasis and lung tissue surrounding metastasis samples from the metastatic patients. A quantitative real-time PCR was used to investigate IGFBP5 expression. Our analyses demonstrate that non-metastatic patients presented lower IGFBP5 expression in their pre-chemotherapy samples compared with metastatic patients, suggesting that low expressions of this gene could help triggering the OS tumorigenesis but that its action alone is not sufficient to activate the metastatic process. Heterogeneity in IGFBP5 expressions within groups was also seen. We observed that IGFBP5 and two MAPK genes, a downstream pathway in the IGFBP5 axis, are differentially expressed in OS samples of non-metastatic patients. Further investigation about these genes' modulations might lead to a better understanding of metastasis development in OS.
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Affiliation(s)
- G M Guimarães
- Pediatrics Department, Pediatric Oncology Institute/GRAACC, Federal University of São Paulo, São Paulo, SP, Brazil; Morphology and Genetics Department, Genetics Discipline, Federal University of São Paulo, São Paulo, SP, Brazil
| | - F Tesser-Gamba
- Pediatrics Department, Pediatric Oncology Institute/GRAACC, Federal University of São Paulo, São Paulo, SP, Brazil; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology - INCT BioOncoPed, Brazil.
| | - A S Petrilli
- Pediatrics Department, Pediatric Oncology Institute/GRAACC, Federal University of São Paulo, São Paulo, SP, Brazil
| | - M T S Alves
- Pediatrics Department, Pediatric Oncology Institute/GRAACC, Federal University of São Paulo, São Paulo, SP, Brazil; Pathology Department, Federal University of São Paulo, São Paulo, SP, Brazil
| | - R J Garcia-Filho
- Pediatrics Department, Pediatric Oncology Institute/GRAACC, Federal University of São Paulo, São Paulo, SP, Brazil; Orthopedics and Traumatology Department, Oncology Orthopedics Group, Federal University of São Paulo, São Paulo, SP, Brazil
| | - R Oliveira
- Pediatrics Department, Pediatric Oncology Institute/GRAACC, Federal University of São Paulo, São Paulo, SP, Brazil; Surgery Department, Federal University of São Paulo, São Paulo, SP, Brazil
| | - S R C Toledo
- Pediatrics Department, Pediatric Oncology Institute/GRAACC, Federal University of São Paulo, São Paulo, SP, Brazil; Morphology and Genetics Department, Genetics Discipline, Federal University of São Paulo, São Paulo, SP, Brazil; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology - INCT BioOncoPed, Brazil
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Lin Z, Wei Y, Yang H. Mg alloys with antitumor and anticorrosion properties for orthopedic oncology: A review from mechanisms to application strategies. APL Bioeng 2024; 8:021504. [PMID: 38638143 PMCID: PMC11026114 DOI: 10.1063/5.0191800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/04/2024] [Indexed: 04/20/2024] Open
Abstract
As a primary malignant bone cancer, osteosarcoma (OS) poses a great threat to human health and is still a huge challenge for clinicians. At present, surgical resection is the main treatment strategy for OS. However, surgical intervention will result in a large bone defect, and some tumor cells remaining around the excised bone tissue often lead to the recurrence and metastasis of OS. Biomedical Mg-based materials have been widely employed as orthopedic implants in bone defect reconstruction, and, especially, they can eradicate the residual OS cells due to the antitumor activities of their degradation products. Nevertheless, the fast corrosion rate of Mg alloys has greatly limited their application scope in the biomedical field, and the improvement of the corrosion resistance will impair the antitumor effects, which mainly arise from their rapid corrosion. Hence, it is vital to balance the corrosion resistance and the antitumor activities of Mg alloys. The presented review systematically discussed the potential antitumor mechanisms of three corrosion products of Mg alloys. Moreover, several strategies to simultaneously enhance the anticorrosion properties and antitumor effects of Mg alloys were also proposed.
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Affiliation(s)
- Zhensheng Lin
- Medical Engineering Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan, China
| | - Yuhe Wei
- Department of Medical Equipment, Tianjin Chest Hospital, Tianjin 300350, China
| | - Huazhe Yang
- School of Intelligent Medicine, China Medical University, Shenyang 110122, China
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Meng XN, Ma JF, Liu YH, Li SQ, Wang X, Zhu J, Cai MD, Zhang HS, Song T, Xing S, Hou LQ, Guo H, Cui XB, Han J, Liu P, Ji GH, Sun WJ, Yu JC, Fu SB. Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance. Br J Cancer 2024; 130:1819-1827. [PMID: 38594370 PMCID: PMC11130306 DOI: 10.1038/s41416-024-02664-0] [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: 06/26/2023] [Revised: 03/15/2024] [Accepted: 03/18/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.
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Affiliation(s)
- Xiang-Ning Meng
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jin-Fa Ma
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Yang-He Liu
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Si-Qing Li
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Xu Wang
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jing Zhu
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Meng-Di Cai
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Hui-Shu Zhang
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Tiantian Song
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Shukai Xing
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Li-Qing Hou
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Huan Guo
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Xiao-Bo Cui
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jiang Han
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Peng Liu
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Guo-Hua Ji
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Wen-Jing Sun
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jing-Cui Yu
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China
| | - Song-Bin Fu
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China.
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China.
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Picher EA, Wahajuddin M, Barth S, Chisholm J, Shipley J, Pors K. The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma. Cancers (Basel) 2024; 16:1012. [PMID: 38473371 DOI: 10.3390/cancers16051012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5-8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation.
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Affiliation(s)
- Enric Arasanz Picher
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Muhammad Wahajuddin
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Stefan Barth
- Medical Biotechnology and Immunotherapy Research Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa
| | - Julia Chisholm
- Children and Young People's Unit, Royal Marsden Hospital, Institute of Cancer Research, Sutton SM2 5PR, UK
| | - Janet Shipley
- Sarcoma Molecular Pathology Group, Division of Molecular Pathology, The Institute of Cancer Research, Sutton SM2 5NG, UK
| | - Klaus Pors
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
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Vorontsova JE, Akishina AA, Cherezov RO, Simonova OB. A new insight into the aryl hydrocarbon receptor/cytochrome 450 signaling pathway in MG63, HOS, SAOS2, and U2OS cell lines. Biochimie 2023; 207:102-112. [PMID: 36332717 DOI: 10.1016/j.biochi.2022.10.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 11/07/2022]
Abstract
Osteosarcoma is the most common malignant tumor of bone, with rapid progressive growth, early distant metastases, and frequent recurrence after surgical treatment. Osteosarcoma is characterized by changes in the ratio and expression of different cytochrome P450 (CYP) isoforms that can affect the effectiveness of anticancer therapies. The inducible expression of CYP1 genes depends on the ligand-dependent functionality of the aryl hydrocarbon receptor (AHR). In this study, we examined the AHR/CYP1 signaling pathway in four osteosarcoma cell lines (MG63, HOS, SAOS2, and U2OS) induced by the known AHR ligands: indirubin, indole-3-carbinol, and beta-naphthoflavone. Using qPCR and Western blot analysis, we explored the effects of these ligands on the expression of the CYP1 genes and studied the correlation between these responses and the changes in the mRNA and protein levels of AHR and the AHR nuclear translocator (ARNT) in these osteosarcoma cell lines. The results show that the AHR/CYP1 signaling pathway retains its function only in MG63 and HOS cells, and is impaired in SAOS2 and U2OS cells. Our data should be taken into account when recommending new strategies for the treatment of osteosarcoma and when evaluating new drugs against osteosarcoma in vitro.
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Affiliation(s)
- Julia E Vorontsova
- Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.
| | - Angelina A Akishina
- Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia
| | - Roman O Cherezov
- Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia
| | - Olga B Simonova
- Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia
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Torres-Zárate C, Vences-Mejía A, Espinosa-Aguirre JJ, Díaz-Díaz E, Palacios-Acosta JM, Cárdenas-Cardós R, Hernández-Arrazola D, Shalkow-Klincovstein J, Jurado RR, Santes-Palacios R, Molina-Ortiz D. Expression of Cytochrome P450 Enzymes in Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Possible Role in Carcinogenesis and Treatment Response. Int J Toxicol 2022; 41:234-242. [PMID: 35437033 DOI: 10.1177/10915818221085909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The 5-year relative survival rate estimate of treated patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) is ∼50% since they generally present with tumor progression, relapse, metastasis, and/or chemoresistance. The expression of cytochrome P450 (CYP) enzymes in malignancies can affect the pharmacology of drugs commonly used in chemotherapy or confer susceptibility to development of chemical carcinogenesis; in addition, their specific tumor expression can be used as a therapeutic target. Using qPCR and Western blot assays, the expression of CYP1B1, CYP2E1, CYP3A4, and CYP3A5 were analyzed in a cohort of tumor tissue paired with non-malignant adjacent tissue of patients with NRSTS. The mRNA and protein expression of CYP1B1, CYP2E1, and CYP3A4 were significantly increased in tumor tissue. We propose that the expression of these isoforms is related to carcinogenesis and chemoresistance frequently observed in these neoplasms.
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Affiliation(s)
- Carmen Torres-Zárate
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Araceli Vences-Mejía
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | | | - Eduardo Díaz-Díaz
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | | | | | | | | | - Rodolfo R Jurado
- Departamento de Anatomía Patológica, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Rebeca Santes-Palacios
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Dora Molina-Ortiz
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Mexico City, Mexico
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Krkoška M, Svobodová J, Kabátková M, Zapletal O, Hyršlová Vaculová A, Nekvindová J, Vondráček J. Deregulation of signaling pathways controlling cell survival and proliferation in cancer cells alters induction of cytochrome P450 family 1 enzymes. Toxicology 2021; 461:152897. [PMID: 34403729 DOI: 10.1016/j.tox.2021.152897] [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: 12/30/2020] [Revised: 07/28/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
Cytochrome P450 family 1 (CYP1) enzymes contribute both to metabolism of xenobiotics and to the control of endogenous levels of ligands of the aryl hydrocarbon receptor (AhR). Their activities, similar to other CYPs, can be altered in tumor tissues. Here, we examined a possible role of proliferative/survival pathways signaling, which is often deregulated in tumor cells, and possible links with p300 histone acetyltransferase (a transcriptional co-activator) in the control of CYP1 expression, focusing particularly on CYP1A1. Using cell models derived from human liver, we observed that the induction of CYP1A1 expression, as well as other CYP1 enzymes, was reduced in exponentially growing cells, as compared with their non-dividing counterparts. The siRNA-mediated inhibition of proliferation/pro-survival signaling pathway effectors (such as β-catenin and/or Hippo pathway effectors YAP/TAZ) increased the AhR ligand-induced CYP1A1 mRNA levels in liver HepaRG cells, and/or in colon carcinoma HCT-116 cells. The activation of proliferative Wnt/β-catenin signaling in HCT-116 cells reduced both the induction of CYP1 enzymes and the binding of p300 to the promoter of CYP1A1 or CYP1B1 genes. These results seem to indicate that aberrant proliferative signaling in tumor cells could suppress induction of CYP1A1 (or other CYP1 enzymes) via competition for p300 binding. This mechanism could be involved in modulation of the metabolism of both endogenous and exogenous substrates of CYP1A1 (and other CYP1 enzymes), with possible further consequences for alterations of the AhR signaling in tumor cells, or additional functional roles of CYP1 enzymes.
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Affiliation(s)
- Martin Krkoška
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Jana Svobodová
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic
| | - Markéta Kabátková
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic
| | - Ondřej Zapletal
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic
| | - Alena Hyršlová Vaculová
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic
| | - Jana Nekvindová
- Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic.
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He K, Chen H, Cao T, Lin J. Elucidation of the Mechanisms and Molecular Targets of Shuanglian Decoction for the Treatment of Hepatocellular Carcinoma Based on Network Pharmacology. ACS OMEGA 2021; 6:917-924. [PMID: 33458543 PMCID: PMC7808160 DOI: 10.1021/acsomega.0c05550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/21/2020] [Indexed: 05/02/2023]
Abstract
Shuanglian decoction (SLD) is traditionally used to treat hepatocellular carcinoma (HCC) in the clinical practice of traditional Chinese medicine. However, its mechanisms of action and molecular targets for the treatment of HCC are not clear. The active compounds of SLD were collected and their targets were identified. HCC-related targets were obtained by analyzing the differentially expressed genes between HCC patients and healthy individuals. Protein-protein interaction (PPI) data were then obtained and PPI networks of SLD putative targets and HCC-related targets were visualized and merged to identify the candidate targets for SLD against HCC. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out. The gene-pathway network was constructed to screen the key target genes. In total, 35 active compounds and 31 targets of SLD were identified. In total, 245 differentially expressed genes with P values <0.005 and |log2 (fold change)| > 1 were identified between HCC patients and control groups, and 68 target genes associated with HCC were finally identified. Twenty-one pathways including cellular senescence, p53 signaling pathway, and cell cycle were significantly enriched. CYP3A4 was the core gene and other several genes including CYP1A2, PPP3CA, PTGS2, CCCNB1, and CDK1 were the key genes in the gene-pathway network of SLD for the treatment of HCC. The results indicated that SLD's effects against HCC may relate to the regulation of an antioxidant function through specific biological processes and related pathways. This study demonstrates the application of network pharmacology in evaluating mechanisms of action and molecular targets of complex herbal formulations.
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Affiliation(s)
- Kun He
- Hepatobiliary
Surgery, Zhongshan People’s Hospital, Zhongshan 528403, China
| | - Hua Chen
- The
Second Tumor Department, Maoming People’s
Hospital, Maoming 525000, China
| | - Tianshou Cao
- Research
Center of Guangdong Medical University, Guangdong Medical University, Dongguan 523808, China
| | - Jiantao Lin
- Research
Center of Guangdong Medical University, Guangdong Medical University, Dongguan 523808, China
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11
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Kannan S, Nallaiyan R. Anticancer Activity of Samarium-Coated Magnesium Implants for Immunocompromised Patients. ACS APPLIED BIO MATERIALS 2020; 3:4408-4416. [PMID: 35025439 DOI: 10.1021/acsabm.0c00400] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The removal of tumors in the osseous tissue leads to functional disorders. To overcome this issue, biodegradable implants are used to replace the damaged part of the system. In the study, samarium oxide was coated on the anodic layer of AZ31 magnesium alloy. The potentiodynamic polarization, electrochemical impedance, and localized electrochemical impedance spectroscopy studies were carried out for the samarium-coated magnesium alloy. The corrosion resistance of the coating improved several folds than the bare alloy. The apatite formed on the 3rd day of immersion in the simulated body fluid showed cuboid and triangular structures, whereas on the 7th day, it exhibited a sea sponge-like appearance. The coating exhibited inherent anticancer and antibacterial properties. Our work suggests that the samarium coating is expected to be a promising orthopedic implant for preventing tumor relapse and metastasis.
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Affiliation(s)
- Saranya Kannan
- Department of Chemistry, CEG Campus, Anna University, Chennai, Tamil Nadu 600 025, India
| | - Rajendran Nallaiyan
- Department of Chemistry, CEG Campus, Anna University, Chennai, Tamil Nadu 600 025, India
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12
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Trujillo-Paolillo A, Salinas-Souza C, Dias-Oliveira I, Petrilli AS, Toledo SRC. CYP Genotypes Are Associated with Toxicity and Survival in Osteosarcoma Patients. J Adolesc Young Adult Oncol 2020; 9:621-627. [PMID: 32298597 DOI: 10.1089/jayao.2019.0180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Purpose: Osteosarcoma is the malignant bone tumor most common in children and adolescents. Many cytochrome P-450 (CYP) members detoxify anticancer drugs used in osteosarcoma treatment, and thus, the aim of the present study was to investigate CYP polymorphisms in osteosarcoma patients. Methods: The present study investigated DNA from peripheral blood from 70 osteosarcoma patients treated with high doses of cisplatin, doxorubicin, and methotrexate. CYP1A2*1F (163C>A; rs762551); CYP2C9*3 (1075A>C; rs1057910); and CYP3A5*3 (6986A>G; rs776746) polymorphisms were investigated through real-time PCR using TaqMan probes. Results: The CYP2C9*3 allele did not present any association with clinical events. The CYP1A2 CC/AC genotypes were associated with ototoxicity occurrence (p = 0.041, odds ratio [OR] = 8.4) and high grades of ototoxicity (p = 0.039, OR = 10.7), when compared with patients carrying the CYP1A2 AA genotype. The CYP1A2 CC genotype was associated with high grades of diarrhea (p = 0.043, OR = 4.6) and fever (p = 0.041, OR = 7.1) in comparison with the CYP1A2 AA/AC genotypes. The CYP3A5 CC genotype was associated with weight loss (p = 0.009, OR = 3.8) and high grades of hepatotoxicity (p = 0.010, OR = 4.3) when compared with the CYP3A5 TT/CT genotypes. The CYP3A5 CC/CT genotypes were associated with high grades of vomit (p = 0.013, OR = 10.8), pulmonary relapse absence (p = 0.029, OR = 9.5), and better overall and event-free survivals (p = 0.017, hazard ratio [HR] = 3.1; p = 0.044, HR = 2.5; respectively) when compared with the CYP3A5 AA genotype. Conclusion: CYP1A2*1A and CYP3A5*3 alleles were associated with toxicity events. CYP3A5*3 allele was associated with better survival. Thus, CYP genotypes might be promising markers to tailoring treatment in osteosarcoma patients.
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Affiliation(s)
- Alini Trujillo-Paolillo
- Support Group for Children and Adolescents with Cancer (GRAACC), Pediatric Oncology Institute (IOP), Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil.,Department of Clinical and Experimental Oncology, Discipline of Hematology and Hemotherapy, Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil
| | - Carolina Salinas-Souza
- Support Group for Children and Adolescents with Cancer (GRAACC), Pediatric Oncology Institute (IOP), Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil
| | - Indhira Dias-Oliveira
- Support Group for Children and Adolescents with Cancer (GRAACC), Pediatric Oncology Institute (IOP), Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil
| | - Antônio S Petrilli
- Support Group for Children and Adolescents with Cancer (GRAACC), Pediatric Oncology Institute (IOP), Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil.,Department of Pediatrics, Discipline of Pediatric Oncology, Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil
| | - Sílvia R C Toledo
- Support Group for Children and Adolescents with Cancer (GRAACC), Pediatric Oncology Institute (IOP), Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil.,Department of Clinical and Experimental Oncology, Discipline of Hematology and Hemotherapy, Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo, Brazil
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13
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Díaz Flaqué MC, Cayrol MF, Sterle HA, Del Rosario Aschero M, Díaz Albuja JA, Isse B, Farías RN, Cerchietti L, Rosemblit C, Cremaschi GA. Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells. Oncotarget 2019; 10:3051-3065. [PMID: 31105885 PMCID: PMC6508960 DOI: 10.18632/oncotarget.26890] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Accepted: 03/23/2019] [Indexed: 01/08/2023] Open
Abstract
Thyroid hormones (THs) – 3,3′,5-triiodo-L-thyronine (T3) and L-thyroxine (T4) – are important regulators of the metabolism and physiology of most normal tissues. Cytochrome P450 family 3A members are drug metabolizing enzymes involved in the activation and detoxification of several drugs. CYP3A4 is the major enzyme involved in the metabolism of chemotherapeutic drugs. In this work, we demonstrate that THs induce a significant increase in CYP3A4 mRNA levels, protein expression and metabolic activity through the membrane receptor integrin αvβ3 and the activation of signalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4 modulation may act as an important regulator in the metabolism of doxorubicin (Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, no TH-mediated chemosensitivity to Doxo was observed. We also found that THs modulate these functions by activating the membrane receptor integrin αvβ3. In addition, we showed that the thyroid status can modulate CYP450 mRNA levels in tumor and liver tissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxo treatment in hypothyroid mice was associated with lower tumors, displaying lower levels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYP enzymes were found in livers from Doxo treated hypothyroid mice respect to control. These results present a new mechanism by which TH could modulate chemotherapy response. These findings highlight the importance of evaluating thyroid status in patients during application of T-cell lymphoma therapeutic regimens.
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Affiliation(s)
- María Celeste Díaz Flaqué
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
| | - Maria Florencia Cayrol
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
| | - Helena Andrea Sterle
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
| | - María Del Rosario Aschero
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
| | - Johanna Abigail Díaz Albuja
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
| | - Blanca Isse
- Departmento de Bioquimica Nutricional, CONICET, Universidad Nacional de Tucuman, Instituto de Quimica Biologica "Dr Bernabe Bloj", San Miguel de Tucuman, Tucuman, Argentina
| | - Ricardo Norberto Farías
- Departmento de Bioquimica Nutricional, CONICET, Universidad Nacional de Tucuman, Instituto de Quimica Biologica "Dr Bernabe Bloj", San Miguel de Tucuman, Tucuman, Argentina
| | - Leandro Cerchietti
- Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Cinthia Rosemblit
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
| | - Graciela Alicia Cremaschi
- Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
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Molina-Ortiz D, Torres-Zárate C, Cárdenas-Cardós R, Palacios-Acosta JM, Hernández-Arrazola D, Shalkow-Klincovstein J, Díaz-Díaz E, Vences-Mejía A. MDR1 not CYP3A4 gene expression is the predominant mechanism of innate drug resistance in pediatric soft tissue sarcoma patients. Cancer Biomark 2018; 22:317-324. [PMID: 29689707 DOI: 10.3233/cbm-171027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Intratumoral up-regulation of genes coding for drug transporters and metabolizing enzymes, such as MDR1 and CYP3A4, after chemotherapy are linked to cancer drug resistance. However their expression in primary soft tissue sarcomas (STS) prior to drug treatment and their role in innate resistance remain unclear. OBJECTIVE The aim of this study was characterize MDR1 and CYP3A4 expression pattern before to chemotherapy and its clinical implication in pediatric STS. METHODS In this prospective study we analyzed MDR1 and CYP3A4 mRNA expression in both normal and tumor tissues from 28 newly diagnosed STS pediatric and then compared with patients' clinical-pathological data, including chemotherapy response. RESULTS Our data showed that the expression of the MDR1 gene was significantly higher in malignant tissue than in the normal tissues of patients with STS. In addition, high MDR1 expression was significantly associated with local advances, as well as poor response to treatment. In contrast, CYP3A4 expression level was negligible in both tumoral and non-tumoral tissues. CONCLUSIONS These results suggest that a significant mRNA level of MDR1 gene was intrinsically present in STS before exposure to chemotherapeutic drugs, suggesting that MDR1 may be important contributors of innate chemoresistance of this tumor type.
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Affiliation(s)
- Dora Molina-Ortiz
- Laboratory of Genetic Toxicology, National Institute of Pediatrics, Mexico City, Mexico
| | - Carmen Torres-Zárate
- Laboratory of Genetic Toxicology, National Institute of Pediatrics, Mexico City, Mexico
| | - Rocío Cárdenas-Cardós
- Department of Pediatric Oncology, National Institute of Pediatrics, Mexico City, Mexico
| | | | | | | | - Erick Díaz-Díaz
- Laboratory of Genetic Toxicology, National Institute of Pediatrics, Mexico City, Mexico
| | - Araceli Vences-Mejía
- Laboratory of Genetic Toxicology, National Institute of Pediatrics, Mexico City, Mexico
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15
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NAT2 Gene Polymorphisms in Turkish Patients with Psoriasis Vulgaris. BIOMED RESEARCH INTERNATIONAL 2018; 2018:3258708. [PMID: 29992137 PMCID: PMC6016222 DOI: 10.1155/2018/3258708] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 04/09/2018] [Accepted: 05/06/2018] [Indexed: 12/18/2022]
Abstract
Psoriasis is a common, chronic, and autoimmune skin disease. Factors that play a role in etiopathogenesis of psoriasis include internal factors such as genetic susceptibility and immunological factors and external factors such as stress, infection, trauma, drug, and environmental compounds. N-acetyltransferase 2 (NAT2) is a xenobiotic enzyme that is involved in the metabolism of drugs, environmental toxins, and carcinogens. In this study, we aimed to demonstrate whether the variations in the NAT2 gene lead to a predisposition to psoriasis by affecting the enzyme's ability to metabolize drugs and environmental components or not. Three polymorphisms (rs1799929, rs1799930, and rs1799931) in NAT2 gene were genotyped and compared by real-time PCR method in 260 psoriasis vulgaris patients and 200 healthy controls. There was no difference in the genotype distributions and allele frequencies of polymorphisms between psoriasis vulgaris patients and controls. When the effects of polymorphisms on the clinical features of the disease, such as onset age and severity, are assessed, it has been found that rs1799930 and rs1799929 are, respectively, associated with early onset age and severity of the disease. In conclusion, rs1799929, rs1799930, and rs1799931 polymorphisms of the NAT-2 gene do not appear to be a risk factor for the development of psoriasis. Conversely, they may have an effect on either more severe or early onset cases of the disease.
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16
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Chen Y, Chen Q, Zou J, Zhang Y, Bi Z. Construction and analysis of a ceRNA‑ceRNA network reveals two potential prognostic modules regulated by hsa‑miR‑335‑5p in osteosarcoma. Int J Mol Med 2018; 42:1237-1246. [PMID: 29845268 PMCID: PMC6089708 DOI: 10.3892/ijmm.2018.3709] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 05/14/2018] [Indexed: 12/24/2022] Open
Abstract
Osteosarcoma is an aggressive cancer of the skeletal system, which is associated with a poor prognosis due to the high recurrence rate. Although previous studies have revealed that competitive endogenous RNAs (ceRNAs) are involved in various biological processes in the physiology and development of osteosarcoma, the roles of ceRNAs in osteosarcoma recurrence remain largely unexplored. The present study constructed a ceRNA-ceRNA network for osteosarcoma by systematically integrating matched expression profiles for microRNAs (miRNAs/miRs) and mRNAs, and identified two ceRNA-mediated modules that were associated with recurrence in patients with osteosarcoma. A multivariate Cox regression analysis demonstrated that the recurrence-free prognosis associated with the expression of the two modules was independent of other clinical factors. In addition, hsa-miR-335-3p was identified as an upstream regulating factor for both modules. In conclusion, the results of the present study suggested that ceRNAs may act as potential therapeutic biomarkers for predicting the recurrence of osteosarcoma, and may help to identify patients with osteosarcoma at a high risk of recurrence, who may benefit from adjuvant therapy.
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Affiliation(s)
- Yuxi Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Qinghe Chen
- Department of Orthopedics, The PLA 211 Hospital, Harbin, Heilongjiang 150080, P.R. China
| | - Jilong Zou
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yan Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhenggang Bi
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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