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Rohr P, Karen S, Francisco LFV, Oliveira MA, dos Santos Neto MF, Silveira HCS. Epigenetic processes involved in response to pesticide exposure in human populations: a systematic review and meta-analysis. ENVIRONMENTAL EPIGENETICS 2024; 10:dvae005. [PMID: 38779494 PMCID: PMC11110075 DOI: 10.1093/eep/dvae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 03/27/2024] [Accepted: 04/19/2024] [Indexed: 05/25/2024]
Abstract
In recent decades, the use of pesticides in agriculture has increased dramatically. This has resulted in these substances being widely dispersed in the environment, contaminating both exposed workers and communities living near agricultural areas and via contaminated foodstuffs. In addition to acute poisoning, chronic exposure to pesticides can lead to molecular changes that are becoming better understood. Therefore, the aim of this study was to assess, through a systematic review of the literature, what epigenetic alterations are associated with pesticide exposure. We performed a systematic review and meta-analysis including case-control, cohort and cross-sectional observational epidemiological studies to verify the epigenetic changes, such as DNA methylation, histone modification and differential microRNA expression, in humans who had been exposed to any type of pesticide. Articles published between the years 2005 and 2020 were collected. Two different reviewers performed a blind selection of the studies using the Rayyan QCRI software. Post-completion, the data of selected articles were extracted and analyzed. Most of the 28 articles included evaluated global DNA methylation levels, and the most commonly reported epigenetic modification in response to pesticide exposure was global DNA hypomethylation. Meta-analysis revealed a significant negative correlation between Alu methylation levels and β-hexachlorocyclohexane, p,p'-dichlorodiphenyldichloroethane and p,p'-dichlorodiphenylethylene levels. In addition, some specific genes were reported to be hypermethylated in promoter regions, such as CDKN2AIGF2, WRAP53α and CDH1, while CDKN2B and H19 were hypomethylated due to pesticide exposure. The expression of microRNAs was also altered in response to pesticides, as miR-223, miR-518d-3p, miR-597, miR-517b and miR-133b that are associated with many human diseases. Therefore, this study provides evidence that pesticide exposure could lead to epigenetic modifications, possibly altering global and gene-specific methylation levels, epigenome-wide methylation and microRNA differential expression.
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Affiliation(s)
- Paula Rohr
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, B. Dr. Paulo Prata, Barretos, SP 14784-390, Brazil
| | - Shimoyama Karen
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, B. Dr. Paulo Prata, Barretos, SP 14784-390, Brazil
| | - Luiza Flávia Veiga Francisco
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, B. Dr. Paulo Prata, Barretos, SP 14784-390, Brazil
| | - Marco Antônio Oliveira
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, B. Dr. Paulo Prata, Barretos, SP 14784-390, Brazil
| | - Martins Fidelis dos Santos Neto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, B. Dr. Paulo Prata, Barretos, SP 14784-390, Brazil
| | - Henrique C S Silveira
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, B. Dr. Paulo Prata, Barretos, SP 14784-390, Brazil
- Campus São Paulo, University of Anhanguera, São Paulo, SP 04119-901, Brazil
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Hu X, Wang Z, Su P, Zhang Q, Kou Y. Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors. Front Oncol 2022; 12:933248. [PMID: 36147927 PMCID: PMC9485670 DOI: 10.3389/fonc.2022.933248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 08/18/2022] [Indexed: 11/15/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.
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Affiliation(s)
- Xiangchen Hu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Peng Su
- Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qiqi Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Youwei Kou
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Youwei Kou,
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Li J, Guo S, Sun Z, Fu Y. Noncoding RNAs in Drug Resistance of Gastrointestinal Stromal Tumor. Front Cell Dev Biol 2022; 10:808591. [PMID: 35174150 PMCID: PMC8841737 DOI: 10.3389/fcell.2022.808591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tracts and a model for the targeted therapy of solid tumors because of the oncogenic driver mutations in KIT and PDGDRA genes, which could be effectively inhibited by the very first targeted agent, imatinib mesylate. Most of the GIST patients could benefit a lot from the targeted treatment of this receptor tyrosine kinase inhibitor. However, more than 50% of the patients developed resistance within 2 years after imatinib administration, limiting the long-term effect of imatinib. Noncoding RNAs (ncRNAs), the non-protein coding transcripts of human, were demonstrated to play pivotal roles in the resistance of various chemotherapy drugs. In this review, we summarized the mechanisms of how ncRNAs functioning on the drug resistance in GIST. During the drug resistance of GIST, there were five regulating mechanisms where the functions of ncRNAs concentrated: oxidative phosphorylation, autophagy, apoptosis, drug target changes, and some signaling pathways. Also, these effects of ncRNAs in drug resistance were divided into two aspects. How ncRNAs regulate drug resistance in GIST was further summarized according to ncRNA types, different drugs and categories of resistance. Moreover, clinical applications of these ncRNAs in GIST chemotherapies concentrated on the prognostic biomarkers and novel therapeutic targets.
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Affiliation(s)
- Jiehan Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuning Guo
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yang Fu, ; Zhenqiang Sun,
| | - Yang Fu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
- *Correspondence: Yang Fu, ; Zhenqiang Sun,
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Stefanou IK, Dovrolis N, Gazouli M, Theodorou D, Zografos GK, Toutouzas KG. miRNAs expression pattern and machine learning models elucidate risk for gastric GIST. Cancer Biomark 2022; 33:237-247. [PMID: 35213356 DOI: 10.3233/cbm-210173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Gatrointestinal stromal tumors (GISTs) are the main mesenchymal tumors found in the gastrointestinal system. GISTs clinical phenotypes differ significantly and their molecular basis is not yet completely known. microRNAs (miRNAs) have been involved in carcinogenesis pathways by regulating gene expression at post-transcriptional level. OBJECTIVE The aim of the present study was to elucidate the expression profiles of miRNAs relevant to gastric GIST carcinogenesis, and to identify miRNA signatures that can discriminate the GIST from normal cases. METHODS miRNA expression was tested by miScript™miRNA PCR Array Human Cancer PathwayFinder kit and then we used machine learning in order to find a miRNA profile that can predict the risk for GIST development. RESULTS A number of miRNAs were found to be differentially expressed in GIST cases compared to healthy controls. Among them the hsa-miR-218-5p was found to be the best predictor for GIST development in our cohort. Additionally, hsa-miR-146a-5p, hsa-miR-222-3p, and hsa-miR-126-3p exhibit significantly lower expression in GIST cases compared to controls and were among the top predictors in all our predictive models. CONCLUSIONS A machine learning classification approach may be accurate in determining the risk for GIST development in patients. Our findings indicate that a small number of miRNAs, with hsa-miR218-5p as a focus, may strongly affect the prognosis of GISTs.
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Affiliation(s)
- Ioannis K Stefanou
- 1st Propaedeutic Department of Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- 1st Propaedeutic Department of Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolas Dovrolis
- Laboratory of Biology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
- 1st Propaedeutic Department of Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, National and Kapodistrian University of Athens, Athens, Greece
- School of Science and Technology, Hellenic Open University, Patras, Greece
| | - Dimitrios Theodorou
- 1st Propaedeutic Department of Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios K Zografos
- 1st Propaedeutic Department of Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos G Toutouzas
- 1st Propaedeutic Department of Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Angerilli V, Galuppini F, Businello G, Dal Santo L, Savarino E, Realdon S, Guzzardo V, Nicolè L, Lazzarin V, Lonardi S, Loupakis F, Fassan M. MicroRNAs as Predictive Biomarkers of Resistance to Targeted Therapies in Gastrointestinal Tumors. Biomedicines 2021; 9:318. [PMID: 33801049 PMCID: PMC8003870 DOI: 10.3390/biomedicines9030318] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
The advent of precision therapies against specific gene alterations characterizing different neoplasms is revolutionizing the oncology field, opening novel treatment scenarios. However, the onset of resistance mechanisms put in place by the tumor is increasingly emerging, making the use of these drugs ineffective over time. Therefore, the search for indicators that can monitor the development of resistance mechanisms and above all ways to overcome it, is increasingly important. In this scenario, microRNAs are ideal candidate biomarkers, being crucial post-transcriptional regulators of gene expression with a well-known role in mediating mechanisms of drug resistance. Moreover, as microRNAs are stable molecules, easily detectable in tissues and biofluids, they are the ideal candidate biomarker to identify patients with primary resistance to a specific targeted therapy and those who have developed acquired resistance. The aim of this review is to summarize the major studies that have investigated the role of microRNAs as mediators of resistance to targeted therapies currently in use in gastro-intestinal neoplasms, namely anti-EGFR, anti-HER2 and anti-VEGF antibodies, small-molecule tyrosine kinase inhibitors and immune checkpoint inhibitors. For every microRNA and microRNA signature analyzed, the putative mechanisms underlying drug resistance were outlined and the potential to be translated in clinical practice was evaluated.
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Affiliation(s)
- Valentina Angerilli
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Francesca Galuppini
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Gianluca Businello
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Luca Dal Santo
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35100 Padua, Italy;
| | - Stefano Realdon
- Istituto Oncologico Veneto (IOV-IRCCS), 35100 Padua, Italy; (S.R.); (S.L.); (F.L.)
| | - Vincenza Guzzardo
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Lorenzo Nicolè
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Vanni Lazzarin
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
| | - Sara Lonardi
- Istituto Oncologico Veneto (IOV-IRCCS), 35100 Padua, Italy; (S.R.); (S.L.); (F.L.)
| | - Fotios Loupakis
- Istituto Oncologico Veneto (IOV-IRCCS), 35100 Padua, Italy; (S.R.); (S.L.); (F.L.)
| | - Matteo Fassan
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35100 Padua, Italy; (V.A.); (F.G.); (G.B.); (L.D.S.); (V.G.); (L.N.); (V.L.)
- Istituto Oncologico Veneto (IOV-IRCCS), 35100 Padua, Italy; (S.R.); (S.L.); (F.L.)
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Amirnasr A, Sleijfer S, Wiemer EAC. Non-Coding RNAs, a Novel Paradigm for the Management of Gastrointestinal Stromal Tumors. Int J Mol Sci 2020; 21:6975. [PMID: 32972022 PMCID: PMC7555847 DOI: 10.3390/ijms21186975] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/14/2020] [Accepted: 09/16/2020] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies found in the gastrointestinal tract. At a molecular level, most GISTs are characterized by gain-of-function mutations in V-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (KIT) and Platelet Derived Growth Factor Receptor Alpha (PDGFRA), leading to constitutive activated signaling through these receptor tyrosine kinases, which drive GIST pathogenesis. In addition to surgery, treatment with the tyrosine kinase inhibitor imatinib forms the mainstay of GIST treatment, particularly in the advanced setting. Nevertheless, the majority of GISTs develop imatinib resistance. Biomarkers that indicate metastasis, drug resistance and disease progression early on could be of great clinical value. Likewise, novel treatment strategies that overcome resistance mechanisms are equally needed. Non-coding RNAs, particularly microRNAs, can be employed as diagnostic, prognostic or predictive biomarkers and have therapeutic potential. Here we review which non-coding RNAs are deregulated in GISTs, whether they can be linked to specific clinicopathological features and discuss how they can be used to improve the clinical management of GISTs.
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Affiliation(s)
| | | | - Erik A. C. Wiemer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; (A.A.); (S.S.)
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Stefanou IK, Gazouli M, Zografos GC, Toutouzas KG. Role of non-coding RNAs in pathogenesis of gastrointestinal stromal tumors. World J Meta-Anal 2020; 8:233-244. [DOI: 10.13105/wjma.v8.i3.233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/22/2020] [Accepted: 06/28/2020] [Indexed: 02/06/2023] Open
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