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1
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Zhou X, Ao X, Jia Z, Li Y, Kuang S, Du C, Zhang J, Wang J, Liu Y. Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications. Front Oncol 2022; 12:951864. [PMID: 36059609 PMCID: PMC9428469 DOI: 10.3389/fonc.2022.951864] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/02/2022] [Indexed: 12/11/2022] Open
Abstract
Cancer is one of the most frequently diagnosed malignant diseases worldwide, posing a serious, long-term threat to patients’ health and life. Systemic chemotherapy remains the first-line therapeutic approach for recurrent or metastatic cancer patients after surgery, with the potential to effectively extend patient survival. However, the development of drug resistance seriously limits the clinical efficiency of chemotherapy and ultimately results in treatment failure and patient death. A large number of studies have shown that non-coding RNAs (ncRNAs), particularly microRNAs, long non-coding RNAs, and circular RNAs, are widely involved in the regulation of cancer drug resistance. Their dysregulation contributes to the development of cancer drug resistance by modulating the expression of specific target genes involved in cellular apoptosis, autophagy, drug efflux, epithelial-to-mesenchymal transition (EMT), and cancer stem cells (CSCs). Moreover, some ncRNAs also possess great potential as efficient, specific biomarkers in diagnosis and prognosis as well as therapeutic targets in cancer patients. In this review, we summarize the recent findings on the emerging role and underlying mechanisms of ncRNAs involved in cancer drug resistance and focus on their clinical applications as biomarkers and therapeutic targets in cancer treatment. This information will be of great benefit to early diagnosis and prognostic assessments of cancer as well as the development of ncRNA-based therapeutic strategies for cancer patients.
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Affiliation(s)
- Xuehao Zhou
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Zhaojun Jia
- College of New Materials and Chemical Engineering, Beijing Key Laboratory of Enze Biomass Fine Chemicals, Beijing Institute of Petrochemical Technology, Beijing, China
| | - Yiwen Li
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Shouxiang Kuang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Chengcheng Du
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jinyu Zhang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Ying Liu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
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2
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Wang L, Zhang J, Xia M, Liu C, Zu X, Zhong J. High Mobility Group A1 (HMGA1): Structure, Biological Function, and Therapeutic Potential. Int J Biol Sci 2022; 18:4414-4431. [PMID: 35864955 PMCID: PMC9295051 DOI: 10.7150/ijbs.72952] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/24/2022] [Indexed: 11/26/2022] Open
Abstract
High mobility group A1 (HMGA1) is a nonhistone chromatin structural protein characterized by no transcriptional activity. It mainly plays a regulatory role by modifying the structure of DNA. A large number of studies have confirmed that HMGA1 regulates genes related to tumours in the reproductive system, digestive system, urinary system and haematopoietic system. HMGA1 is rare in adult cells and increases in highly proliferative cells such as embryos. After being stimulated by external factors, it will produce effects through the Wnt/β-catenin, PI3K/Akt, Hippo and MEK/ERK pathways. In addition, HMGA1 also affects the ageing, apoptosis, autophagy and chemotherapy resistance of cancer cells, which are linked to tumorigenesis. In this review, we summarize the mechanisms of HMGA1 in cancer progression and discuss the potential clinical application of targeted HMGA1 therapy, indicating that targeted HMGA1 is of great significance in the diagnosis and treatment of malignancy.
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Affiliation(s)
- Lu Wang
- Institute of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
| | - Ji Zhang
- Department of Clinical Laboratory, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong, China
| | - Min Xia
- Institute of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.,Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
| | - Chang Liu
- Department of Endocrinology and Metabolism, The First People's Hospital of Chenzhou, First School of Clinical Medicine, University of Southern Medical, Guangzhou 510515, Guangdong, China
| | - Xuyu Zu
- Institute of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.,Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
| | - Jing Zhong
- Institute of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.,Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
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3
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Szczepanek J, Skorupa M, Tretyn A. MicroRNA as a Potential Therapeutic Molecule in Cancer. Cells 2022; 11:1008. [PMID: 35326459 PMCID: PMC8947269 DOI: 10.3390/cells11061008] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/11/2022] [Accepted: 03/16/2022] [Indexed: 12/11/2022] Open
Abstract
Small noncoding RNAs, as post-translational regulators of many target genes, are not only markers of neoplastic disease initiation and progression, but also markers of response to anticancer therapy. Hundreds of miRNAs have been identified as biomarkers of drug resistance, and many have demonstrated the potential to sensitize cancer cells to therapy. Their properties of modulating the response of cells to therapy have made them a promising target for overcoming drug resistance. Several methods have been developed for the delivery of miRNAs to cancer cells, including introducing synthetic miRNA mimics, DNA plasmids containing miRNAs, and small molecules that epigenetically alter endogenous miRNA expression. The results of studies in animal models and preclinical studies for solid cancers and hematological malignancies have confirmed the effectiveness of treatment protocols using microRNA. Nevertheless, the use of miRNAs in anticancer therapy is not without limitations, including the development of a stable nanoconstruct, delivery method choices, and biodistribution. The aim of this review was to summarize the role of miRNAs in cancer treatment and to present new therapeutic concepts for these molecules. Supporting anticancer therapy with microRNA molecules has been verified in numerous clinical trials, which shows great potential in the treatment of cancer.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
| | - Monika Skorupa
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
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4
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Yun BD, Choi YJ, Son SW, Cipolla GA, Berti FCB, Malheiros D, Oh TJ, Kuh HJ, Choi SY, Park JK. Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers. Int J Mol Sci 2022; 23:ijms23020930. [PMID: 35055115 PMCID: PMC8781283 DOI: 10.3390/ijms23020930] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell-cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.
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Affiliation(s)
- Ba Da Yun
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Ye Ji Choi
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Seung Wan Son
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Gabriel Adelman Cipolla
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Fernanda Costa Brandão Berti
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Danielle Malheiros
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Tae-Jin Oh
- Department of Pharmaceutical Engineering and Biotechnology, SunMoon University, 70 Sunmoon-ro 221, Tangjeong-myeon, Asan-si 31460, Korea;
- Genome-Based BioIT Convergence Institute, 70 Sunmoon-ro 221, Tangjeong-myeon, Asan-si 31460, Korea
| | - Hyo Jeong Kuh
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Soo Young Choi
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Jong Kook Park
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
- Correspondence: ; Tel.: +82-33-248-2114
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5
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Tang SY, Zhou PJ, Meng Y, Zeng FR, Deng GT. Gastric cancer: An epigenetic view. World J Gastrointest Oncol 2022; 14:90-109. [PMID: 35116105 PMCID: PMC8790429 DOI: 10.4251/wjgo.v14.i1.90] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/17/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.
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Affiliation(s)
- Si-Yuan Tang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Pei-Jun Zhou
- Cancer Research Institute, School of Basic Medicine Science, Central South University, School of Basic Medicine Science, Central South University 410008, Hunan Province, China
| | - Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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6
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HMGA1 Has Predictive Value in Response to Chemotherapy in Gastric Cancer. Curr Oncol 2021; 29:56-67. [PMID: 35049679 PMCID: PMC8774981 DOI: 10.3390/curroncol29010005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is a serious health problem worldwide. Although its incidence is decreasing, the five-year survival rate remains low. Thus, it is essential to identify new biomarkers that could promote better diagnosis and treatment of patients with gastric cancer. High-mobility group AT-hook 1 (HMGA1) is a non-histone, chromatin-binding protein that has been found overexpressed in several tumor types. It has been correlated with invasion, metastasis, and drug resistance, leading to worse patient survival. The aim of this work was to evaluate the clinical value of HMGA1 in gastric cancer. HMGA1 expression was analyzed by immunohistochemistry in a single hospital series (n = 323) of gastric adenocarcinoma cases (stages I to IV) with clinicopathological and treatment data. In this series, HMGA1 expression showed no significant relevance as a prognostic biomarker. Nevertheless, a significantly better overall survival was observed in cases with high levels of HMGA1 when they were treated with chemotherapy, compared to the nontreated ones, implying that they can benefit more from treatment than patients with low expression of HMGA1. We thereby show for the first time that HMGA1 expression has a substantial value as a biomarker of response to chemotherapy in gastric cancer.
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7
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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8
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Wu S, Zhou Y, Liu P, Zhang H, Wang W, Fang Y, Shen X. MicroRNA-29b-3p promotes 5-fluorouracil resistance <em>via</em> suppressing TRAF5-mediated necroptosis in human colorectal cancer. Eur J Histochem 2021; 65:3247. [PMID: 34155879 PMCID: PMC8239451 DOI: 10.4081/ejh.2021.3247] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/21/2021] [Indexed: 02/07/2023] Open
Abstract
Drug resistance in colorectal cancer is a great challenge in clinic. Elucidating the deep mechanism underlying drug resistance will bring much benefit to diagnosis, therapy and prognosis in patients with colorectal cancer. In this study, miR-29b-3p was shown to be involved in resistance to 5-fluorouracil (5-FU)-induced necroptosis of colorectal cancer. Further, miR-29b-3p was shown to target a regulatory subunit of necroptosis TRAF5. Rescue of TRAF5 could reverse the effect of miR-29b-3p on 5-FU-induced necroptosis, which was consistent with the role ofnecrostatin-1 (a specific necroptosis inhibitor). Then it was demonstrated that miR-29b-3p was positively correlated with chemo-resistance in colorectal cancer while TRAF5 negatively. In conclusion, it is deduced that miR-29b-3p/TRAF5 signaling axis plays critical role in drug resistance in chemotherapy for colorectal cancer patients by regulating necroptosis. The findings in this study provide us a new target for interfere therapy in colorectal cancer.
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Affiliation(s)
- Shuimei Wu
- Department of Gastroenterology, Wuhu No.1 People's Hospital, Wuhu City.
| | - Yun Zhou
- Department of Gastroenterology, Wuhu No.1 People's Hospital, Wuhu City.
| | - Ping Liu
- Department of Gastroenterology, Wuhu No.1 People's Hospital, Wuhu City.
| | - Hui Zhang
- Department of Gastroenterology, Wuhu No.1 People's Hospital, Wuhu City.
| | - Wanliang Wang
- Department of Gastroenterology, Wuhu No.1 People's Hospital, Wuhu City.
| | - Yuan Fang
- Department of Gastroenterology, Wuhu No.1 People's Hospital, Wuhu City.
| | - Xiang Shen
- Department of Gastroenterology, Wuhu No.1 People's Hospital, Wuhu City.
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Ghafouri-Fard S, Abak A, Tondro Anamag F, Shoorei H, Fattahi F, Javadinia SA, Basiri A, Taheri M. 5-Fluorouracil: A Narrative Review on the Role of Regulatory Mechanisms in Driving Resistance to This Chemotherapeutic Agent. Front Oncol 2021; 11:658636. [PMID: 33954114 PMCID: PMC8092118 DOI: 10.3389/fonc.2021.658636] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/24/2021] [Indexed: 12/14/2022] Open
Abstract
5-fluorouracil (5-FU) is among the mostly administrated chemotherapeutic agents for a wide variety of neoplasms. Non-coding RNAs have a central impact on the determination of the response of patients to 5-FU. These transcripts via modulation of cancer-related pathways, cell apoptosis, autophagy, epithelial-mesenchymal transition, and other aspects of cell behavior can affect cell response to 5-FU. Modulation of expression levels of microRNAs or long non-coding RNAs may be a suitable approach to sensitize tumor cells to 5-FU treatment via modulating multiple biological signaling pathways such as Hippo/YAP, Wnt/β-catenin, Hedgehog, NF-kB, and Notch cascades. Moreover, there is an increasing interest in targeting these transcripts in various kinds of cancers that are treated by 5-FU. In the present article, we provide a review of the function of non-coding transcripts in the modulation of response of neoplastic cells to 5-FU.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Dental Research Center, Research Institute for Dental Sciences, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Faranak Fattahi
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, United States
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, United States
| | - Seyed Alireza Javadinia
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Abbas Basiri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wang Y, Zhang D, Li Y, Fang F. MiR-138 Suppresses the PDK1 Expression to Decrease the Oxaliplatin Resistance of Colorectal Cancer. Onco Targets Ther 2020; 13:3607-3618. [PMID: 32431512 PMCID: PMC7198439 DOI: 10.2147/ott.s242929] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/29/2020] [Indexed: 12/25/2022] Open
Abstract
Background Oxaliplatin is one kind of platinum-based drug. It is effective and commonly used in the treatment of colorectal cancer (CRC). However, development of acquired drug resistance is still a big obstacle during the oxaliplatin therapy. It is urgent to take strategies to decrease the oxaliplatin resistance of CRC. Materials and Methods Oxaliplatin-resistant HT29 and SW480 (HT29/R and SW480/R) cells were acquired through long-term exposure to oxaliplatin by using the routine HT29 and SW480 cells. Relative glucose consumption, lactate generation and LDH activity were tested to evaluate the glycolysis of CRC cell lines. MTT assays were conducted to evaluate the differences of oxaliplatin sensitivity between HT29/R (SW480/R) cells and their parental HT29 (SW480) cells. Regulation of miR-138 on PDK1 was confirmed through qRT-PCR, Western blot and dual-luciferase reporter assays. Reactive oxygen species (ROS) levels were measured by flow cytometry. Results HT29/R and SW480/R cells exhibited higher glucose consumption, lactate production and LDH activity compared to their parental HT29 and SW480 cells. However, oxygen consumption rate (OCR) in HT29/R and SW480/R cells is lower than that in HT29 and SW480 cells, respectively. Results of MTT assays showed that treatment with miR-138 can increase the cytotoxicity of oxaliplatin to HT29/R and SW480/R cells. Research on mechanisms showed that PDK1 was the target of miR-138. Overexpression of miR-138 can inhibit the expression of PDK1, and thus increase the OCR of HT29/R and SW480/R cells. Under the treatment of oxaliplatin, the miR-138-overexpressed HT29/R and SW480/R cells generated more amount of ROS to get into the apoptosis process. Conclusion Overexpression of miR-138 suppressed the PDK1 expression to decrease the oxaliplatin resistance of CRC.
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Affiliation(s)
- Yao Wang
- Inspection Institute, Jilin Medical University, Jilin City, Jilin Province 132013, People's Republic of China
| | - Duo Zhang
- Inspection Institute, Jilin Medical University, Jilin City, Jilin Province 132013, People's Republic of China
| | - Yao Li
- Inspection Institute, Jilin Medical University, Jilin City, Jilin Province 132013, People's Republic of China
| | - Fang Fang
- Inspection Institute, Jilin Medical University, Jilin City, Jilin Province 132013, People's Republic of China
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