|
1
|
Song YJ, Kim JE, Rajbongshi L, Lim YS, Ok YJ, Hwang SY, Park HY, Lee JE, Oh SO, Kim BS, Lee D, Kim HG, Yoon S. Silencing of Epidermal Growth Factor-like Domain 8 Promotes Proliferation and Cancer Aggressiveness in Human Ovarian Cancer Cells by Activating ERK/MAPK Signaling Cascades. Int J Mol Sci 2024; 26:274. [PMID: 39796130 PMCID: PMC11720593 DOI: 10.3390/ijms26010274] [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: 11/22/2024] [Revised: 12/24/2024] [Accepted: 12/29/2024] [Indexed: 01/13/2025] Open
Abstract
Ovarian cancer (OC) is the second most common female reproductive cancer and the most lethal gynecological malignancy worldwide. Most human OCs are characterized by high rates of drug resistance and metastasis, leading to poor prognosis. Improving the outcomes of patients with relapsed and treatment-resistant OC remains a challenge. This study aimed to investigate the role of epidermal growth factor-like domain 8 (EGFL8) in human OC by examining the effects of siRNA-mediated EGFL8 knockdown on cancer progression. EGFL8 knockdown in human OC cells promoted aggressive traits associated with cancer progression, including enhanced proliferation, colony formation, migration, invasion, chemoresistance, and reduced apoptosis. Additionally, knockdown upregulated the expression of epithelial-mesenchymal transition (EMT) markers (Snail, Twist1, Zeb1, Zeb2, and vimentin) and cancer stem cell biomarkers (Oct4, Sox2, Nanog, KLF4, and ALDH1A1), and increased the expression of matrix metallopeptidases (MMP-2 and MMP-9), drug resistance genes (MDR1 and MRP1), and Notch1. Low EGFL8 expression also correlated with poor prognosis in human OC. Overall, this study provides crucial evidence that EGFL8 inhibits the proliferation and cancer aggressiveness of human OC cells by suppressing ERK/MAPK signaling. Therefore, EGFL8 may serve as a valuable prognostic biomarker and a potential target for developing novel human OC therapies.
Collapse
Affiliation(s)
- Yong-Jung Song
- Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital and Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (Y.-J.S.); (H.-G.K.)
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
| | - Ji-Eun Kim
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| | - Lata Rajbongshi
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| | - Ye-Seon Lim
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| | - Ye-Jin Ok
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| | - Seon-Yeong Hwang
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| | - Hye-Yun Park
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| | - Jin-Eui Lee
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| | - Sae-Ock Oh
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| | - Byoung-Soo Kim
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan 50612, Republic of Korea;
| | - Dongjun Lee
- Department of Convergence Medicine, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea;
| | - Hwi-Gon Kim
- Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital and Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (Y.-J.S.); (H.-G.K.)
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
| | - Sik Yoon
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
- Department of Anatomy and Convergence Medical Sciences, Pusan National University College of Medicine, Yangsan 50612, Republic of Korea; (J.-E.K.); (L.R.); (Y.-S.L.); (Y.-J.O.); (S.-Y.H.); (H.-Y.P.); (J.-E.L.)
| |
Collapse
|
|
2
|
Yu X, Zhang Y, Luo F, Zhou Q, Zhu L. The role of microRNAs in the gastric cancer tumor microenvironment. Mol Cancer 2024; 23:170. [PMID: 39164671 PMCID: PMC11334576 DOI: 10.1186/s12943-024-02084-x] [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: 06/25/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME. MAIN TEXT A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC. CONCLUSIONS miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.
Collapse
Affiliation(s)
- Xianzhe Yu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Sichuan Province, No. 10 Qinyun Nan Street, Chengdu, 610041, People's Republic of China
| | - Yin Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fengming Luo
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qinghua Zhou
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
| | - Lingling Zhu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
| |
Collapse
|
|
3
|
Molodtsova D, Guryev DV, Osipov AN. Composition of Conditioned Media from Radioresistant and Chemoresistant Cancer Cells Reveals miRNA and Other Secretory Factors Implicated in the Development of Resistance. Int J Mol Sci 2023; 24:16498. [PMID: 38003688 PMCID: PMC10671404 DOI: 10.3390/ijms242216498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/12/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Resistance to chemo- or radiotherapy is the main obstacle to consistent treatment outcomes in oncology patients. A deeper understanding of the mechanisms driving the development of resistance is required. This review focuses on secretory factors derived from chemo- and radioresistant cancer cells, cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), and cancer stem cells (CSCs) that mediate the development of resistance in unexposed cells. The first line of evidence considers the experiments with conditioned media (CM) from chemo- and radioresistant cells, CAFs, MSCs, and CSCs that elevate resistance upon the ionizing radiation or anti-cancer drug exposure of previously untreated cells. The composition of CM revealed factors such as circular RNAs; interleukins; plasminogen activator inhibitor; and oncosome-shuttled lncRNAs, mRNAs, and miRNAs that aid in cellular communication and transmit signals inducing the chemo- and radioresistance of sensitive cancer cells. Data, demonstrating that radioresistant cancer cells become resistant to anti-neoplastic drug exposure and vice versa, are also discussed. The mechanisms driving the development of cross-resistance between chemotherapy and radiotherapy are highlighted. The secretion of resistance-mediating factors to intercellular fluid and blood brings attention to its diagnostic potential. Highly stable serum miRNA candidates were proposed by several studies as prognostic markers of radioresistance; however, clinical studies are needed to validate their utility. The ability to predict a treatment response with the help of the miRNA resistance status database will help with the selection of an effective therapeutic strategy. The possibility of miRNA-based therapy is currently being investigated with ongoing clinical studies, and such approaches can be used to alleviate resistance in oncology patients.
Collapse
Affiliation(s)
- Daria Molodtsova
- N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russia;
- State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC—FMBC), 123098 Moscow, Russia;
| | - Denis V. Guryev
- State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC—FMBC), 123098 Moscow, Russia;
| | - Andreyan N. Osipov
- N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, 119991 Moscow, Russia;
- State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC—FMBC), 123098 Moscow, Russia;
- Joint Institute for Nuclear Research, 6 Joliot-Curie St., 141980 Dubna, Russia
| |
Collapse
|
|
4
|
Liu C, Li S, Tang Y. Mechanism of cisplatin resistance in gastric cancer and associated microRNAs. Cancer Chemother Pharmacol 2023; 92:329-340. [PMID: 37535106 DOI: 10.1007/s00280-023-04572-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/27/2023] [Indexed: 08/04/2023]
Abstract
Gastric cancer (GC) is a common malignant tumor with high morbidity and mortality rates that seriously affects human health worldwide. Although surgery is currently the preferred clinical treatment for GC, chemotherapy remains the first choice for perioperative treatment, adjuvant therapy, and palliative care for patients with advanced GC. Cisplatin (DDP) is an antineoplastic agent that has been used clinically for decades, and it is the first-line chemotherapy for many solid tumors. However, the therapeutic efficacy of DDP is often limited by resistance and the complexity of its resistance mechanisms, which involve multiple proteins and signaling pathways. It is well documented that a variety of microRNAs (miRNAs) differentially expressed in DDP-resistant GC cells play important roles in regulating or reversing DDP resistance via various pathways. In this review, we first provide an introduction to the cytotoxicity and major resistance mechanisms of DDP in GC and then discuss the role and mechanism of miRNAs in regulating the DDP resistance process in GC cells. This work demonstrates the potential of relevant miRNAs to become diagnostic and prognostic biomarkers for gastric cancer and targets of action to enhance chemosensitivity and provides directions for future research.
Collapse
Affiliation(s)
- Changqing Liu
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical School, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Shan Li
- Department of Pathology, People's Hospital of Shaoyang County, Hengyang, Hunan Province, People's Republic of China
| | - Yunlian Tang
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical School, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan Province, People's Republic of China.
| |
Collapse
|
|
5
|
Fathi D, Elballal MS, Elesawy AE, Abulsoud AI, Elshafei A, Elsakka EG, Ismail A, El-Mahdy HA, Elrebehy MA, Doghish AS. An emphasis on the interaction of signaling pathways highlights the role of miRNAs in the etiology and treatment resistance of gastric cancer. Life Sci 2023; 322:121667. [PMID: 37023952 DOI: 10.1016/j.lfs.2023.121667] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/07/2023]
Abstract
Gastric cancer (GC) is 4th in incidence and mortality rates globally. Several genetic and epigenetic factors, including microRNAs (miRNAs), affect its initiation and progression. miRNAs are short chains of nucleic acids that can regulate several cellular processes by controlling their gene expression. So, dysregulation of miRNAs expressions is associated with GC initiation, progression, invasion capacity, apoptosis evasions, angiogenesis, promotion and EMT enhancement. Of important pathways in GC and controlled by miRNAs are Wnt/β-catenin signaling, HMGA2/mTOR/P-gp, PI3K/AKT/c-Myc, VEGFR and TGFb signaling. Hence, this review was conducted to review an updated view of the role of miRNAs in GC pathogenesis and their modulatory effects on responses to different GC treatment modalities.
Collapse
|
|
6
|
Liu J, Lin Y, Peng C, Jiang C, Li J, Wang W, Luo S, Fu P, Lin Z, Liang Y, Shen H, Lin Y, Wei J. Bisphenol F induced hyperglycemia via activation of oxidative stress-responsive miR-200 family in the pancreas. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 255:114769. [PMID: 36924560 DOI: 10.1016/j.ecoenv.2023.114769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 03/06/2023] [Accepted: 03/09/2023] [Indexed: 06/18/2023]
Abstract
Bisphenol F (BPF), BPS and BPAF are gaining popularity as main substitutes to BPA, but there is no clear evidence that these compounds disrupt glycemic homeostasis in the same way. In this study, four bisphenols were administered to C57BL/6 J mice, and showed that the serum insulin was elevated in the BPA and BPS exposed mice, whereas BPF exposed mice exhibited lower serum insulin and higher blood glucose. BPF decreased oxidized glutathione/reduced glutathione ratio (GSSG/GSH) and N6-methyladenosine (m6A) levels, which was responsible for pancreatic apoptosis in mice. Additionally, the downregulation of Nrf2 and the aberrant regulation of the p53-lncRNA H19 signaling pathway further increased miR-200 family in the BPF-exposed pancreas. The miR-200 family directly suppressed Mettl14 and Xiap by targeting their 3' UTR, leading to islet apoptosis. Antioxidant treatment not only elevated m6A levels and insulin contents but also suppressed the miR-200 family in the pancreas, ultimately improving BPF-induced hyperglycemia. Taken together, miR-200 family could serve as a potential oxidative stress-responsive regulator in the pancreas. And moreover, we demonstrated a novel toxicological mechanism in that BPF disrupted the Keap1-Nrf2 redox system to upregulate miR-141/200b/c which controlled pancreatic insulin production and apoptosis via Mettl14 and Xiap, respectively. As the major surrogates of BPA in various applications, BPF was also diabetogenic, which warrants attention in future research.
Collapse
Affiliation(s)
- Jintao Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yilong Lin
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Cai Peng
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Chunyang Jiang
- Department of Thoracic Surgery, Tianjin Union Medical Center, Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, China
| | - Juan Li
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Wenyu Wang
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Shuyue Luo
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Pengbin Fu
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Zhenxin Lin
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Yujie Liang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Heqing Shen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Yi Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Jie Wei
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China.
| |
Collapse
|
|
7
|
Baig MS, Deepanshu, Prakash P, Alam P, Krishnan A. In silico analysis reveals hypoxia-induced miR-210-3p specifically targets SARS-CoV-2 RNA. J Biomol Struct Dyn 2023; 41:12305-12327. [PMID: 36752331 DOI: 10.1080/07391102.2023.2175255] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 01/01/2023] [Indexed: 02/09/2023]
Abstract
Human coronaviruses (HCoVs) until the emergence of SARS in 2003 were associated with mild cold and upper respiratory tract infections. The ongoing pandemic caused by SARS-CoV-2 has enhanced the potential for infection and transmission as compared to other known members of this family. MicroRNAs (miRNA) are 21-25 nucleotides long non-coding RNA that bind to 3' UTR of genes and regulate almost every aspect of cellular function. Several human miRNAs have been known to target viral genomes, mostly to downregulate their expression and sometimes to upregulate also. In some cases, host miRNAs could be sequestered by the viral genome to create a condition for favourable virus existence. The ongoing SARS CoV-2 pandemic is unique based on its transmissibility and severity and we hypothesised that there could be a unique mechanism for its pathogenesis. In this study, we exploited in silico approach to identify human respiratory system-specific miRNAs targeting the viral genome of three highly pathogenic HCoVs (SARS-CoV-2 Wuhan strain, SARS-CoV, and MERS-CoV) and three low pathogenic HCoVs (OC43, NL63, and HKU1). We identified ten common microRNAs that target all HCoVs studied here. In addition, we identified unique miRNAs which targeted specifically one particular HCoV. miR-210-3p was the single unique lung-specific miRNA, which was found to target the NSP3, NSP4, and NSP13 genes of SARS-CoV-2. Further miR-210-NSP3, miR-210-NSP4, and miR-210-NSP13 SARS-CoV-2 duplexes were docked with the hAGO2 protein (PDB ID 4F3T) which showed Z-score values of -1.9, -1.7, and -1.6, respectively. The role of miR-210-3p as master hypoxia regulator and inflammation regulation may be important for SARS-CoV-2 pathogenesis. Overall, this analysis advocates that miR-210-3p be investigated experimentally in SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
| | - Deepanshu
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
| | - Prem Prakash
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
| | - Pravej Alam
- Department of Biology, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Anuja Krishnan
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, India
| |
Collapse
|
|
8
|
Mondal P, Meeran SM. Emerging role of non-coding RNAs in resistance to platinum-based anti-cancer agents in lung cancer. Front Pharmacol 2023; 14:1105484. [PMID: 36778005 PMCID: PMC9909610 DOI: 10.3389/fphar.2023.1105484] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023] Open
Abstract
Platinum-based drugs are the first line of therapeutics against many cancers, including lung cancer. Lung cancer is one of the leading causes of cancer-related death worldwide. Platinum-based agents target DNA and prevent replication, and transcription, leading to the inhibition of cell proliferation followed by cellular apoptosis. About twenty-three platinum-based drugs are under different stages of clinical trials, among cisplatin, carboplatin, and oxaliplatin are widely used for the treatment of various cancers. Among them, cisplatin is the most commonly used drug for cancer therapy, which binds with RNA, and hinders the cellular RNA process. However, long-term use of platinum-based drugs can cause different side effects and has been shown to develop chemoresistance, leading to poor clinical outcomes. Chemoresistance became an important challenge for cancer treatment. Platinum-based chemoresistance occurs due to the influence of intrinsic factors such as overexpression of multidrug resistance proteins, advancement of DNA repair mechanism, degradation, and deactivation of intracellular thiols. Recently, epigenetic modifications, especially non-coding RNAs (ncRNAs) mediated gene regulation, grasp the attention for reversing the sensitivity of platinum-based drugs due to their reversible nature without altering genome sequence. ncRNAs can also modulate the intrinsic and non-intrinsic mechanisms of resistance in lung cancer cells. Therefore, targeting ncRNAs could be an effective approach for developing novel therapeutics to overcome lung cancer chemoresistance. The current review article has discussed the role of ncRNA in chemoresistance and its underlying molecular mechanisms in human lung cancer.
Collapse
Affiliation(s)
- Priya Mondal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Syed Musthapa Meeran
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India,*Correspondence: Syed Musthapa Meeran, ,
| |
Collapse
|
|
9
|
Köhler B, Dubovik S, Hörterer E, Wilk U, Stöckl JB, Tekarslan-Sahin H, Ljepoja B, Paulitschke P, Fröhlich T, Wagner E, Roidl A. Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification. Cancers (Basel) 2022; 14:cancers14225554. [PMID: 36428646 PMCID: PMC9688189 DOI: 10.3390/cancers14225554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
Acquired drug resistance constitutes a serious obstacle to the successful therapy of cancer. In the process of therapy resistance, microRNAs can play important roles. In order to combat resistance formation and to improve the efficacy of chemotherapeutics, the mechanisms of the multifaceted hsa-miR-200c on drug resistance were elucidated. Upon knockout of hsa-miR-200c in breast carcinoma cells, a proteomic approach identified altered expression of glutathione S-transferases (GSTs) when cells were treated with the chemotherapeutic drug doxorubicin. In different hsa-miR-200c expression systems, such as knockout, inducible sponge and inducible overexpression, the differential expression of all members of the GST family was evaluated. Expression of hsa-miR-200c in cancer cells led to the repression of a multitude of these GSTs and as consequence, enhanced drug-induced tumor cell death which was evaluated for two chemotherapeutic drugs. Additionally, the influence of hsa-miR-200c on the glutathione pathway, which is part of the phase II detoxification mechanism, was investigated. Finally, the long-term effects of hsa-miR-200c on drug efficacy were studied in vitro and in vivo. Upon doxycycline induction of hsa-miR-200c, MDA-MB 231 xenograft mouse models revealed a strongly reduced tumor growth and an enhanced treatment response to doxorubicin. A combined treatment of these tumors with hsa-miR-200c and doxorubicin resulted in complete regression of the tumor in 60% of the animals. These results identify hsa-miR-200c as an important player regulating the cellular phase II detoxification, thus sensitizing cancer cells not expressing this microRNA to chemotherapeutics and reversing drug resistance through suppression of GSTs.
Collapse
Affiliation(s)
- Bianca Köhler
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | - Sviatlana Dubovik
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | - Elisa Hörterer
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | - Ulrich Wilk
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | - Jan Bernd Stöckl
- Laboratory of Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | - Hande Tekarslan-Sahin
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | - Bojan Ljepoja
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | | | - Thomas Fröhlich
- Laboratory of Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
| | - Andreas Roidl
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany
- Correspondence: ; Tel.: +49-89-2180-77456
| |
Collapse
|
|
10
|
Todosenko N, Yurova K, Khaziakhmatova O, Malashchenko V, Khlusov I, Litvinova L. Heparin and Heparin-Based Drug Delivery Systems: Pleiotropic Molecular Effects at Multiple Drug Resistance of Osteosarcoma and Immune Cells. Pharmaceutics 2022; 14:pharmaceutics14102181. [PMID: 36297616 PMCID: PMC9612132 DOI: 10.3390/pharmaceutics14102181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/29/2022] [Accepted: 10/10/2022] [Indexed: 11/23/2022] Open
Abstract
One of the main problems of modern health care is the growing number of oncological diseases both in the elderly and young population. Inadequately effective chemotherapy, which remains the main method of cancer control, is largely associated with the emergence of multidrug resistance in tumor cells. The search for new solutions to overcome the resistance of malignant cells to pharmacological agents is being actively pursued. Another serious problem is immunosuppression caused both by the tumor cells themselves and by antitumor drugs. Of great interest in this context is heparin, a biomolecule belonging to the class of glycosaminoglycans and possessing a broad spectrum of biological activity, including immunomodulatory and antitumor properties. In the context of the rapid development of the new field of “osteoimmunology,” which focuses on the collaboration of bone and immune cells, heparin and delivery systems based on it may be of intriguing importance for the oncotherapy of malignant bone tumors. Osteosarcoma is a rare but highly aggressive, chemoresistant malignant tumor that affects young adults and is characterized by constant recurrence and metastasis. This review describes the direct and immune-mediated regulatory effects of heparin and drug delivery systems based on it on the molecular mechanisms of (multiple) drug resistance in (onco) pathological conditions of bone tissue, especially osteosarcoma.
Collapse
Affiliation(s)
- Natalia Todosenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Kristina Yurova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Olga Khaziakhmatova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Vladimir Malashchenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Igor Khlusov
- Department of Morphology and General Pathology, Siberian State Medical University, 634050 Tomsk, Russia
| | - Larisa Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
- Correspondence:
| |
Collapse
|
|
11
|
Zhang X, Luo M, Zhang J, Guo B, Singh S, Lin X, Xiong H, Ju S, Wang L, Zhou Y, Zhou J. The role of lncRNA H19 in tumorigenesis and drug resistance of human Cancers. Front Genet 2022; 13:1005522. [PMID: 36246634 PMCID: PMC9555214 DOI: 10.3389/fgene.2022.1005522] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022] Open
Abstract
Systemic therapy is one of the most significant cancer treatments. However, drug resistance often appears and has become the primary cause of cancer therapy failure. Regulation of drug target, drug metabolism and drug efflux, cell death escape (apoptosis, autophagy, et al.), epigenetic changes, and many other variables are complicatedly involved in the mechanisms of drug resistance. In various types of cancers, long non-coding RNA H19 (lncRNA H19) has been shown to play critical roles in tumor development, proliferation, metastasis, and multiple drug resistance as well. The efficacy of chemotherapy, endocrine therapy, and targeted therapy are all influenced by the expression of H19, especially in breast cancer, liver cancer, lung cancer and colorectal cancer. Here, we summarize the relationship between lncRNA H19 and tumorigenesis, and illustrate the drug resistance mechanisms caused by lncRNA H19 as well. This review may provide more therapeutic potential targets for future cancer treatments.
Collapse
Affiliation(s)
- Xun Zhang
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Mingpeng Luo
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiahang Zhang
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Bize Guo
- Zhejiang University School of Medicine, Hangzhou, China
| | - Shreya Singh
- Zhejiang University School of Medicine, Hangzhou, China
| | - Xixi Lin
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Hanchu Xiong
- Zhejiang University School of Medicine, Hangzhou, China
| | - Siwei Ju
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Linbo Wang
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- *Correspondence: Linbo Wang, ; Yulu Zhou, ; Jichun Zhou,
| | - Yulu Zhou
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- *Correspondence: Linbo Wang, ; Yulu Zhou, ; Jichun Zhou,
| | - Jichun Zhou
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- *Correspondence: Linbo Wang, ; Yulu Zhou, ; Jichun Zhou,
| |
Collapse
|
|
12
|
Chen Y, Li X, Shi L, Ma P, Wang W, Wu N, Gan Y, Han X, Huang S, Kang X, Liu S, Zhen Y. Combination of 7- O-geranylquercetin and microRNA-451 enhances antitumor effect of Adriamycin by reserving P-gp-mediated drug resistance in breast cancer. Aging (Albany NY) 2022; 14:7156-7169. [PMID: 36107024 PMCID: PMC9512499 DOI: 10.18632/aging.204287] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 09/05/2022] [Indexed: 11/30/2022]
Abstract
Although there are a lot of chemical drugs to treat breast cancer, increasing drug resistance of cancer cells has strongly hindered the effectiveness of chemotherapy. ATP-binding cassette transporters represented by P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) play an important role in drug resistance. This study aims to investigate the effect of 7-O-geranylquercetin (GQ) combining microRNA-451(miR-451) on reversing drug resistance of breast cancer and reveal the mechanism related to P-gp. Real-time RT-PCR and western blot assays showed that miR-326, miR-328, miR-451 and miR-155 inhibitor down-regulated the expression of genes MRP1, BCRP, MDR1 and the corresponding proteins MRP1, BCRP, P-gp, respectively. Cell counting kit-8 (CCK-8) assay indicated that these miRNAs reversed the resistance of MCF-7/ADR cells to Adriamycin (ADR), and miR-451 showed the greatest reversal effect. Combination of GQ and miR-451 enhanced the inhibitory effects of ADR on the proliferation and migration of MCF-7/ADR cells, and attenuated the expression of MDR1 and P-gp in MCF-7/ADR cells. A xenograft tumor model was used to show that GQ and miR-451 amplified the antitumor effect of ADR in nude mice, while western blot and immunohistochemical assays revealed the decreased expression of P-gp in tumor tissues. These results suggest that GQ and miR-451 have synergistic effect on reversing drug resistance through reducing the expression of MDR1 and P-gp in breast cancer MCF-7/ADR cells.
Collapse
MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Animals
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Cell Line, Tumor
- Doxorubicin/pharmacology
- Doxorubicin/therapeutic use
- Drug Resistance, Neoplasm/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Mice
- Mice, Nude
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Multidrug Resistance-Associated Proteins/genetics
- Multidrug Resistance-Associated Proteins/metabolism
- Multidrug Resistance-Associated Proteins/pharmacology
- Neoplasm Proteins/metabolism
- Quercetin/analogs & derivatives
Collapse
Affiliation(s)
- Yuling Chen
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Xiaohong Li
- Affiliated Dalian Friendship Hospital of Dalian Medical University, Dalian 116001, China
| | - Lei Shi
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Pengfei Ma
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Wei Wang
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Nan Wu
- The First Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Youlin Gan
- The Second Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xu Han
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Shanshan Huang
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Xiaohui Kang
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Shuxin Liu
- Affiliated Dalian Municipal Central Hospital of Dalian Medical University, Dalian 116033, China
- Dalian Key Laboratory of Intelligent Blood Purification, Dalian 116033, China
| | - Yuhong Zhen
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| |
Collapse
|
|
13
|
Konoshenko M, Lansukhay Y, Krasilnikov S, Laktionov P. MicroRNAs as Predictors of Lung-Cancer Resistance and Sensitivity to Cisplatin. Int J Mol Sci 2022; 23:7594. [PMID: 35886942 PMCID: PMC9321818 DOI: 10.3390/ijms23147594] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Platinum-based chemotherapy, cisplatin (DDP) specifically, is the main strategy for treating lung cancer (LC). However, currently, there is a lack of predictive drug-resistance markers, and there is increased interest in the development of a reliable and sensitive panels of markers for DDP chemotherapy-effectiveness prediction. MicroRNAs represent a perspective pool of markers for chemotherapy effectiveness. OBJECTIVES Data on miRNAs associated with LC DDP chemotherapy response are summarized and analyzed. MATERIALS AND METHODS A comprehensive review of the data in the literature and an analysis of bioinformatics resources were performed. The gene targets of miRNAs, as well as their reciprocal relationships with miRNAs, were studied using several databases. RESULTS AND DISCUSSION The complex analysis of bioinformatics resources and the literature indicated that the expressions of 12 miRNAs have a high predictive potential for LC DDP chemotherapy responses. The obtained information was discussed from the point of view of the main mechanisms of LC chemoresistance. CONCLUSIONS An overview of the published data and bioinformatics resources, with respect to the predictive microRNA markers of chemotherapy response, is presented in this review. The selected microRNAs and gene panel have a high potential for predicting LC DDP sensitiveness or DDP resistance as well as for the development of a DDP co-therapy.
Collapse
Affiliation(s)
- Maria Konoshenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, 630090 Novosibirsk, Russia;
- Meshalkin Siberian Federal Biomedical Research Center, Ministry of Public Health of the Russian Federation, 630055 Novosibirsk, Russia; (Y.L.); (S.K.)
| | - Yuriy Lansukhay
- Meshalkin Siberian Federal Biomedical Research Center, Ministry of Public Health of the Russian Federation, 630055 Novosibirsk, Russia; (Y.L.); (S.K.)
| | - Sergey Krasilnikov
- Meshalkin Siberian Federal Biomedical Research Center, Ministry of Public Health of the Russian Federation, 630055 Novosibirsk, Russia; (Y.L.); (S.K.)
| | - Pavel Laktionov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, 630090 Novosibirsk, Russia;
- Meshalkin Siberian Federal Biomedical Research Center, Ministry of Public Health of the Russian Federation, 630055 Novosibirsk, Russia; (Y.L.); (S.K.)
| |
Collapse
|
|
14
|
Loren P, Saavedra N, Saavedra K, De Godoy Torso N, Visacri MB, Moriel P, Salazar LA. Contribution of MicroRNAs in Chemoresistance to Cisplatin in the Top Five Deadliest Cancer: An Updated Review. Front Pharmacol 2022; 13:831099. [PMID: 35444536 PMCID: PMC9015654 DOI: 10.3389/fphar.2022.831099] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/16/2022] [Indexed: 12/02/2022] Open
Abstract
Cisplatin (DDP) is a well-known anticancer drug used for the treatment of numerous human cancers in solid organs, including bladder, breast, cervical, head and neck squamous cell, ovarian, among others. Its most important mode of action is the DNA-platinum adducts formation, inducing DNA damage response, silencing or activating several genes to induce apoptosis; these mechanisms result in genetics and epigenetics modifications. The ability of DDP to induce tumor cell death is often challenged by the presence of anti-apoptotic regulators, leading to chemoresistance, wherein many patients who have or will develop DDP-resistance. Cancer cells resist the apoptotic effect of chemotherapy, being a problem that severely restricts the successful results of treatment for many human cancers. In the last 30 years, researchers have discovered there are several types of RNAs, and among the most important are non-coding RNAs (ncRNAs), a class of RNAs that are not involved in protein production, but they are implicated in gene expression regulation, and representing the 98% of the human genome non-translated. Some ncRNAs of great interest are long ncRNAs, circular RNAs, and microRNAs (miRs). Accumulating studies reveal that aberrant miRs expression can affect the development of chemotherapy drug resistance, by modulating the expression of relevant target proteins. Thus, identifying molecular mechanisms underlying chemoresistance development is fundamental for setting strategies to improve the prognosis of patients with different types of cancer. Therefore, this review aimed to identify and summarize miRs that modulate chemoresistance in DDP-resistant in the top five deadliest cancer, both in vitro and in vivo human models.
Collapse
Affiliation(s)
- Pía Loren
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco, Chile
| | - Nicolás Saavedra
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco, Chile
| | - Kathleen Saavedra
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco, Chile
| | | | | | - Patricia Moriel
- Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil
| | - Luis A Salazar
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco, Chile
| |
Collapse
|
|
15
|
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.
Collapse
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
| |
Collapse
|
|
16
|
Du J, Ji Q, Dong L, Meng Y, Xin G. Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs)-Derived MicroRNA-378a-3p (miR-378a-3p) Inhibits the Migration of Gestational Trophoblast Cells and Epithelial Mesenchymal Transition via Regulating X-Linked Inhibitor of Apoptosis Protein (XIAP) Pathway. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The components of the in vivo microenvironment are BMSCs and miRNAs that have a critical role in the development of pregnancy. Our aim was to further investigate the effect of the miRNAs of BMSC origin on pregnancy injury. Exosomal miR-378a-3p secreted by BMSCs was identified
by electron microscopy and miR-378a-3p expression was measured during gestational injury. Target scan detects the correlation of XIAP and miR-378a-3p which was confirmed by luciferase activity along with analysis of cell growth by MTT assay and cell invasion by Transwell and EMT expression.
Exosomal miR-378a-3p derived from BMSCs promoted proliferation and migration and invasion of trophoblast. miR-378a-3p targeted XIAP and its overexpression could significantly increase EMT switching. The miR-378a-3p/XIAP axis is critical in trophoblastic cell migration and EMT and is involved
in pregnancy injury progression, indicating that it might be a novel potential target for the treatment of pregnancy injury.
Collapse
Affiliation(s)
- Juan Du
- Department of Obstetrics, Women and Children’s Hospital of Jinan, Jinan, Shandong, 250001, China
| | - Qinghong Ji
- Department of Obstetrics, The Second Hospital of Shandong University, Jinan, Shandong, 250031, China
| | - Lihua Dong
- Department of Obstetrics, The Second Hospital of Shandong University, Jinan, Shandong, 250031, China
| | - Yanping Meng
- Department of Obstetrics, The Second Hospital of Shandong University, Jinan, Shandong, 250031, China
| | - Gang Xin
- Department of Obstetrics, The Second Hospital of Shandong University, Jinan, Shandong, 250031, China
| |
Collapse
|
|
17
|
Ramorola BR, Goolam-Hoosen T, Alves de Souza Rios L, Mowla S. Modulation of Cellular MicroRNA by HIV-1 in Burkitt Lymphoma Cells-A Pathway to Promoting Oncogenesis. Genes (Basel) 2021; 12:genes12091302. [PMID: 34573283 PMCID: PMC8468732 DOI: 10.3390/genes12091302] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/12/2021] [Accepted: 08/20/2021] [Indexed: 11/16/2022] Open
Abstract
Viruses and viral components have been shown to manipulate the expression of host microRNAs (miRNAs) to their advantage, and in some cases to play essential roles in cancer pathogenesis. Burkitt lymphoma (BL), a highly aggressive B-cell derived cancer, is significantly over-represented among people infected with HIV. This study adds to accumulating evidence demonstrating that the virus plays a direct role in promoting oncogenesis. A custom miRNA PCR was used to identify 32 miRNAs that were differently expressed in Burkitt lymphoma cells exposed to HIV-1, with a majority of these being associated with oncogenic processes. Of those, hsa-miR-200c-3p, a miRNA that plays a crucial role in cancer cell migration, was found to be significantly downregulated in both the array and in single-tube validation assays. Using an in vitro transwell system we found that this downregulation correlated with significantly enhanced migration of BL cells exposed to HIV-1. Furthermore, the expression of the ZEB1 and ZEB2 transcription factors, which are promotors of tumour invasion and metastasis, and which are direct targets of hsa-miR-200c-3p, were found to be enhanced in these cells. This study therefore identifies novel miRNAs as role players in the development of HIV-associated BL, with one of these miRNAs, hsa-miR-200c-3p, being a candidate for further clinical studies as a potential biomarker for prognosis in patients with Burkitt lymphoma, who are HIV positive.
Collapse
|
|
18
|
Dan VM, Raveendran RS, Baby S. Resistance to Intervention: Paclitaxel in Breast Cancer. Mini Rev Med Chem 2021; 21:1237-1268. [PMID: 33319669 DOI: 10.2174/1389557520999201214234421] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/22/2020] [Accepted: 11/02/2020] [Indexed: 12/22/2022]
Abstract
Breast cancer stands as the most prevalent cancer in women globally, and contributes to the highest percentage of mortality due to cancer-related deaths in women. Paclitaxel (PTX) is heavily relied on as a frontline chemotherapy drug in breast cancer treatment, especially in advanced metastatic cancer. Generation of resistance to PTX often derails clinical management and adversely affects patient outcomes. Understanding the molecular mechanism of PTX resistance is necessary to device methods to aid in overcoming the resistance. Recent studies exploring the mechanism of development of PTX resistance have led to unveiling of a range novel therapeutic targets. PTX resistance pathways that involve major regulatory proteins/RNAs like RNF8/Twist/ROR1, TLR, ErbB3/ErbB2, BRCA1- IRIS, MENA, LIN9, MiRNA, FoxM1 and IRAK1 have expanded the complexity of resistance mechanisms, and brought newer insights into the development of drug targets. These resistance-related targets can be dealt with synthetic/natural therapeutics in combination with PTX. The present review encompasses the recent understanding of PTX resistance mechanisms in breast cancer and possible therapeutic combinations to overcome resistance.
Collapse
Affiliation(s)
- Vipin Mohan Dan
- Microbiology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Pacha-Palode 695562, Thiruvananthapuram, Kerala, India
| | - Reji Saradha Raveendran
- Microbiology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Pacha-Palode 695562, Thiruvananthapuram, Kerala, India
| | - Sabulal Baby
- Phytochemistry and Phytopharmacology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Pacha-Palode 695562, Thiruvananthapuram, Kerala, India
| |
Collapse
|
|
19
|
Zhou C, Chen L, Chen R, Xu F, Huang Z, Huang R, Wang W, Xu Q. miR-4486 enhances cisplatin sensitivity of gastric cancer cells by restraining the JAK3/STAT3 signalling pathway. J Chemother 2021; 34:35-44. [PMID: 34167436 DOI: 10.1080/1120009x.2021.1936957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Along with the occurrence of cisplatin resistance, treatment on gastric cancer (GC) becomes difficult. Therefore, researches on new therapeutic methods to revert cisplatin resistance are becoming increasingly urgent. qRT-PCR was used to quantify the expression of miR-4486, JAK3 in SGC-7901 or SGC-7901/DDP cell lines. WB was utilized to analyze the expression of JAK3, STAT3 and p-STAT3 in SGC-7901/DDP cell lines. CCK-8 assay was used to determine the IC50 of cisplatin on both cell lines and cell viability of SGC-7901/DDP cell lines. The target relationship between miR-4486 and JAK3 was determined by luciferase assay. MiR-4486 expression on apoptosis of SGC-7901/DDP cell lines was determined by flow cytometry. qRT-PCR testified that miR-4486 decreased in SGC-7901/DDP cells, and the expression of miR-4486 mimic increased significantly compared with miR-4486 NC. By CCK-8 assay, the IC50 of cisplatin on both cell lines were 9 μg/mL and 81.3 μg/mL, and overexpression of miR-4486 decreased the viability of SGC-7901/DDP cells. Compared with DDP group, the expression of miR-4486 accelerated SGC-7901/DDP cells apoptosis. Dual-luciferase assay suggested that JAK3 was the target gene of miR-4486. qRT-PCR and WB proved that miR-4486/JAK3 axis inhibit the activation of JAK3/STAT3 pathway, and JAK3 overexpression can partly reverse this. As shown by CCK-8 and flow cytometry, miR-4486 overexpression decreased viability and stimulated apoptosis of SGC-7901/DDP cells. However, JAK3 overexpression can also partly revert this. miR-4486 overexpression could decrease viability and improve apoptosis of SGC-7901/DDP cells to revert its cisplatin-resistance, and the mechanism may be related to JAK3/STAT3 signalling pathway.
Collapse
Affiliation(s)
- Caijin Zhou
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Linxia Chen
- Department of Operating Room, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Rihong Chen
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Feipeng Xu
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Zhe Huang
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Renwei Huang
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Weiwei Wang
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Qingwen Xu
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| |
Collapse
|
|
20
|
Carrella S, Massa F, Indrieri A. The Role of MicroRNAs in Mitochondria-Mediated Eye Diseases. Front Cell Dev Biol 2021; 9:653522. [PMID: 34222230 PMCID: PMC8249810 DOI: 10.3389/fcell.2021.653522] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/20/2021] [Indexed: 12/15/2022] Open
Abstract
The retina is among the most metabolically active tissues with high-energy demands. The peculiar distribution of mitochondria in cells of retinal layers is necessary to assure the appropriate energy supply for the transmission of the light signal. Photoreceptor cells (PRs), retinal pigment epithelium (RPE), and retinal ganglion cells (RGCs) present a great concentration of mitochondria, which makes them particularly sensitive to mitochondrial dysfunction. To date, visual loss has been extensively correlated to defective mitochondrial functions. Many mitochondrial diseases (MDs) show indeed neuro-ophthalmic manifestations, including retinal and optic nerve phenotypes. Moreover, abnormal mitochondrial functions are frequently found in the most common retinal pathologies, i.e., glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), that share clinical similarities with the hereditary primary MDs. MicroRNAs (miRNAs) are established as key regulators of several developmental, physiological, and pathological processes. Dysregulated miRNA expression profiles in retinal degeneration models and in patients underline the potentiality of miRNA modulation as a possible gene/mutation-independent strategy in retinal diseases and highlight their promising role as disease predictive or prognostic biomarkers. In this review, we will summarize the current knowledge about the participation of miRNAs in both rare and common mitochondria-mediated eye diseases. Definitely, given the involvement of miRNAs in retina pathologies and therapy as well as their use as molecular biomarkers, they represent a determining target for clinical applications.
Collapse
Affiliation(s)
| | - Filomena Massa
- Telethon Institute of Genetics and Medicine, Naples, Italy
| | - Alessia Indrieri
- Telethon Institute of Genetics and Medicine, Naples, Italy.,Institute for Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy
| |
Collapse
|
|
21
|
Karimi F, Mollaei H. Potential of miRNAs in cervical cancer chemoresistance. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
|
|
22
|
Sun J, Wang X, Zhang Z, Zeng Z, Ouyang S, Kang W. The Sensitivity Prediction of Neoadjuvant Chemotherapy for Gastric Cancer. Front Oncol 2021; 11:641304. [PMID: 33937042 PMCID: PMC8085495 DOI: 10.3389/fonc.2021.641304] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/22/2021] [Indexed: 12/24/2022] Open
Abstract
The overall efficacy of neoadjuvant chemoradiotherapy (NACT) for locally advanced gastric cancer (LAGC) has been recognized. However, the response rate of NACT is limited due to tumor heterogeneity. For patients who are resistant to NACT, not only the operation timing will be postponed, patients will also suffer from the side effects of it. Thus, it is important to develop a comprehensive strategy and screen out patients who may be sensitive to NACT. This article summarizes the related research progress on the sensitivity prediction of NACT for GC in the following aspects: microRNAs, metabolic enzymes, exosomes, other biomarkers; inflammatory indicators, and imageological assessments. The results showed that there were many studies on biomarkers, but no unified conclusion has been drawn. The inflammatory indicators are related to the survival and prognosis of patients under NACT. For imageological assessments such as CT, MRI, and PET, with careful integration and optimization, they will have unique advantages in early screening for patients who are sensitive to NACT.
Collapse
Affiliation(s)
- Juan Sun
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Xianze Wang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Zimu Zhang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Ziyang Zeng
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Siwen Ouyang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Weiming Kang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital (CAMS), Beijing, China
| |
Collapse
|
|
23
|
MacDonagh L, Gallagher MF, Ffrench B, Gasch C, Gray SG, Reidy M, Nicholson S, Leonard N, Ryan R, Young V, O'Leary JJ, Cuffe S, Finn SP, O'Byrne KJ, Barr MP. MicroRNA expression profiling and biomarker validation in treatment-naïve and drug resistant non-small cell lung cancer. Transl Lung Cancer Res 2021; 10:1773-1791. [PMID: 34012792 PMCID: PMC8107736 DOI: 10.21037/tlcr-20-959] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Background In the absence of targetable mutations or immune checkpoints, cisplatin-doublet chemotherapy remains the standard of care in non-small cell lung cancer (NSCLC). Drug resistance has however become a significant clinical challenge. Exploring a role for small non-coding microRNAs (miRNA) as biomarker candidates in cisplatin resistant (CisR) lung cancer is lacking and warrants further investigation. Methods miRNA expression profiling was assessed in a panel of cisplatin sensitive and resistant NSCLC cell lines and validated by qPCR. Modulation of altered miRNAs was studied using antagomiRs and pre-miRs while functional assays were used to assess cisplatin response. The translational relevance of these miRNAs as potential biomarkers was assessed in serum and matched normal and tumour lung tissues from chemo-naïve NSCLC patients, in addition to xenograft formalin-fixed paraffin-embedded (FFPE) tumours derived from cisplatin sensitive and resistant cell lines. Results Differential expression of a 5-miR signature (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286) demonstrated their ability to distinguish between normal and tumour lung tissue and between NSCLC histologies. In squamous cell carcinoma (SqCC), tissue miRNA expression was associated with poor survival. miR-4286 showed promise as a blood-based diagnostic biomarker that could distinguish between adenocarcinoma and SqCC histologies. In a xenograft model of cisplatin resistance, using 7-9 week old female NOD/SCID mice (NOD.CB17-Prkdcscid/NCrCrl), a 5-miRNA panel showed altered expression between sensitive and resistant tumours. Conclusions This study identified a panel of miRNAs which may have diagnostic and prognostic potential as novel biomarkers in lung cancer and furthermore, may have a predictive role in monitoring the emergence of resistance to cisplatin.
Collapse
Affiliation(s)
- Lauren MacDonagh
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland
| | - Michael F Gallagher
- Histopathology Department, Sir Patrick Dun Laboratories, Central Pathology Laboratory, St. James's Hospital & Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland
| | - Brendan Ffrench
- Histopathology Department, Sir Patrick Dun Laboratories, Central Pathology Laboratory, St. James's Hospital & Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland
| | - Claudia Gasch
- Histopathology Department, Sir Patrick Dun Laboratories, Central Pathology Laboratory, St. James's Hospital & Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland
| | - Steven G Gray
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland
| | - Marie Reidy
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | | | - Niamh Leonard
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Ronan Ryan
- Department of Cardiothoracic Surgery, St. James's Hospital, Dublin, Ireland
| | - Vincent Young
- Department of Cardiothoracic Surgery, St. James's Hospital, Dublin, Ireland
| | - John J O'Leary
- Histopathology Department, Sir Patrick Dun Laboratories, Central Pathology Laboratory, St. James's Hospital & Pathology Research Laboratory, Coombe Women and Infant's University Hospital, Dublin, Ireland
| | - Sinead Cuffe
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland.,Department of Medical Oncology, St James's Hospital, Dublin, Ireland
| | - Stephen P Finn
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland.,Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Kenneth J O'Byrne
- Cancer & Ageing Research Program, Queensland University of Technology, Brisbane, Australia
| | - Martin P Barr
- Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland
| |
Collapse
|
|
24
|
Budakoti M, Panwar AS, Molpa D, Singh RK, Büsselberg D, Mishra AP, Coutinho HDM, Nigam M. Micro-RNA: The darkhorse of cancer. Cell Signal 2021; 83:109995. [PMID: 33785398 DOI: 10.1016/j.cellsig.2021.109995] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 12/21/2022]
Abstract
The discovery of micro RNAs (miRNA) in cancer has opened up new vistas for researchers in recent years. Micro RNAs area set of small, endogenous, highly conserved, non-coding RNAs that control the expression of about 30% genes at post-transcriptional levels. Typically, microRNAs impede the translation and stability of messenger RNAs (mRNA), control genes associated with cellular processes namely inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and migration. Compelling findings revealed that miRNA mutations or disruption correspond to diverse human cancers and suggest that miRNAs can function as tumor suppressors or oncogenes. Here we summarize the literature on these master regulators in clinical settings from last three decades as both abrupt cancer therapeutics and as an approach to sensitize tumors to chemotherapy. This review highlights (I) the prevailing perception of miRNA genomics, biogenesis, as well as function; (II) the significant advancements in regulatory mechanisms in the expression of carcinogenic genes; and (III) explains, how miRNA is utilized as a diagnostic and prognostic biomarker for the disease stage indicating survival as well as therapeutic targets in cancer.
Collapse
Affiliation(s)
- Mridul Budakoti
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Abhay Shikhar Panwar
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Diksha Molpa
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Rahul Kunwar Singh
- Department of Microbiology, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| | - Abhay Prakash Mishra
- Department of Pharmaceutical Chemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India.
| | | | - Manisha Nigam
- Department of Biochemistry, H. N. B. Garhwal University, Srinagar Garhwal 246174, Uttarakhand, India.
| |
Collapse
|
|
25
|
Singh S, Raza W, Parveen S, Meena A, Luqman S. Flavonoid display ability to target microRNAs in cancer pathogenesis. Biochem Pharmacol 2021; 189:114409. [PMID: 33428895 DOI: 10.1016/j.bcp.2021.114409] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are non-coding, conserved, single-stranded nucleotide sequences involved in physiological and developmental processes. Recent evidence suggests an association between miRNAs' deregulation with initiation, promotion, progression, and drug resistance in cancer cells. Besides, miRNAs are known to regulate the epithelial-mesenchymal transition, angiogenesis, autophagy, and senescence in different cancer types. Previous reports proposed that apart from the antioxidant potential, flavonoids play an essential role in miRNAs modulation associated with changes in cancer-related proteins, tumor suppressor genes, and oncogenes. Thus, flavonoids can suppress proliferation, help in the development of drug sensitivity, suppress metastasis and angiogenesis by modulating miRNAs expression. In the present review, we summarize the role of miRNAs in cancer, drug resistance, and the chemopreventive potential of flavonoids mediated by miRNAs. The potential of flavonoids to modulate miRNAs expression in different cancer types demonstrate their selectivity and importance as regulators of carcinogenesis. Flavonoids as chemopreventive agents targeting miRNAs are extensively studied in vitro, in vivo, and pre-clinical studies, but their efficiency in targeting miRNAs in clinical studies is less investigated. The evidence presented in this review highlights the potential of flavonoids in cancer prevention/treatment by regulating miRNAs, although further investigations are required to validate and establish their clinical usefulness.
Collapse
Affiliation(s)
- Shilpi Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Waseem Raza
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Jawahar Lal Nehru University, New Delhi 110067, India
| | - Shahnaz Parveen
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
| |
Collapse
|
|
26
|
Lu H, Zhang Q, Sun Y, Wu D, Liu L. LINC00689 induces gastric cancer progression via modulating the miR-338-3p/HOXA3 axis. J Gene Med 2020; 22:e3275. [PMID: 32926751 DOI: 10.1002/jgm.3275] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/08/2020] [Accepted: 08/29/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND LINC00689 acts one critical regulatory role in several tumors. However, the functional, regulatory mechanism and expression of LINC00689 remains unknown in gastric cancer. METHODS LINC00689 and miR-338-3p levels were determined using a quantitative reverse transcriptase-polymerase chain reaction analysis and an enzyme-linked immunoassay and a cell-counting kit-8 assay were utilized to detect interleukin (IL)-8, IL-6 and IL-1β expression and cell proliferation, respectively. RESULTS We found that LINC00689 and HOXA3 are overexpressed and miR-338-3p is decreased in gastric cancer cells. Compared to control specimens, LINC00689 is overexpressed in gastric cancer specimens and the level of LINC00689 was up-regulated in 32 cases (32/40; 80.0%) compared to control samples. LINC00689 increased cell growth, epithelial-mesenchymal transition (EMT) development and secretion of inflammatory factors in gastric cancer. Compared to control specimens, miR-338-3p expression was decreased in gastric cancer specimens and a Pearson's correlation assay revealed that miR-338-3p was negatively correlated with LINC00689 expression in gastric cancer specimens. HOXA3 was identified as one target gene of miR-338-3p and Ectopic expression of LINC00689 suppressed miR-338-3p and enhanced HOXA3 expression in HGC-27 cells. LINC00689 enhanced cell growth, EMT development and secretion of inflammatory factors by promoting HOXA3. CONCLUSIONS LINC00689 may present a potential future target for gastric cancer treatment.
Collapse
Affiliation(s)
- Hui Lu
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| | - Qian Zhang
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| | - Yaqiong Sun
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| | - Dedong Wu
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| | - Liying Liu
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| |
Collapse
|
|
27
|
Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals. Molecules 2020; 25:molecules25204701. [PMID: 33066509 PMCID: PMC7587345 DOI: 10.3390/molecules25204701] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/08/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer is a global health concern and one of the main causes of disease-related death. Even with considerable progress in investigations on cancer therapy, effective anti-cancer agents and regimens have thus far been insufficient. There has been compelling evidence that natural phytochemicals and their derivatives have potent anti-cancer activities. Plant-based anti-cancer agents, such as etoposide, irinotecan, paclitaxel, and vincristine, are currently being applied in medical treatments for patients with cancer. Further, the efficacy of plenty of phytochemicals has been evaluated to discover a promising candidate for cancer therapy. For developing more effective cancer therapy, it is required to apprehend the molecular mechanism deployed by natural compounds. MicroRNAs (miRNAs) have been realized to play a pivotal role in regulating cellular signaling pathways, affecting the efficacy of therapeutic agents in cancer. This review presents a feature of phytochemicals with anti-cancer activity, focusing mainly on the relationship between phytochemicals and miRNAs, with insights into the role of miRNAs as the mediators and the regulators of anti-cancer effects of phytochemicals.
Collapse
|
|
28
|
Wang XY, Zhou YC, Wang Y, Liu YY, Wang YX, Chen DD, Fan Y. miR-149 contributes to resistance of 5-FU in gastric cancer via targeting TREM2 and regulating β-catenin pathway. Biochem Biophys Res Commun 2020; 532:329-335. [PMID: 32977944 DOI: 10.1016/j.bbrc.2020.05.135] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/15/2020] [Indexed: 02/07/2023]
Abstract
Drug resistance remains the unresolved obstacle for gastric cancer (GC) treatment. Recently more and more studies have shown that microRNAs are involved in cancer resistance and could apply to drug resistance therapy in tumors. The relationship between miR-149 and 5-fluorouracil (5-FU) resistance in GC remains unclear. Here we detected miR-149 expression in 5-FU resistance tumor tissues and cell lines, and found that miR-149 expression is upregulated in AGS/5-FU cells compared with AGS cells. Further experiments indicated that overexpression of miR-149 can alleviate 5-FU-induced apoptosis and proliferation inhibition by targeting TREM2. It was also confirmed that TREM2 regulated 5-FU resistance through β-catenin pathway. Generally speaking, our results indicated that miR-149 contributes to resistance of 5-FU in gastric cancer via targeting TREM2 and regulating β-catenin pathway.
Collapse
Affiliation(s)
- Xiao-Yan Wang
- Department of Gastroenterology, The First People's Hospital of Suqian, Su'qian, Jiangsu, 223800, China
| | - Yi-Chan Zhou
- Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, 210006, China
| | - Yan Wang
- Department of Gastroenterology, The First People's Hospital of Suqian, Su'qian, Jiangsu, 223800, China
| | - Yun-Yun Liu
- Department of Gastroenterology, The First People's Hospital of Suqian, Su'qian, Jiangsu, 223800, China
| | - Yu-Xin Wang
- Department of Gastroenterology, The First People's Hospital of Suqian, Su'qian, Jiangsu, 223800, China
| | - Dan-Dan Chen
- Department of Gastroenterology, The First People's Hospital of Suqian, Su'qian, Jiangsu, 223800, China
| | - Yu Fan
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China.
| |
Collapse
|
|
29
|
Mao Z, Li T, Zhao H, Qin Y, Wang X, Kang Y. Identification of epigenetic interactions between microRNA and DNA methylation associated with polycystic ovarian syndrome. J Hum Genet 2020; 66:123-137. [PMID: 32759991 DOI: 10.1038/s10038-020-0819-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/20/2020] [Accepted: 07/20/2020] [Indexed: 12/11/2022]
Abstract
Aberration in microRNA expression or DNA methylation is a causal factor for polycystic ovarian syndrome. However, the epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. We conducted a novel integrated analysis of RNA-seq, miRNA-seq, and methylated DNA-binding domain sequencing on ovarian granulosa cells to reveal the epigenetic interactions involved in the pathogenesis of PCOS. We identified 830 genes and 30 miRNAs that were expressed differently in PCOS, and seven miRNAs negatively regulated target mRNA expression. 130 miRNAs' promoters were significantly differently methylated, while 13 were associated with miRNA expression. Furthermore, the hypermethylation of miR-429, miR-141-3p, and miR-126-3p' promoter was found related to miRNA expression suppression and therefore their corresponding genes upregulation, including XIAP, BRD3, MAPK14, and SLC7A5. Our findings provide a novel insight in PCOS. The consequential reversal of genes silencing may participate in PCOS pathogenesis and served as potential molecular targets for PCOS.
Collapse
Affiliation(s)
- Zhanrui Mao
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ting Li
- Department of Obstetrics and Gynecology, Yuncheng Central Hospital, Yuncheng, 044000, Shanxi Province, China
| | - Hui Zhao
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yulan Qin
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xuesong Wang
- Department of Obstetrics and Gynecology, Yuncheng Central Hospital, Yuncheng, 044000, Shanxi Province, China
| | - Yani Kang
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, 200240, China.
| |
Collapse
|
|
30
|
Çınar Ayan İ, Çetinkaya S, Dursun HG, Süntar İ. Bioactive Compounds of Rheum ribes L. and its Anticancerogenic Effect via Induction of Apoptosis and miR-200 Family Expression in Human Colorectal Cancer Cells. Nutr Cancer 2020; 73:1228-1243. [DOI: 10.1080/01635581.2020.1792947] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- İlknur Çınar Ayan
- Department of Medical Biology, Medical Faculty, Necmettin Erbakan University, Meram, Konya, Turkey
| | - Sümeyra Çetinkaya
- Biotechnology Research Center of Ministry of Agriculture and Forestry, Yenimahalle, Ankara, Turkey
| | - Hatice Gül Dursun
- Department of Medical Biology, Medical Faculty, Necmettin Erbakan University, Meram, Konya, Turkey
| | - İpek Süntar
- Department of Pharmacognosy Faculty of Pharmacy, Gazi University, Etiler, Ankara, Turkey
| |
Collapse
|
|
31
|
Ghafouri-Fard S, Vafaee R, Shoorei H, Taheri M. MicroRNAs in gastric cancer: Biomarkers and therapeutic targets. Gene 2020; 757:144937. [PMID: 32640300 DOI: 10.1016/j.gene.2020.144937] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/09/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are a group of non-coding RNAs that have critical roles in regulation of expression of genes. They can inhibit or decrease expression of target genes mostly via interaction with 3' untranslated region of their targets. Their crucial roles in the regulation of expression of tumor suppressor genes and oncogenes have potentiated them as contributors in tumorigenesis. Moreover, their stability in body fluids has enhanced their potential as cancer biomarkers. In the present review article, we describe the role of miRNAs in the pathogenesis of gastric cancer and advances in application of miRNAs as biomarkers and therapeutic targets in this kind of malignancy.
Collapse
Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Vafaee
- Proteomics Research Center, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
32
|
Huang T, Ren K, Ding G, Yang L, Wen Y, Peng B, Wang G, Wang Z. miR‑10a increases the cisplatin resistance of lung adenocarcinoma circulating tumor cells via targeting PIK3CA in the PI3K/Akt pathway. Oncol Rep 2020; 43:1906-1914. [PMID: 32186774 PMCID: PMC7160533 DOI: 10.3892/or.2020.7547] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 12/13/2019] [Indexed: 12/28/2022] Open
Abstract
Circulating tumor cells (CTCs) that are shed from the primary tumor invade the blood stream or surrounding parenchyma to form new tumors. The present study aimed to explore the underlying mechanism of cisplatin resistance in lung adenocarcinoma CTCs and provide clinical treatment guidance for lung cancer treatment. CTCs from the blood samples of 6 lung adenocarcinoma patients were treated with different concentrations of cisplatin along with A549 and H1299 cells. The sensitivity of CTCs to cisplatin was explored by detecting the inhibitory rate via CCK‑8 assay. The related molecular mechanism was investigated by western blot analysis. miR‑10a expression was detected using quantitative real‑time PCR (RT‑qPCR). The relationship between miR‑10a and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α (PIK3CA) was verified and further confirmed by luciferase reporter assay, western blotting and RT‑qPCR assay. The results revealed that CTCs exhibited lower cisplatin sensitivity than A549 and H1299 cells. Moreover, CTCs treated with cisplatin demonstrated higher miR‑10a expression and lower PIK3CA expression than that in A549 and H1299 cells (P<0.01). Expression of phosphoinositide 3‑kinase (PI3K) and protein kinase B (Akt) phosphorylation were also decreased in A549 and H1299 cells compared with CTCs after cisplatin treatment. PIK3CA is a target of miR‑10a, and both miR‑10a overexpression and PIK3CA knockdown obviously decreased the sensitivity of A549 and H1299 cells to cisplatin as well as the expression of PI3K and phosphorylation of Akt. PIK3CA overexpression attenuated the cisplatin resistance of A549 and H1299 cells induced by miR‑10a. In conclusion, miR‑10a suppressed the PI3K/Akt pathway to strengthen the resistance of CTCs to cisplatin via targeting PIK3CA, providing a new therapeutic target for lung cancer treatment.
Collapse
Affiliation(s)
- Tonghai Huang
- Department of Thoracic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Kangqi Ren
- Department of Thoracic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Guanggui Ding
- Department of Thoracic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Lin Yang
- Department of Thoracic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Yuxin Wen
- Department of Thoracic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Bin Peng
- Department of Thoracic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Guangsuo Wang
- Department of Thoracic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Zheng Wang
- Department of Thoracic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong 518020, P.R. China
| |
Collapse
|
|
33
|
Chen P, Kuang P, Wang L, Li W, Chen B, Liu Y, Wang H, Zhao S, Ye L, Yu F, He Y, Zhou C. Mechanisms of drugs-resistance in small cell lung cancer: DNA-related, RNA-related, apoptosis-related, drug accumulation and metabolism procedure. Transl Lung Cancer Res 2020; 9:768-786. [PMID: 32676338 PMCID: PMC7354133 DOI: 10.21037/tlcr-19-547] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Small-cell lung cancer (SCLC), the highest malignant cancer amongst different types of lung cancer, has the feature of lower differentiation, rapid growth, and poor survival rate. Despite the dramatically initial sensitivity of SCLC to various types of treatment methods, including chemotherapy, radiotherapy and immunotherapy, the emergence of drugs-resistance is still a grandly clinical challenge. Therefore, in order to improve the prognosis and develop new therapeutic approaches, having a better understanding of the complex mechanisms of resistance in SCLC is of great clinical significance. This review summarized recent advances in understanding of multiple mechanisms which are involved in the resistance during SCLC treatment, including DNA-related process, RNA-related process, apoptosis-related mechanism, and the process of drug accumulation and metabolism.
Collapse
Affiliation(s)
- Peixin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Department of Medical School, Tongji University, Shanghai, China
| | - Peng Kuang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Department of Medical Oncology, The First Affiliated Hospital Of Nanchang University, Nanchang, China
| | - Lei Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Wei Li
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Bin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Yu Liu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Department of Medical School, Tongji University, Shanghai, China
| | - Hao Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Department of Medical School, Tongji University, Shanghai, China
| | - Sha Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Lingyun Ye
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Feng Yu
- Department of Medical Oncology, The First Affiliated Hospital Of Nanchang University, Nanchang, China
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| |
Collapse
|
|
34
|
Lin W, Miao Y, Meng X, Huang Y, Zhao W, Ruan J. miRNA-765 mediates multidrug resistance via targeting BATF2 in gastric cancer cells. FEBS Open Bio 2020; 10:1021-1030. [PMID: 32166887 PMCID: PMC7262883 DOI: 10.1002/2211-5463.12838] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 02/17/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Elucidation of the mechanisms underlying multidrug resistance (MDR) is required to ensure the efficacy of chemotherapy against gastric cancer (GC). To investigate this issue, here we identified that microRNA-765 (miRNA-765) is up-regulated both in MDR GC cell lines and in specimens from patients who are not responding to chemotherapy. In addition, down-regulation of miRNA-765 increased the sensitivity of GC cells to anticancer drugs, whereas its overexpression had the opposite effect. Moreover, miRNA-765 suppressed drug-induced apoptosis and positively regulated the expression of MDR-related genes. Finally, we showed that the basic leucine zipper ATF-like transcription factor 2, a tumor suppressor gene, is the functional target of miRNA-765. In summary, these results suggest that miRNA-765 may promote MDR via basic leucine zipper ATF-like transcription factor 2 in GC cells.
Collapse
Affiliation(s)
- Wan Lin
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Yu Miao
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xiangkun Meng
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Ying Huang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Wanli Zhao
- Department of Anesthesiology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Jigang Ruan
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| |
Collapse
|
|
35
|
Aghaei Zarch SM, Dehghan Tezerjani M, Talebi M, Vahidi Mehrjardi MY. Molecular biomarkers in diabetes mellitus (DM). Med J Islam Repub Iran 2020; 34:28. [PMID: 32617267 PMCID: PMC7320976 DOI: 10.34171/mjiri.34.28] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
Background: Diabetes mellitus (DM) is a growing epidemic metabolic syndrome, which affects near 5.6% of the world's population. Almost 12% of health expenditure is dedicated to this disorder. Discovering and developing biomarkers as a practical guideline with high specificity and sensitivity for the diagnosis, prognosis, and clinical management of DM is one of the subjects of great interest among DM researchers due to the long-lasting asymptomatic clinical manifestation of DM. In this study, we described a recently identified molecular biomarker involved in DM. Methods: This review study was done at the Diabetes Research Center affiliated to Shahid Sadoughi University of Medical Sciences. PubMed, Scopus, Google Scholar, and Web of Science were searched using the following keywords: "diabetes mellitus", "biomarker", "microRNA", "diagnostic tool" and "clinical manifestation." Results: A total of 107 studies were finally included in this review. After evaluating numerous articles, including original, metaanalysis, and review studies, we focused on molecular biomarkers involved in DM diagnosis and management. Conclusion: Increasing interest in biomarkers associated with DM goes back to its role in decreasing diabetes-related morbidity and mortality. This review focused on major molecular biomarkers such as proteomic and microRNA (miRNAs) as novel and interesting DM biomarkers that can help achieve timely diagnosis of DM.
Collapse
Affiliation(s)
| | - Masoud Dehghan Tezerjani
- Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mehrdad Talebi
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | |
Collapse
|
|
36
|
Wei L, Sun J, Zhang N, Zheng Y, Wang X, Lv L, Liu J, Xu Y, Shen Y, Yang M. Noncoding RNAs in gastric cancer: implications for drug resistance. Mol Cancer 2020; 19:62. [PMID: 32192494 PMCID: PMC7081551 DOI: 10.1186/s12943-020-01185-7] [Citation(s) in RCA: 332] [Impact Index Per Article: 66.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 03/12/2020] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.
Collapse
Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yan Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Liyan Lv
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Jiandong Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yeyang Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yue Shen
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China.
| |
Collapse
|
|
37
|
Cui F, Hao ZX, Li J, Zhang YL, Li XK, He JX. SOX2 mediates cisplatin resistance in small-cell lung cancer with downregulated expression of hsa-miR-340-5p. Mol Genet Genomic Med 2020; 8:e1195. [PMID: 32130794 PMCID: PMC7216814 DOI: 10.1002/mgg3.1195] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 01/19/2020] [Accepted: 02/14/2020] [Indexed: 12/12/2022] Open
Abstract
Background This study is aimed to unravel the genetic factors associated with microRNA (miRNA) expression in regulating sex‐determining region Y‐box 2 (SOX2)‐mediated cisplatin resistance in small‐cell lung cancer (SCLC). Methods The relevance of SOX2 expression in SCLC was analyzed in a panel of SCLC cells by quantitative real‐time PCR (qPCR) and western blot (WB). We selected DMS114 cell line, in which SOX2 was amplified via lentiviral vector‐mediated transfection of the SOX2 genes and tested for the half‐maximal inhibitory concentration (IC50) by MTS assay. High‐throughput sequencing and screening of differentially expressed miRNAs between SOX2‐overexpressing and normal control cells were performed. Finally, miRanda software was used to verify the miRNAs bound with SOX2 and qPCR was used to identify the expression of miRNAs which were binding with SOX2. Results Cisplatin‐resistant SOX2‐overexpressing DMS114 cell lines were successfully developed, showing a statistically significant increase in SOX2 expression by qPCR and WB. Our results showed a typically higher IC50 value in SOX2‐overexpressing cells compared with the negative controls. The high‐throughput sequencing analysis revealed that 68 miRNAs were upregulated and 24 miRNAs were downregulated in the SOX2‐overexpressing cells. The 24 downregulated miRNAs were further verified. Of them, a cancer‐related miRNA, hsa‐miR‐340‐5p, showed a higher binding affinity with SOX2 in network regulation mapping, which was also found to be markedly downregulated under qPCR analysis. Conclusion We demonstrated that downregulated expression of hsa‐miR‐340‐5p may affect cisplatin resistance by mediating SOX2 expression in SCLC cells, which may provide a potential target for the therapy of chemoresistant SCLCs.
Collapse
Affiliation(s)
- Fei Cui
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhe-Xue Hao
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jin Li
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ya-Lei Zhang
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xu-Kai Li
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jian-Xing He
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
38
|
Kabekkodu SP, Shukla V, Varghese VK, Adiga D, Vethil Jishnu P, Chakrabarty S, Satyamoorthy K. Cluster miRNAs and cancer: Diagnostic, prognostic and therapeutic opportunities. WILEY INTERDISCIPLINARY REVIEWS. RNA 2020; 11:e1563. [PMID: 31436881 DOI: 10.1002/wrna.1563] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 07/05/2019] [Accepted: 07/25/2019] [Indexed: 02/06/2023]
Abstract
MiRNAs are class of noncoding RNA important for gene expression regulation in many plants, animals and viruses. MiRNA clusters contain a set of two or more miRNA encoding genes, transcribed together as polycistronic miRNAs. Currently, there are approximately 159 miRNA clusters reported in the human genome consisting of miRNAs ranging from two or more miRNA genes. A large proportion of clustered miRNAs resides in and around the fragile sites or cancer associated genomic hotspots and plays an important role in carcinogenesis. Altered expression of miRNA cluster can be pro-tumorigenic or anti-tumorigenic and can be targeted for clinical management of cancer. Over the past few years, manipulation of miRNA clusters expression is attempted for experimental purpose as well as for diagnostic, prognostic and therapeutic applications in cancer. Re-expression of miRNAs by epigenetic therapy, genome editing such as clustered regulatory interspaced short palindromic repeats (CRISPR) and miRNA mowers showed promising results in cancer therapy. In this review, we focused on the potential of miRNA clusters as a biomarker for diagnosis, prognosis, targeted therapy as well as strategies for modulating their expression in a therapeutic context. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Processing > Processing of Small RNAs RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.
Collapse
Affiliation(s)
- Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Vaibhav Shukla
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Vinay Koshy Varghese
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Padacherri Vethil Jishnu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| |
Collapse
|
|
39
|
Ruan T, Liu W, Tao K, Wu C. A Review of Research Progress in Multidrug-Resistance Mechanisms in Gastric Cancer. Onco Targets Ther 2020; 13:1797-1807. [PMID: 32184615 PMCID: PMC7053652 DOI: 10.2147/ott.s239336] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/15/2020] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is one of the most common malignant tumors, and it is also one of the leading causes of cancer death worldwide. Because of its insidious symptoms and lack of early dictation screening, many cases of gastric cancer are at late stages which make it more complicated to cure. For these advanced-stage gastric cancers, combination therapy of surgery, chemotherapy, radiotherapy and target therapy would bring more benefit to the patients. However, the drug-resistance to the chemotherapy restricts its effect and might lead to treatment failure. In this review article, we discuss the mechanisms which have been found in recent years of drug resistance in gastric cancer. And we also want to find new approaches to counteract chemotherapy resistance and bring more benefits to the patients.
Collapse
Affiliation(s)
- Tuo Ruan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weizhen Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chuanqing Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| |
Collapse
|
|
40
|
Kozak J, Jonak K, Maciejewski R. The function of miR-200 family in oxidative stress response evoked in cancer chemotherapy and radiotherapy. Biomed Pharmacother 2020; 125:110037. [PMID: 32187964 DOI: 10.1016/j.biopha.2020.110037] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 12/14/2022] Open
Abstract
Since the beginning of the discovery of microRNAs (miRs), these molecules have attracted highly progressive attention due to their powerful regulatory roles in a broad spectrum of biological processes, including proliferation, differentiation, apoptosis and carcinogenesis. With regard to carcinogenesis, the miRs regulatory potency has been associated with cancer onset, progression, metastasis, diagnosis and therapeutic response. In this review we discuss the impact of miR-200 family on drug resistance development during anti-cancer therapy. Developing resistance to chemotherapeutic drugs as well as radiotherapy are major clinical obstacles in the successful therapeutic strategies to cancer treatment. Acquired cancer chemoresistance is a multifactorial phenomenon involving such factors as tumor type, tumor stage, cellular reactive oxygen species (ROS) level or ROS-responsive miRs profile. ROS level could influence the miRs expression level, which changes the cellular profile of the content of miRs. Such significant changes in the cellular miRs profile generate subsequent biological effects through the regulation of their target genes. This review outlines the interactions between ROS and miR-200 family in different kinds of cancers in response to chemotherapy.
Collapse
Affiliation(s)
- Joanna Kozak
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Katarzyna Jonak
- Interfaculty Centre for Didactics, Department of Foreign Languages, Medical University of Lublin, 20-081 Lublin, Poland
| | - Ryszard Maciejewski
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
| |
Collapse
|
|
41
|
Verma HK, Ratre YK, Mazzone P, Laurino S, Bhaskar LVKS. Micro RNA facilitated chemoresistance in gastric cancer: a novel biomarkers and potential therapeutics. ALEXANDRIA JOURNAL OF MEDICINE 2020; 56:81-92. [DOI: 10.1080/20905068.2020.1779992] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Affiliation(s)
- Henu Kumar Verma
- Developmental and Stem Cell Biology Laboratory, Institute of Experimental Endocrinology and Oncology CNR, Naples, Italy
- Section of Stem Cell and Development, Istituto di Ricerche Genetiche “Gaetano Salvatore” Biogem, Ariano Irpino, Italy
| | | | - Pellegrino Mazzone
- Section of Stem Cell and Development, Istituto di Ricerche Genetiche “Gaetano Salvatore” Biogem, Ariano Irpino, Italy
| | - Simona Laurino
- Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, Italy
| | | |
Collapse
|
|
42
|
Petrek H, Yu A. MicroRNAs in non-small cell lung cancer: Gene regulation, impact on cancer cellular processes, and therapeutic potential. Pharmacol Res Perspect 2019; 7:e00528. [PMID: 31859460 PMCID: PMC6923806 DOI: 10.1002/prp2.528] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/16/2019] [Accepted: 09/18/2019] [Indexed: 12/29/2022] Open
Abstract
Lung cancer remains the most lethal cancer among men and women in the United States and worldwide. The majority of lung cancer cases are classified as non-small cell lung cancer (NSCLC). Developing new therapeutics on the basis of better understanding of NSCLC biology is critical to improve the treatment of NSCLC. MicroRNAs (miRNAs or miRs) are a superfamily of genome-derived, small noncoding RNAs that govern posttranscriptional gene expression in cells. Functional miRNAs are commonly dysregulated in NSCLC, caused by genomic deletion, methylation, or altered processing, which may lead to the changes of many cancer-related pathways and processes, such as growth and death signaling, metabolism, angiogenesis, cell cycle, and epithelial to mesenchymal transition, as well as sensitivity to current therapies. With the understanding of miRNA biology in NSCLC, there are growing interests in developing new therapeutic strategies, namely restoration of tumor suppressive miRNAs and inhibition of tumor promotive miRNAs, to combat against NSCLC. In this article, we provide an overview on the molecular features of NSCLC and current treatment options with a focus on pharmacotherapy and personalized medicine. By illustrating the roles of miRNAs in the control of NSCLC tumorigenesis and progression, we highlight the latest efforts in assessing miRNA-based therapies in animal models and discuss some critical challenges in developing RNA therapeutics.
Collapse
Affiliation(s)
- Hannah Petrek
- Department of Biochemistry & Molecular MedicineUC Davis School of MedicineSacramentoCAUSA
| | - Ai‐Ming Yu
- Department of Biochemistry & Molecular MedicineUC Davis School of MedicineSacramentoCAUSA
| |
Collapse
|
|
43
|
Zhu P, Shan X, Liu J, Zhou X, Zhang H, Wang T, Wu J, Zhu W, Liu P. miR-3622b-5p regulates cisplatin resistance of human gastric cancer cell line by targeting BIRC5. J Biomed Res 2019; 33:382. [PMCID: PMC6891874 DOI: 10.7555/jbr.33.20180078] [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: 08/17/2018] [Accepted: 06/04/2019] [Indexed: 08/30/2023] Open
Abstract
Many evidences showed that drug resistance of gastric cancer cells could be regulated by the abnormal expression of microRNAs (miRNAs), a post-transcriptional regulator of gene expression. Thus, we investigated the role of miR-3622b-5p in the development of cisplatin (DDP) resistance in human gastric cancer cell lines. A set of biochemical assays were used to elucidate the mechanism by which miR-3622b-5p regulates drug resistance in cancer cells. The expression of miR-3622b-5p was measured by quantitative real-time PCR and showed that miR-3622b-5p was significantly downregulated in the plasma of patients with acquired drug resistance to platinum-based chemotherapy for gastric cancer. miR-3622b-5p was also found significantly downregulated in DDP-resistant gastric cancer cell line SGC7901/DDP, compared with the parental SGC7901 cells. An in vitro drug sensitivity assay showed that overexpression of miR-3622b-5p sensitized SGC7901/DDP cells to DDP. The luciferase activity of reporters constructed by BIRC5 3′-untranslated regions in SGC7901/DDP cells suggested that BIRC5 was target gene of miR-3622b-5p. Ecpotic miR-3622b-5p expression in SGC7901/DDP cells significantly repressed the expression of the BIRC5 and sensitized the cells to DDP-induced apoptosis. By contrast, treatment with miR-3622b-5p inhibitor increased the protein expression of BIRC5 and led to a lower proportion of apoptotic cells in the SGC7901 cells. In conclusion, our findings suggest that miR-3622b-5p regulates DDP resistance of human gastric cancer cells at least in part by repressing the expression of BIRC5. Altering miR-3622b-5p expression may be a potential therapeutic strategy for the treatment of chemoresistance in gastric cancer in the future.
Collapse
Affiliation(s)
- Ping Zhu
- Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics
| | - Xia Shan
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Department of Respiration, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China
| | - Jinhui Liu
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xin Zhou
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Huo Zhang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Tongshan Wang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Jianqing Wu
- Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics
| | - Wei Zhu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Department of Oncology, the Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu 215000, China
| | - Ping Liu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| |
Collapse
|
|
44
|
Liu X, Pan CG, Luo ZQ. High expression of NFAT2 contributes to carboplatin resistance in lung cancer. Exp Mol Pathol 2019; 110:104290. [DOI: 10.1016/j.yexmp.2019.104290] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 07/24/2019] [Accepted: 07/26/2019] [Indexed: 11/30/2022]
|
|
45
|
Ding Q, Li X, Sun Y, Zhang X. Schizandrin A inhibits proliferation, migration and invasion of thyroid cancer cell line TPC-1 by down regulation of microRNA-429. Cancer Biomark 2019; 24:497-508. [PMID: 30909188 DOI: 10.3233/cbm-182222] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Schizandrin A (SchA) exerts anticancer potential. However, the effects of SchA on thyroid cancer (TC) have not been clear illuminated. Therefore, we investigated the effects of SchA on TC cell line TPC-1 and the underlying mechanisms. METHODS TPC-1 cells were treated with SchA and/or transfected with miR-429 mimic, anti-miR-429 and their corresponding negative controls (NC). Cell viability, proliferation, migration, invasion and cell apoptosis were examined by CCK-8 assay, bromodeoxyuridine, modified two-chamber migration assay, Millicell Hanging Cell Culture and flow cytometry analysis, respectively. The expression of miR-429, p16, Cyclin D1, cyclin-dependent kinases 4 (CDK4), matrix metalloprotein (MMP)-2, MMP-9 and Vimentin was detected by qRT-PCR. All protein expression was examined by western blot. RESULTS SchA inhibited cell proliferation, metastasis and induced cell apoptosis. Moreover, SchA negatively regulated miR-429 expression. Treatment with miR-429 mimic and SchA reversed the results led by SchA and NC. Furthermore, the phosphorylation β-catenin, mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) were statistically down-regulated by SchA while co-treatment with miR-429 mimic and SchA led to the opposite trend. Moreover, miR-429 knockdown showed contrary results. CONCLUSION SchA inhibits cell proliferation, migration, invasion and inactivates Wnt/β-catenin and MEK/ERK signaling pathways by down regulating miR-429.
Collapse
|
|
46
|
Ghasabi M, Majidi J, Mansoori B, Mohammadi A, Shomali N, Shirafkan N, Baghbani E, Kazemi T, Baradaran B. The effect of combined miR‐200c replacement and cisplatin on apoptosis induction and inhibition of gastric cancer cell line migration. J Cell Physiol 2019; 234:22581-22592. [DOI: 10.1002/jcp.28823] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/06/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Mehri Ghasabi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Jafar Majidi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Behzad Mansoori
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine University of Southern Denmark Odense Denmark
- Student Research Committee Tabriz University of Medical Sciences Tabriz Iran
| | - Ali Mohammadi
- Aging Research Institute, Physical Medicine and Rehabilitation Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Navid Shomali
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Naghmeh Shirafkan
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Elham Baghbani
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Tohid Kazemi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Behzad Baradaran
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| |
Collapse
|
|
47
|
Chen C, Tang X, Liu Y, Zhu J, Liu J. Induction/reversal of drug resistance in gastric cancer by non-coding RNAs (Review). Int J Oncol 2019; 54:1511-1524. [PMID: 30896792 PMCID: PMC6438417 DOI: 10.3892/ijo.2019.4751] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/21/2019] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is one of the most prevalent and malignant types of cancer worldwide. In China, it is the second most common type of cancer and the malignancy with the highest incidence and mortality rate. Chemotherapy for GC is not always effective due to the development of drug resistance. Drug resistance, which is frequently observed in GC, undermines the success rate of chemotherapy and the survival of patients with GC. The dysregulation of non‑coding RNAs (ncRNAs), primarily microRNAs (miRNAs or miRs) and long non‑coding RNAs (lncRNAs), is involved in the development of GC drug resistance via numerous mechanisms. These mechanisms contribute to the involvement of a large and complex network of ncRNAs in drug resistance. In this review, we focus on and summarize the latest research on the specific mechanisms of action of miRNAs and lncRNAs that modulate drug resistance in GC. In addition, we discuss future prospects and clinical applications of ncRNAs as potential targeted therapies against the chemoresistance of GC.
Collapse
Affiliation(s)
- Chao Chen
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xiaohuan Tang
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yuanda Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jiaming Zhu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jingjing Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| |
Collapse
|
|
48
|
Wu X, Shen J, Xiao Z, Li J, Zhao Y, Zhao Q, Cho CH, Li M. An overview of the multifaceted roles of miRNAs in gastric cancer: Spotlight on novel biomarkers and therapeutic targets. Biochem Pharmacol 2019; 163:425-439. [PMID: 30857828 DOI: 10.1016/j.bcp.2019.03.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 03/07/2019] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs that have displayed strong association with gastric cancer (GC). Through the repression of target mRNAs, miRNAs regulate many biological pathways that are involved in cell proliferation, apoptosis, migration, invasion, metastasis as well as drug resistance. The detection of miRNAs in tissues and in body fluids emerges as a promising method in the diagnosis and prognosis of GC, due to their unique expression pattern in correlation with GC. Notably, miRNAs are also identified as potential therapeutic targets for GC therapy. The present review is thus to highlight the multifaceted roles of miRNAs in GC and in GC therapies, which would give indications for future research.
Collapse
Affiliation(s)
- Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Li
- Department of Oncology and Hematology, Hospital (T.C.M.) Affiliated to Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qijie Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.
| |
Collapse
|
|
49
|
Du E, Cao Y, Feng C, Lu J, Yang H, Zhang Y. The Possible Involvement of miR-371a-5p Regulating XIAP in the Pathogenesis of Recurrent Pregnancy Loss. Reprod Sci 2019; 26:1468-1475. [PMID: 30819044 DOI: 10.1177/1933719119828051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Apoptosis is an interactive and dynamic biological process involved in all phases of embryogenesis. If apoptosis dominates the trophoblast cell growth process, it will result in adverse pregnancy outcomes. X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death. MicroRNAs involve in posttranscriptional gene expression regulation and apoptosis. Online sequence alignment analysis showed that there was a putative binding site of miR-371a-5p on the 3'-untranslated region (UTR) of XIAP. Thirty chorionic villi samples were collected to examine the expression of miR-371a-5p and XIAP. The dual-luciferase reporter assay was applied to determine the relationship between miR-371a-5p and XIAP by human placental choriocarcinoma cells (JEG-3) cells in vitro. After 48-hour transfection of mimics and inhibitor by JEG-3 cells in vitro, Western blotting was used to, respectively, detect the protein expression levels of XIAP and caspase-3. Flow cytometry was used to validate the apoptosis ratio of transfection. The expression of miR-371a-5p and XIAP in recurrent pregnancy loss was greatly decreased. The results from the luciferase reporter assay strongly suggested binding of the XIAP 3'-UTR by miR-371a-5p. Apoptosis percentage of miR-371a-5p mimic was significantly greater than that of normal control. However, apoptosis percentage of miR-371a-5p inhibitor was significantly lower than that of normal control. A significant decrease in luciferase activity was observed in miR-371a-5p mimics-transfected JEG-3 cells compared with controls. These findings provide the evidence that miR-371a-5p is one of the regulating factors according to apoptosis pathway of XIAP-caspase-3 and may be involved in the pathogenesis of recurrent pregnancy loss.
Collapse
Affiliation(s)
- Erqiu Du
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China.,Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Yuming Cao
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
| | - Chun Feng
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
| | - Jing Lu
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
| | - Hanxiao Yang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
| | - Yuanzhen Zhang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
| |
Collapse
|
|
50
|
The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenetics 2019; 11:25. [PMID: 30744689 PMCID: PMC6371621 DOI: 10.1186/s13148-018-0587-8] [Citation(s) in RCA: 483] [Impact Index Per Article: 80.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 11/19/2018] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.
Collapse
|