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Guo H, Zhang N, Huang T, Shen N. MicroRNA-200c in Cancer Generation, Invasion, and Metastasis. Int J Mol Sci 2025; 26:710. [PMID: 39859424 PMCID: PMC11766322 DOI: 10.3390/ijms26020710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/05/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
MicroRNA-200c (miR-200c) is increasingly recognized as a crucial small RNA molecule that plays a significant and multifaceted role in the complex processes of tumor development, invasion, and metastasis across various types of cancers. Recent studies have compellingly demonstrated that miR-200c exerts its influence on tumor biology by meticulously regulating a range of critical processes, including cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), and cell migration, all of which are essential for the progression and aggressiveness of tumors. This comprehensive review aims to summarize the expression characteristics and functional implications of miR-200c across a diverse array of tumor types, delving into its potential utility as both a biomarker for early detection and a therapeutic target in the realm of cancer treatment. By synthesizing current research findings and insights, we aspire to provide valuable information that could significantly enhance early diagnostic capabilities and inform the strategic development of targeted therapy approaches in oncology.
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Affiliation(s)
| | | | | | - Na Shen
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; (H.G.); (N.Z.); (T.H.)
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2
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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.
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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.
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3
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Pawlicka M, Gumbarewicz E, Błaszczak E, Stepulak A. Transcription Factors and Markers Related to Epithelial-Mesenchymal Transition and Their Role in Resistance to Therapies in Head and Neck Cancers. Cancers (Basel) 2024; 16:1354. [PMID: 38611032 PMCID: PMC11010970 DOI: 10.3390/cancers16071354] [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: 02/14/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Head and neck cancers (HNCs) are heterogeneous and aggressive tumors of the upper aerodigestive tract. Although various histological types exist, the most common is squamous cell carcinoma (HNSCC). The incidence of HNSCC is increasing, making it an important public health concern. Tumor resistance to contemporary treatments, namely, chemo- and radiotherapy, and the recurrence of the primary tumor after its surgical removal cause huge problems for patients. Despite recent improvements in these treatments, the 5-year survival rate is still relatively low. HNSCCs may develop local lymph node metastases and, in the most advanced cases, also distant metastases. A key process associated with tumor progression and metastasis is epithelial-mesenchymal transition (EMT), when poorly motile epithelial tumor cells acquire motile mesenchymal characteristics. These transition cells can invade different adjacent tissues and finally form metastases. EMT is governed by various transcription factors, including the best-characterized TWIST1 and TWIST2, SNAIL, SLUG, ZEB1, and ZEB2. Here, we highlight the current knowledge of the process of EMT in HNSCC and present the main protein markers associated with it. This review focuses on the transcription factors related to EMT and emphasizes their role in the resistance of HNSCC to current chemo- and radiotherapies. Understanding the role of EMT and the precise molecular mechanisms involved in this process may help with the development of novel anti-cancer therapies for this type of tumor.
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Affiliation(s)
| | | | | | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.P.); (E.G.); (E.B.)
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4
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Sahib AS, Fawzi A, Zabibah RS, Koka NA, Khudair SA, Muhammad FA, Hamad DA. miRNA/epithelial-mesenchymal axis (EMT) axis as a key player in cancer progression and metastasis: A focus on gastric and bladder cancers. Cell Signal 2023; 112:110881. [PMID: 37666286 DOI: 10.1016/j.cellsig.2023.110881] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
The metastasis a major hallmark of tumors that its significant is not only related to the basic research, but clinical investigations have revealed that majority of cancer deaths are due to the metastasis. The metastasis of tumor cells is significantly increased due to EMT mechanism and therefore, inhibition of EMT can reduce biological behaviors of tumor cells and improve the survival rate of patients. One of the gaps related to cancer metastasis is lack of specific focus on the EMT regulation in certain types of tumor cells. The gastric and bladder cancers are considered as two main reasons of death among patients in clinical level. Herein, the role of EMT in regulation of their progression is evaluated with a focus on the function of miRNAs. The inhibition/induction of EMT in these cancers and their ability in modulation of EMT-related factors including ZEB1/2 proteins, TGF-β, Snail and cadherin proteins are discussed. Moreover, lncRNAs and circRNAs in crosstalk of miRNA/EMT regulation in these tumors are discussed and final impact on cancer metastasis and response of tumor cells to the chemotherapy is evaluated. Moreover, the impact of miRNAs transferred by exosomes in regulation of EMT in these cancers are discussed.
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Affiliation(s)
- Ameer S Sahib
- Department of Pharmacy, Al- Mustaqbal University College, 51001 Hilla, Iraq
| | - Amjid Fawzi
- Medical Technical College, Al-Farahidi University, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Nisar Ahmad Koka
- Department of English, Faculty of Languages and Translation, King Khalid University, Abha, Kingdom of Saudi Arabia.
| | | | | | - Doaa A Hamad
- Nursing Department, Hilla University College, Babylon, Iraq
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5
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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.
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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.
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Gupta J, Ahmed AT, Tayyib NA, Zabibah RS, Shomurodov Q, Kadheim MN, Alsaikhan F, Ramaiah P, Chinnasamy L, Samarghandian S. A state-of-art of underlying molecular mechanisms and pharmacological interventions/nanotherapeutics for cisplatin resistance in gastric cancer. Biomed Pharmacother 2023; 166:115337. [PMID: 37659203 DOI: 10.1016/j.biopha.2023.115337] [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: 06/19/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 09/04/2023] Open
Abstract
The fourth common reason of death among patients is gastric cancer (GC) and it is a dominant tumor type in Ease Asia. One of the problems in GC therapy is chemoresistance. Cisplatin (CP) is a platinum compound that causes DNA damage in reducing tumor progression and viability of cancer cells. However, due to hyperactivation of drug efflux pumps, dysregulation of genes and interactions in tumor microenvironment, tumor cells can develop resistance to CP chemotherapy. The current review focuses on the CP resistance emergence in GC cells with emphasizing on molecular pathways, pharmacological compounds for reversing chemoresistance and the role of nanostructures. Changes in cell death mechanisms such as upregulation of pro-survival autophagy can prevent CP-mediated apoptosis that results in drug resistance. Moreover, increase in metastasis via EMT induction induces CP resistance. Dysregulation of molecular pathways such as PTEN, PI3K/Akt, Nrf2 and others result in changes in CP response of GC cells. Non-coding RNAs determine CP response of GC cells and application of pharmacological compounds with activity distinct of CP can result in sensitivity in tumor cells. Due to efficacy of exosomes in transferring bioactive molecules such as RNA and DNA molecules among GC cells, exosomes can also result in CP resistance. One of the newest progresses in overcoming CP resistance in GC is application of nanoplatforms for delivery of CP in GC therapy that they can increase accumulation of CP at tumor site and by suppressing carcinogenic factors and overcoming biological barriers, they increase CP toxicity on cancer cells.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, U.P., India
| | | | - Nahla A Tayyib
- Faculty of Nursing, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Qakhramon Shomurodov
- Department of Maxillofacial Surgery, Tashkent State Dental Institute, Tashkent, Uzbekistan; Department of Scientific Affairs, Samarkand State Medical University, Samarkand, Uzbekistan
| | - Mostafai N Kadheim
- Department of Dentistry, Kut University College, Kut, Wasit 52001, Iraq; Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad 10022 Iraq
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
| | | | | | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, the Islamic Republic of Iran.
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circ-ZEB1 regulates epithelial-mesenchymal transition and chemotherapy resistance of colorectal cancer through acting on miR-200c-5p. Transl Oncol 2022; 28:101604. [PMID: 36542990 PMCID: PMC9792398 DOI: 10.1016/j.tranon.2022.101604] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/27/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
Circular RNAs (circRNAs) have been demonstrated to be important regulators in human malignant tumors, including colorectal cancer (CRC). While the role circ-ZEB1 played in CRC remains unclear. In this study, we aim to explore the biological function and the underlying mechanism of circ-ZEB1 in CRC. RNAscope was used to analyze the expression and localization of circ-ZEB1 in CRC tissues. Loss of function experiments were conducted, including CCK-8, transwell assays, flow cytometry analysis, and murine xenograft models, so as to detect the effect of circ-ZEB1 on CRC cells. IC50 assay was used to evaluate the influence of circ-ZEB1 on the chemoresistance of CRC cells. Epithelial-mesenchymal transition (EMT) related markers were detected. The relationship between circ-ZEB1 and miR-200c-5p was investigated by FISH, dual-luciferase reporter assay, and RIP assay. We found in our study that circ-ZEB1 was significantly upregulated in CRC tissues. Downregulation of circ-ZEB1 inhibited cell proliferation, colony formation, as well as cell migration and invasion abilities of CRC cell lines. In vivo experiments indicated that knockdown of circ-ZEB1 suppressed tumorigenesis and distant metastasis of CRC cells in nude mice. What's more, EMT and chemoresistance of CRC cells were also attenuated following circ-ZEB1 knockdown. Mechanistically, we proved that circ-ZEB1 could directly bind with miR-200c and functioned as miR-200c sponge to exert its biological functions in CRC cells. In conclusion, circ-ZEB1 could promote CRC cells progression, EMT, and chemoresistance via acting on miR-200c, elucidating a potential therapeutic target to inhibit CRC progression.
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Klicka K, Grzywa TM, Mielniczuk A, Klinke A, Włodarski PK. The role of miR-200 family in the regulation of hallmarks of cancer. Front Oncol 2022; 12:965231. [PMID: 36158660 PMCID: PMC9492973 DOI: 10.3389/fonc.2022.965231] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
MiRNAs are short non-coding RNAs that regulate gene expression post-transcriptionally contributing to the development of different diseases including cancer. The miR-200 family consists of five members, miR-200a, miR-200b, miR-200c, miR-141, and miR-429. Their expression is dysregulated in cancer tissue and their level is altered in the body fluids of cancer patients. Moreover, the levels of miR-200 family members correlate with clinical parameters such as cancer patients' survival which makes them potentially useful as diagnostic and prognostic biomarkers. MiRNAs can act as either oncomiRs or tumor suppressor miRNAs depending on the target genes and their role in the regulation of key oncogenic signaling pathways. In most types of cancer, the miR-200 family acts as tumor suppressor miRNA and regulates all features of cancer. In this review, we summarized the expression pattern of the miR-200 family in different types of cancer and their potential utility as biomarkers. Moreover, we comprehensively described the role of miR-200 family members in the regulation of all hallmarks of cancer proposed by Hanahan and Weinberg with the focus on the epithelial-mesenchymal transition, invasiveness, and metastasis of tumor cells.
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Affiliation(s)
- Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
- Laboratory of Experimental Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Alicja Klinke
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland
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9
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Yi H, Han Y, Li S. Oncogenic circular RNA circ_0007534 contributes to paclitaxel resistance in endometrial cancer by sponging miR-625 and promoting ZEB2 expression. Front Oncol 2022; 12:985470. [PMID: 35992812 PMCID: PMC9386306 DOI: 10.3389/fonc.2022.985470] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 07/18/2022] [Indexed: 12/05/2022] Open
Abstract
Circular RNAs (circRNAs) and epithelial to mesenchymal transition (EMT) have been implicated in the development of human cancer and paclitaxel resistance. CircRNA circ_0007534 has been described as a key oncogenic circular RNA that is upregulated in a variety of cancer tissues. However, whether circ_0007534 causes EMT and paclitaxel resistance in endometrial cancer is still unknown. In this work, we revealed that circ_0007534 levels were significantly higher in endometrial cancer tissues, and that high circ_0007534 expression was associated with poor differentiation, advanced tumor stage, cancer invasion, cancer metastasis, and poor prognosis in endometrial cancer patients. Overexpression of circ_0007534 boosted endometrial cancer cell proliferation, invasion, EMT, and paclitaxel resistance. Knockdown of circ_0007534 restored paclitaxel sensitivity and reversed EMT in endometrial cancer cells. We also showed that circ_0007534 enhanced endometrial cancer aggressiveness, progression, and paclitaxel resistance by sponging microRNA-625 (miR-625) and subsequently increasing the expression of the miR-625 target gene ZEB2. Our cell functional studies demonstrated that inhibiting miR-625 or increasing ZEB2 mimicked the effects of circ_0007534 overexpression. Consequently, our data show that circ_0007534 plays a crucial role in EMT and paclitaxel resistance through miR-625/ZEB2 signaling. Targeting the circ_0007534/miR-625/ZEB2 pathway might be an effective strategy for overcoming paclitaxel resistance in endometrial cancer.
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Affiliation(s)
- Hanjie Yi
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yongqing Han
- Department of Oncology, ShangRao People’s Hospital, Shangrao, China
| | - Shanfeng Li
- Department of Nosocomial Infection Management, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Shanfeng Li,
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10
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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: 5] [Impact Index Per Article: 1.7] [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.
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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
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Sui Q, Chen Z, Hu Z, Huang Y, Liang J, Bi G, Bian Y, Zhao M, Zhan C, Lin Z, Wang Q, Tan L. Cisplatin resistance-related multi-omics differences and the establishment of machine learning models. J Transl Med 2022; 20:171. [PMID: 35410350 PMCID: PMC9004122 DOI: 10.1186/s12967-022-03372-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/29/2022] [Indexed: 01/05/2023] Open
Abstract
Objectives Platinum-based chemotherapies are currently the first-line treatment of non-small cell lung cancer. This study will improve our understanding of the causes of resistance to cisplatin, especially in lung adenocarcinoma (LUAD) and provide a reference for therapeutic decisions in clinical practice. Methods Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA) and Zhongshan hospital affiliated to Fudan University (zs-cohort) were used to identify the multi-omics differences related to platinum chemotherapy. Cisplatin-resistant mRNA and miRNA models were constructed by Logistic regression, classification and regression tree and C4.5 decision tree classification algorithm with previous feature selection performed via least absolute shrinkage and selection operator (LASSO). qRT-PCR and western-blotting of A549 and H358 cells, as well as single-cell Seq data of tumor samples were applied to verify the tendency of certain genes. Results 661 cell lines were divided into three groups according to the IC50 value of cisplatin, and the top 1/3 (220) with a small IC50 value were defined as the sensitive group while the last 1/3 (220) were enrolled in the insensitive group. TP53 was the most common mutation in the insensitive group, in contrast to TTN in the sensitive group. 1348 mRNA, 80 miRNA, and 15 metabolites were differentially expressed between 2 groups (P < 0.05). According to the LASSO penalized logistic modeling, 6 of the 1348 mRNAs, FOXA2, BATF3, SIX1, HOXA1, ZBTB38, IRF5, were selected as the associated features with cisplatin resistance and for the contribution of predictive mRNA model (all of adjusted P-values < 0.001). Three of 6 (BATF3, IRF5, ZBTB38) genes were finally verified in cell level and patients in zs-cohort. Conclusions Somatic mutations, mRNA expressions, miRNA expressions, metabolites and methylation were related to the resistance of cisplatin. The models we created could help in the prediction of the reaction and prognosis of patients given platinum-based chemotherapies. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03372-0.
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12
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Wang S, Guo J, Mo Z, Shi X, Qu C. Clinical significance and correlation of miR-200c and P-gp expression in gastric cancer and the effects on multidrug resistance. J Gastrointest Oncol 2022; 13:581-592. [PMID: 35557580 PMCID: PMC9086044 DOI: 10.21037/jgo-22-167] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/02/2022] [Indexed: 09/11/2023] Open
Abstract
BACKGROUND Poor prognosis is common in gastric cancer patients due to multidrug resistance (MDR)-induced recurrence and metastasis. In the present study, we investigated the expression of microRNA (miR)-200c in gastric cancer tissues and cell lines and its relationship with the expression of the drug resistant gene ABCB1, which encodes P-glycoprotein (P-gp). METHODS The basic characteristics of 102 patients with gastric cancer were reviewed. Real time-polymerase chain reaction (PCR), immunohistochemistry, and Western blot were employed to detect the expression levels of miR-200c and P-gp in gastric carcinoma tissues and cell lines. The correlation of miR-200c messenger RNA (mRNA) level with clinicopathological characteristics and P-gp protein expression were analyzed. SGC7901/vincristine (VCR) cells were transfected with miR-200c mimics or a specific small interfering RNA (siRNA) targeting the ABCB1 gene. The methyl thiazolyl tetrazolium (MTT) assay and flow cytometry were used to determine the role of miR-200c and ABCB1 on the viability and apoptosis of gastric carcinoma cell lines. RESULTS The level of miR-200c in carcinoma tissues was significantly lower than that in adjacent tissues, and the expression level of P-gp in carcinoma tissues was obviously higher than that in adjacent tissues (P<0.01, P=0.029). The expression levels of miR-200c and P-gp were associated with the malignant characteristics of gastric cancer, and patients with high expression of miR-200c or negative expression of P-gp had a better prognosis (P=0.006, P=0.022). MiR-200c negatively regulated the ABCB1 gene in gastric cancer cell lines. MiR-200c overexpression and ABCB1 down-regulation increased the sensitivity of SGC7901/VCR cells to VCR and reversed MDR by promoting cell apoptosis. CONCLUSIONS The expression level of miR-200c decreases in gastric carcinoma tissues and drug-resistant gastric cancer SGC7901/VCR cells. Overexpression of miR-200c may enhance the sensitivity of SGC7901/VCR cells to VCR by regulating the expression of P-gp.
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Affiliation(s)
- Shen Wang
- Department of Gastrointestinal and Pancreatic Surgery, Shanxi Provincial People’s Hospital, Taiyuan, China
| | - Jien Guo
- Department of Gastrointestinal and Pancreatic Surgery, Shanxi Provincial People’s Hospital, Taiyuan, China
| | - Zhenzhou Mo
- Department of Gastrointestinal and Pancreatic Surgery, Shanxi Provincial People’s Hospital, Taiyuan, China
| | - Xiangcheng Shi
- Department of Pathology, Shanxi Provincial People’s Hospital, Taiyuan, China
| | - Chongxiao Qu
- Department of Pathology, Shanxi Provincial People’s Hospital, Taiyuan, China
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13
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Feng YL, Ke T, Wang GL, Qi HY, Xiao Y. MicroRNA-200c-3p Negatively Regulates ATP2A2 and Promotes the Progression of Papillary Thyroid Carcinoma. Biochem Genet 2022; 60:1676-1694. [PMID: 35079913 PMCID: PMC8788908 DOI: 10.1007/s10528-022-10184-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 01/05/2022] [Indexed: 11/29/2022]
Abstract
microRNA-200c-3p (miR-200c-3p) has emerged as an important tumor growth regulator. However, its function in papillary thyroid carcinoma (PTC) is poorly understood. This study was conducted to investigate the role of miR-200c-3p in the progression of human PTC. The miR-200c-3p expression in human PTC tissues and cell lines was evaluated. The target relationship between miR-200c-3p and candidate genes was predicted through bioinformatic analysis and confirmed with a luciferase reporter assay. miRNA or gene expression was altered using transfection, and cell behavior was analyzed using CCK-8, wound healing, Transwell, and colony formation assays. The tumor-promoting effects of miR-200c-3p were evaluated by xenografting tumors with K1 cells in nude mice. The expression level of miR-200c-3p in human PTC tissues and cell lines markedly increased, and this increased expression was significantly associated with a worse overall survival. When inactivated, miR-200c-3p suppressed K1 cells’ malignant behaviors, including decreasing proliferation and attenuating colony formation, migration, and invasion. Its inactivation also attenuated the development of xenografted K1 cells in nude mice. The effects of miR-200c-3p mimics on promoting the malignant behaviors of PTC cells were remarkably reversed by the overexpression of ATP2A2, as a downstream target of miR-200c-3p. miR-200c-3p acts as an oncogenic gene and promotes the malignant biological behaviors of human PTC cells, thereby directly targeting ATP2A2. This regulated axis may be used as a potential therapy of PTC.
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Affiliation(s)
- Yu-Lai Feng
- Department of Oncology, Lianyungang Hospital of Traditional Chinese Medicine, Chaoyang Middle Road, No. 160, Lianyungang, 222004, China
| | - Ting Ke
- Second Department of Endocrinology, Shaanxi Hospital of Traditional Chinese Medicine, Xihuamen, Lianhu district, No. 2, Xi'an, 710003, China
| | - Gao-Lei Wang
- Second Department of Endocrinology, Shaanxi Hospital of Traditional Chinese Medicine, Xihuamen, Lianhu district, No. 2, Xi'an, 710003, China
| | - Hai-Yan Qi
- Second Department of Endocrinology, Shaanxi Hospital of Traditional Chinese Medicine, Xihuamen, Lianhu district, No. 2, Xi'an, 710003, China.
| | - Yang Xiao
- Second Department of Endocrinology, Shaanxi Hospital of Traditional Chinese Medicine, Xihuamen, Lianhu district, No. 2, Xi'an, 710003, China.
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14
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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15
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Sai S, Kim EH, Koom WS, Vares G, Suzuki M, Yamada S, Hayashi M. Carbon-Ion Beam Irradiation and the miR-200c Mimic Effectively Eradicate Pancreatic Cancer Stem Cells Under in vitro and in vivo Conditions. Onco Targets Ther 2021; 14:4749-4760. [PMID: 34556996 PMCID: PMC8453446 DOI: 10.2147/ott.s311567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose The study investigated the molecular mechanisms that killed pancreatic cancer cells, including cancer stem cells (CSCs), by carbon ion beam irradiation alone or in combination with miRNA-200c under in vitro and in vivo conditions. Methods Human pancreatic cancer (PC) cells, PANC1 and PK45, were treated with carbon-ion beam irradiation alone or in combination with microRNA-200c (miR-200c) mimic. Cell viability assay, colony and spheroid formation assay, quantitative real-time PCR analysis of apoptosis-, autophagy-, and angiogenesis-related gene expression, xenograft tumor control and histopathological analyses were performed. Results The cell viability assay showed that transfection of the miRNA-200c (10 nM) mimic into pancreatic CSC (CD44+/ESA+) and non-CSC (CD44-/ESA-) significantly suppressed proliferation of both types of cell populations described above. Combining carbon-ion beam irradiation with the miRNA-200c mimic significantly reduced the colony as well as spheroid formation abilities compared to that observed with the treatment of carbon-ion beam alone or X-ray irradiation combined with the miRNA-200c mimic. Moreover, the combination of carbon ion beam irradiation and miRNA-200c mimic increased the expression of apoptosis-related gene BAX, autophagy-related genes Beclin-1 and p62, addition of gemcitabine (GEM) further enhanced the expression of these genes. In vivo data showed that carbon-ion beam irradiation in combination with the miRNA-200c mimic effectively suppressed xenograft tumor growth and significantly induced tumor necrosis and cavitation. Conclusion The combination of miRNA-200c mimic and carbon ion beam irradiation may be powerful radiotherapy that significantly kills pancreatic cancer cells containing CSCs and enhances the effect of carbon-ion beam irradiation compared to carbon-ion beam irradiation alone.
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Affiliation(s)
- Sei Sai
- Department of Charged Particle Therapy Research, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - Eun Ho Kim
- Department of Biochemistry, School of Medicine, Daegu Catholic University, Nam-gu, Daegu, 42472, South Korea
| | - Woong Sub Koom
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Guillaume Vares
- Institute of Radioprotection and Nuclear Safety (IRSN), Fontenay-aux-Roses Cedex, France
| | - Masao Suzuki
- Department of Charged Particle Therapy Research, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - Shigeru Yamada
- QST Hospital, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - Mitsuhiro Hayashi
- Breast Center, Dokkyo Medical University Hospital, Tochigi, 321-0293, Japan
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16
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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: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
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.
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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
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17
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Zangouei AS, Moghbeli M. MicroRNAs as the critical regulators of cisplatin resistance in gastric tumor cells. Genes Environ 2021; 43:21. [PMID: 34099061 PMCID: PMC8182944 DOI: 10.1186/s41021-021-00192-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/24/2021] [Indexed: 12/13/2022] Open
Abstract
Combined chemotherapeutic treatment is the method of choice for advanced and metastatic gastric tumors. However, resistance to chemotherapeutic agents is one of the main challenges for the efficient gastric cancer (GC) treatment. Cisplatin (CDDP) is used as an important regimen of chemotherapy for GC which induces cytotoxicity by interfering with DNA replication in cancer cells and inducing their apoptosis. Majority of patients experience cisplatin-resistance which is correlated with tumor metastasis and relapse. Moreover, prolonged and high-dose cisplatin administrations cause serious side effects such as nephrotoxicity, ototoxicity, and anemia. Since, there is a high rate of recurrence after CDDP treatment in GC patients; it is required to clarify the molecular mechanisms associated with CDDP resistance to introduce novel therapeutic methods. There are various cell and molecular processes associated with multidrug resistance (MDR) including drug efflux, detoxification, DNA repair ability, apoptosis alteration, signaling pathways, and epithelial-mesenchymal transition (EMT). MicroRNAs are a class of endogenous non-coding RNAs involved in chemo resistance of GC cells through regulation of all of the MDR mechanisms. In present review we have summarized all of the miRNAs associated with cisplatin resistance based on their target genes and molecular mechanisms in gastric tumor cells. This review paves the way of introducing a miRNA-based panel of prognostic markers to improve the efficacy of chemotherapy and clinical outcomes in GC patients. It was observed that miRNAs are mainly involved in cisplatin response of gastric tumor cells via regulation of signaling pathways, autophagy, and apoptosis.
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Affiliation(s)
- Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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Soleymani L, Zarrabi A, Hashemi F, Hashemi F, Zabolian A, Banihashemi SM, Moghadam SS, Hushmandi K, Samarghandian S, Ashrafizadeh M, Khan H. Role of ZEB family members in proliferation, metastasis and chemoresistance of prostate cancer cells: Revealing signaling networks. Curr Cancer Drug Targets 2021; 21:749-767. [PMID: 34077345 DOI: 10.2174/1568009621666210601114631] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/10/2021] [Accepted: 03/19/2021] [Indexed: 11/22/2022]
Abstract
Prostate cancer (PCa) is one of the leading causes of death worldwide. A variety of strategies including surgery, chemotherapy, radiotherapy and immunotherapy are applied for PCa treatment. PCa cells are responsive towards therapy at early stages, but they can obtain resistance in the advanced stage. Furthermore, their migratory ability is high in advanced stages. It seems that genetic and epigenetic factors play an important in this case. Zinc finger E-box-binding homeobox (ZEB) is a family of transcription with two key members including ZEB1 and ZEB2. ZEB family members are known due to their involvement in promoting cancer metastasis via EMT induction. Recent studies have shown their role in cancer proliferation and inducing therapy resistance. In the current review, we focus on revealing role of ZEB1 and ZEB2 in PCa. ZEB family members that are able to significantly promote proliferation and viability of cancer cells. ZEB1 and ZEB2 enhance migration and invasion of PCa cells via EMT induction. Overexpression of ZEB1 and ZEB2 is associated with poor prognosis of PCa. ZEB1 and ZEB2 upregulation occurs during PCa progression and can provide therapy resistance to cancer cells. PRMT1, Smad2, and non-coding RNAs can function as upstream mediators of the ZEB family. Besides, Bax, Bcl-2, MRP1, N-cadherin and E-cadherin can be considered as downstream targets of ZEB family in PCa.
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Affiliation(s)
- Leyla Soleymani
- Department of biology, school of science, Urmia university, Urmia, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul. Turkey
| | - Farid Hashemi
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Fardin Hashemi
- Student Research Committee, Department of Physiotherapy, Faculty of Rehabilitation, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shirin Sabouhi Moghadam
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite -Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul. Turkey
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200. Pakistan
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19
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Wang H, Sui ZL, Wu XX, Tang P, Zhang HD, Yu ZT. Reversal of Chemotherapy Resistance to Cisplatin in NSCLC by miRNA-195-5p via Targeting the FGF2 Gene. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:497-508. [PMID: 33953601 PMCID: PMC8092352 DOI: 10.2147/pgpm.s302755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/26/2021] [Indexed: 12/20/2022]
Abstract
Objective To explore the mechanism of miR-195-5p in the pathogenesis non-small cell lung cancer (NSCLC) and cisplatin resistance. Methods The function of miR-195-5p in NSCLC and cisplatin resistance were determined by MTT, scratch assay, transwell assay, and nude mice xenograft experiments. miR-195-5p target gene was identified by dual-luciferase reporter assays and real-time PCR analysis. Results miR-195-5p content was lower in A549/DDP than that in A549 cells, with reduced chemotherapy sensitivity and increased cell invasion and migration ability. The loss-of-function and gain-of-function assays illustrated that miR-195-5p might have increased the chemosensitivity to cisplatin in the A549/DDP cells and decreased cell migration and invasion. FGF2 is a negatively correlated action target of miR-195-5p. miR-195-5p might affect EMT by inhibiting FGF2. Overexpression of FGF2 resulted in enhanced cisplatin resistance in the cells, while miR-195-5p might have reversed this resistance. Conclusion Overall, miR-195-5p might target FGF2 to reduce cisplatin resistance in A549/DDP cells and enhance chemosensitivity.
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Affiliation(s)
- Hao Wang
- Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, 300060, People's Republic of China.,Department of Surgical Oncology, Baotou Cancer Hospital, Baotou, People's Republic of China
| | - Zhi-Lin Sui
- Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, 300060, People's Republic of China
| | - Xian-Xian Wu
- Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, 300060, People's Republic of China
| | - Peng Tang
- Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, 300060, People's Republic of China
| | - Hong-Dian Zhang
- Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, 300060, People's Republic of China
| | - Zhen-Tao Yu
- Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, 300060, People's Republic of China.,Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, People's Republic of China
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20
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Non-coding RNAs underlying chemoresistance in gastric cancer. Cell Oncol (Dordr) 2020; 43:961-988. [PMID: 32495294 DOI: 10.1007/s13402-020-00528-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 04/17/2020] [Accepted: 04/24/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major health issue in the Western world. Current clinical imperatives for this disease include the identification of more effective biomarkers to detect GC at early stages and enhance the prevention and treatment of metastatic and chemoresistant GC. The advent of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long-non coding RNAs (lncRNAs), has led to a better understanding of the mechanisms by which GC cells acquire features of therapy resistance. ncRNAs play critical roles in normal physiology, but their dysregulation has been detected in a variety of cancers, including GC. A subset of ncRNAs is GC-specific, implying their potential application as biomarkers and/or therapeutic targets. Hence, evaluating the specific functions of ncRNAs will help to expand novel treatment options for GC. CONCLUSIONS In this review, we summarize some of the well-known ncRNAs that play a role in the development and progression of GC. We also review the application of such ncRNAs in clinical diagnostics and trials as potential biomarkers. Obviously, a deeper understanding of the biology and function of ncRNAs underlying chemoresistance can broaden horizons toward the development of personalized therapy against GC.
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21
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Kipkeeva F, Muzaffarova T, Korotaeva A, Nikulin M, Grishina K, Mansorunov D, Apanovich P, Karpukhin A. MicroRNA in Gastric Cancer Development: Mechanisms and Biomarkers. Diagnostics (Basel) 2020; 10:E891. [PMID: 33142817 PMCID: PMC7692123 DOI: 10.3390/diagnostics10110891] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/20/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the most common and difficult diseases to treat. The study of signaling pathway regulation by microRNA provides information on the mechanisms of GC development and is the basis for biomarker creation. In this study, a circuit of microRNA interactions with signaling pathways was constructed. The microRNAs, associated with metastasis and chemoresistance, are described. In most cases, microRNAs in GC regulate the Wnt/β-catenin, PI3K/AKT/mTOR, RAS/RAF/ERK/MAPK, NF-kB, TGF-β, and JAK/STAT pathways. Part of the microRNA acts on several target genes that function in different pathways. This often leads to an intensification of the induced processes. MicroRNAs have also been described that have the opposite effect on different pathways, causing different functional consequences. By acting on several target genes, or genes associated with several pathways, microRNAs can function in a signaling network. MicroRNAs associated with metastasis most often interact with the Wnt/β-catenin pathway. MicroRNAs affecting chemoresistance, in most cases, affect the regulators of apoptosis and are associated with the PI3K/AKT/mTOR pathway. The characteristics of microRNAs proposed as candidates for GC biomarkers were analyzed. The currently developed diagnostic and prognostic panels of microRNAs are also considered.
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Affiliation(s)
- Fatimat Kipkeeva
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Tatyana Muzaffarova
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Alexandra Korotaeva
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Maxim Nikulin
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, Moscow 115478, Russia;
| | - Kristina Grishina
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Danzan Mansorunov
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Pavel Apanovich
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Alexander Karpukhin
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
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22
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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.
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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.
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23
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Jiang Y, Ji X, Liu K, Shi Y, Wang C, Li Y, Zhang T, He Y, Xiang M, Zhao R. Exosomal miR-200c-3p negatively regulates the migraion and invasion of lipopolysaccharide (LPS)-stimulated colorectal cancer (CRC). BMC Mol Cell Biol 2020; 21:48. [PMID: 32600257 PMCID: PMC7325272 DOI: 10.1186/s12860-020-00291-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 06/16/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a leading cancer and a major cause of death. Lipopolysaccharide (LPS), an abundant component in gut microbiome, is involved in CRC progression and metastasis, potentially through regulating the miRNA composition of CRC-derived exosomes. In this study, we aimed to identify miRNA species in exosome which regulates CRC progression after LPS stimulation. RESULTS Firstly, we discovered a shift of miRNA profile in CRC exosome after LPS stimulation. Among the differentially expressed miRNAs, we identified miR-200c-3p as a potential key regulator of CRC progression and metastasis. Retrospective analysis revealed that miR-200c-3p was elevated in CRC tumor tissues, but decreased in the serum exosome in CRC patients. In vitro experiments demonstrated that exosomal miR-200c-3p expression did not influence CRC cell proliferation, but negatively regulated their capacity of migration and invasion in the presence of LPS. miR-200c-3p level in exosome influenced exosomal expression of Zinc finger E-box-binding homeobox-1 (ZEB-1) mRNA, one of the miR-200c targets which affects migration and invasion capacity, and further altered ZEB-1 protein expression in CRC cell. In addition, exosomal miR-200c-3p promotes apoptosis of HCT-116 cells. CONCLUSIONS Our findings indicate that exosomal miR-200c-3p inhibits CRC migration and invasion, and promotes their apoptosis after LPS stimulation. It is suggested as a potential diagnostic marker and therapeutic target of CRC.
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Affiliation(s)
- Yimei Jiang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Xiaopin Ji
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Kun Liu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Yiqing Shi
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Changgang Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - You Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Tao Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Yonggang He
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Ming Xiang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
| | - Ren Zhao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
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Reactivation of microRNA-506 inhibits gastric carcinoma cell metastasis through ZEB2. Aging (Albany NY) 2020; 11:1821-1831. [PMID: 30923258 PMCID: PMC6461178 DOI: 10.18632/aging.101877] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 03/10/2019] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are frequently dysregulated in a variety of human cancers, including gastric carcinoma. To improve our understanding of the role of miRNAs in gastric carcinoma and potential identify novel biomarkers or therapeutic agents, we performed microarray analysis to identify differentially expressed miRNAs in gastric carcinoma, compared with paired non-cancerous gastric tissues. We identified significantly differentially expressed miRNAs in gastric carcinoma tissues, including miR-506. We validated the microarray results by quantitative reverse transcription polymerase chain reaction in 26 specimens and confirmed significant downregulation of miR-506 in gastric carcinoma. Bioinformatics analysis predicted ZEB2 (zinc finger E-box-binding homeobox 2) as a potential target of miR-506. MiR-506 levels and ZEB2 levels were inversely correlated in gastric carcinoma, and low miR-506 levels in gastric carcinoma were associated with poor prognosis. Overexpression of miR-506 in gastric carcinoma cells significantly inhibited cell migration and invasion, while depletion of miR-506 in gastric carcinoma cells significantly increased cell migration and invasion. Transplantation of miR-506-overexpressing gastric carcinoma cells developed significantly smaller tumor, compared to the control. Thus, our results suggest that miR-506 may function as a tumor suppressor and targets and inhibits ZEB2 in gastric carcinoma.
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25
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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: 324] [Impact Index Per Article: 64.8] [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.
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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.
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26
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Zhao X, Hu GF, Shi YF, Xu W. Research Progress in microRNA-Based Therapy for Gastric Cancer. Onco Targets Ther 2019; 12:11393-11411. [PMID: 31920330 PMCID: PMC6935305 DOI: 10.2147/ott.s221354] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/10/2019] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is one of the leading causes of tumor-related mortality. In addition to surgery and endoscopic resection, systemic therapy remains the main treatment option for GC, especially for advanced-stage disease and for cases not suitable for surgical therapy. Hence, improving the efficacy of systemic therapy is still an urgent problem to overcome. In the past decade, the essential roles of microRNAs (miRNAs) in tumor treatment have been increasingly recognized. In particular, miRNAs were recently shown to reverse the resistance to chemotherapy drugs such as 5-fluorouracil, cisplatin, and doxorubicin. Synthesized nanoparticles loaded with mimics or inhibitors of miRNAs can directly target tumor cells to suppress their growth. Moreover, exosomes may serve as promising safe carriers for mimics or inhibitors of miRNAs to treat GC. Some miRNAs have also been shown to play roles in the mechanism of action of other anti-tumor drugs. Therefore, in this review, we highlight the research progress on microRNA-based therapy in GC and discuss the challenges and prospects associated with this strategy. We believe that microRNA-based therapy has the potential to offer a clinical benefit to GC patients, and this review would contribute to and motivate further research to promote this field toward this ultimate goal.
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Affiliation(s)
- Xu Zhao
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Gao-Feng Hu
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.,Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Yan-Fen Shi
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
| | - Wei Xu
- Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
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27
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Luo YJ, Huang QM, Ren Y, Liu ZL, Xu CF, Wang H, Xiao JW. Non-coding RNA in drug resistance of gastric cancer. World J Gastrointest Oncol 2019; 11:957-970. [PMID: 31798777 PMCID: PMC6883183 DOI: 10.4251/wjgo.v11.i11.957] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 09/21/2019] [Accepted: 10/03/2019] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. The poorly prognosis and survival of GC are due to diagnose in an advanced, non-curable stage and with a limited response to chemotherapy. The acquisition of drug resistance accounts for the majority of therapy failure of chemotherapy in GC patients. Although the mechanisms of anticancer drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of non-coding RNAs (ncRNAs), including long non-coding RNAs and microRNAs, in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of GC. We review the literature on ncRNAs in drug resistance of GC. This review summarizes the current knowledge about the ncRNAs’ characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant GC.
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Affiliation(s)
- Ya-Jun Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Qing-Mei Huang
- Department of Oncology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yan Ren
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Zi-Lin Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Cheng-Fei Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Hao Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Jiang-Wei Xiao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
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28
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Peng C, Huang K, Liu G, Li Y, Yu C. MiR-876-3p regulates cisplatin resistance and stem cell-like properties of gastric cancer cells by targeting TMED3. J Gastroenterol Hepatol 2019; 34:1711-1719. [PMID: 30843262 DOI: 10.1111/jgh.14649] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 02/26/2019] [Accepted: 03/04/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Gastric cancer (GC), a prevalent tumor, exerts a major economic burden, and we aimed to explore miR-876-3p's effects on GC and related mechanisms. METHODS Cell viability was analyzed via CCK-8 and colony formation assay. Stem cell-like properties were examined via spheroid colony formation assay. mRNA abundance of key genes was analyzed via quantitative polymerase chain reaction. Protein level of TMED3 and stem cell markers was examined by western blot. TargetScan, luciferase, and biotin-miRNA pulldown assay were used to identify miR-876-3p's target. RESULTS MiR-876-3p was downregulated in GC, and its mRNA level had negative relationship with cisplatin resistance of GC. Moreover, decreased miR-876-3p expression level suggested poor prognosis of GC patients. MiR-876-3p inhibited drug resistance of cisplatin-resistant cell line SGC-7901/DDP and MKN-45/DDP, as shown by decreased cell viability, IC50 , and colony formation ability. MiR-876-3p inhibited stem cell-like features and downregulated the expressions of Sox-2, Oct-4, CD133, and CD44 in GC cells. Luciferase and biotin-miRNA pulldown assay confirmed that TMED3 was miR-876-3p's direct target. TMED3 siRNA inhibited miR-876-3p's effects on cisplatin resistance and stem cell-like features of SGC-7901/DDP cells. CONCLUSION MiR-876-3p enhanced cisplatin sensitivity and restricted stem cell-like features of GC through targeting TMED3.
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Affiliation(s)
- Chunwei Peng
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Kai Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guangjie Liu
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yunsong Li
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Changjun Yu
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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29
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Wang P, Liu X, Han G, Dai S, Ni Q, Xiao S, Huang J. Downregulated lncRNA UCA1 acts as ceRNA to adsorb microRNA-498 to repress proliferation, invasion and epithelial mesenchymal transition of esophageal cancer cells by decreasing ZEB2 expression. Cell Cycle 2019; 18:2359-2376. [PMID: 31387451 PMCID: PMC6738578 DOI: 10.1080/15384101.2019.1648959] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/04/2019] [Accepted: 07/07/2019] [Indexed: 12/24/2022] Open
Abstract
Objective: Esophageal cancer (EC) is one of the most general malignant tumors in humans. There were few studies researching the connections between lncRNA UCA1 and EC. This study is to research the effect of lncRNA UCA1 adsorbing microRNA-498 (miR-498) as a ceRNA to regulate ZEB2 expression on epithelial mesenchymal transition (EMT), invasion and migration of EC cells. Methods: UCA1, miR-498 and ZEB2 expression in EC tissues and cells was detected by RT-qPCR or western blot analysis. EC cells were transfected with siRNA-UCA1, miR-498 mimics or their controls to determine cell colony, proliferation, cycle distribution, apoptosis, migration and invasion by colony formation assay, CCK-8 assay, flow cytometry, and Transwell assay, respectively. The protein expression of PCNA, c-Myc, E-cadherin, N-cadherin, MMP-2 and MMP-9 was detected by Western blot analysis. The growth rate and weight of transplanted tumor in nude mice were observed. Results: There were overly expressed UCA1 and ZEB2 and lowly expressed miR-498 in EC tissues and cells. LncRNA UCA1 acted as ceRNA to inhibit miR-498 expression and thereby increasing ZEB2 expression. With down-regulated UCA1 and up-regulated miR-498, ZEB2 expression, cell proliferation, colony formation, invasion, migration ability, EMT, tumor growth rate and weight in nude mice were apparently reduced. Conclusion: This study demonstrates that inhibited UCA1 up-regulated miR-498 and down-regulated ZEB2, thereby repressing proliferation activity, invasion, migration, and EMT of EC cells.
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Affiliation(s)
- Peng Wang
- Department of Oncology, Taizhou People’s Hospital, Taizhou, PR. China
| | - Xinfa Liu
- Anesthesiology Department, Taizhou People’s Hospital, Taizhou, PR. China
| | - Gaohua Han
- Department of Oncology, Taizhou People’s Hospital, Taizhou, PR. China
| | - Shengbin Dai
- Department of Oncology, Taizhou People’s Hospital, Taizhou, PR. China
| | - Qingtao Ni
- Department of Oncology, Taizhou People’s Hospital, Taizhou, PR. China
| | - Shujun Xiao
- Department of Gerontology, Taizhou People’s Hospital, Taizhou, PR. China
| | - Junxing Huang
- Department of Oncology, Taizhou People’s Hospital, Taizhou, PR. China
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30
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Fardi M, Alivand M, Baradaran B, Farshdousti Hagh M, Solali S. The crucial role of ZEB2: From development to epithelial-to-mesenchymal transition and cancer complexity. J Cell Physiol 2019; 234:14783-14799. [PMID: 30773635 DOI: 10.1002/jcp.28277] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 01/13/2019] [Accepted: 01/15/2019] [Indexed: 01/24/2023]
Abstract
Zinc finger E-box binding homeobox 2 (ZEB2) is a DNA-binding transcription factor, which is mainly involved in epithelial-to-mesenchymal transition (EMT). EMT is a conserved process during which mature and adherent epithelial-like state is converted into a mobile mesenchymal state. Emerging data indicate that ZEB2 plays a pivotal role in EMT-induced processes such as development, differentiation, and malignant mechanisms, for example, drug resistance, cancer stem cell-like traits, apoptosis, survival, cell cycle arrest, tumor recurrence, and metastasis. In this regard, the understanding of mentioned subjects in the development of normal and cancerous cells could be helpful in cancer complexity of diagnosis and therapy. In this study, we review recent findings about the biological properties of ZEB2 in healthy and cancerous states to find new approaches for cancer treatment.
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Affiliation(s)
- Masoumeh Fardi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Department, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Department, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Saeed Solali
- Immunology Department, Tabriz University of Medical Sciences, Tabriz, Iran
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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31
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Tan BB, Li Y. Role of microRNAs in drug resistance of gastric cancer cells. Shijie Huaren Xiaohua Zazhi 2019; 27:913-917. [DOI: 10.11569/wcjd.v27.i15.913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Drug therapy is an important component of comprehensive treatments for gastric cancer (GC), but drug resistance of cancer cells often leads to treatment failure. It is significant to explore the drug resistance mechanism of GC cells. It has been reported that microRNAs (miRNAs) are closely related to drug resistance in GC. However, there are many kinds of microRNAs, which possess complex mechanisms and are not widely applied in clinical patients, so there are still many areas to be investigated about the relationship between microRNAs and drug resistance in GC. In this review, we review the role of miRNAs in the formation of drug resistance and discuss the existing problems and future directions.
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Affiliation(s)
- Bi-Bo Tan
- Third Department of Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Yong Li
- Third Department of Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
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32
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Martinez-Gutierrez AD, Catalan OM, Vázquez-Romo R, Porras Reyes FI, Alvarado-Miranda A, Lara Medina F, Bargallo-Rocha JE, Orozco Moreno LT, Cantú De León D, Herrera LA, López-Camarillo C, Pérez-Plasencia C, Campos-Parra AD. miRNA profile obtained by next‑generation sequencing in metastatic breast cancer patients is able to predict the response to systemic treatments. Int J Mol Med 2019; 44:1267-1280. [PMID: 31364724 PMCID: PMC6713405 DOI: 10.3892/ijmm.2019.4292] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 07/03/2019] [Indexed: 12/20/2022] Open
Abstract
Metastatic breast cancer (MBC) is a challenge for oncologists, and public efforts should focus on identifying additional molecular markers and therapeutic management to improve clinical outcomes. Among all diagnosed cases of breast cancer (BC; approximately 10%) involve metastatic disease; notably, approximately 40% of patients with early-stage BC develop metastasis within 5 years. The management of MBC consists of systemic therapy. Despite different treatment options, the 5-year survival rate is <20%, which may be due to a lack of response with de novo or acquired resistance. MicroRNAs (miRNAs or miRs) are promising biomarkers as they are readily detectable and have a broad spectrum and potential clinical applications. The aim of this study was to identify a miRNA profile for distinguishing patients with MBC who respond to systemic treatment. Patients with MBC were treated according to the National Comprehensive Cancer Network guidelines. We performed miRNA-Seq on 9 primary tumors using the Thermo Fisher Scientific Ion S5 system. To obtain global miRNA profiles, we carried out differentially expressed gene elimination strategy (DEGES) analysis between the responsive and non-responsive patients. The results identified a profile of 12 miRNAs associated with the response to systemic treatment. The data were validated in an independent cohort (TCGA database). Based on the results, the upregulation of miR-342-3p and miR-187-3p was associated with the response to systemic treatment, and with an increased progression-free survival (PFS) and overall survival (OS); by contrast, the downregulation of miR-301a-3p was associated with a higher PFS and OS. On the whole, the findings of this study indicate that these miRNAs may serve as biomarkers for the response to systemic treatment or the prognosis of patients with MBC. However, these data should be validated experimentally in other robust cohorts and using different specimens before implementing these miRNAs as biomarkers in clinical practice to benefit this group of patients.
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Affiliation(s)
| | - Oliver Millan Catalan
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), UNAM, Mexico City 14080, Mexico
| | - Rafael Vázquez-Romo
- Departamento de Cirugía de Tumores Mamarios, Instituto Nacional de Cancerología (INCan), UNAM, Mexico City 14080, Mexico
| | - Fany Iris Porras Reyes
- Servicio de Anatomía Patológica, Instituto Nacional de Cancerología (INCan), UNAM, Mexico City 14080, Mexico
| | - Alberto Alvarado-Miranda
- Unidad de Cáncer de Mama, Instituto Nacional de Cancerología (INCan), UNAM, Mexico City 14080, Mexico
| | - Fernando Lara Medina
- Unidad de Cáncer de Mama, Instituto Nacional de Cancerología (INCan), UNAM, Mexico City 14080, Mexico
| | - Juan E Bargallo-Rocha
- Unidad de Cáncer de Mama, Instituto Nacional de Cancerología (INCan), UNAM, Mexico City 14080, Mexico
| | | | - David Cantú De León
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología (INCan)‑Instituto de Investigaciones Biomédicas, UNAM, Mexico City 14080, Mexico
| | - Luis Alonso Herrera
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología (INCan)‑Instituto de Investigaciones Biomédicas, UNAM, Mexico City 14080, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX, Mexico City 03100, Mexico
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), UNAM, Mexico City 14080, Mexico
| | - Alma D Campos-Parra
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), UNAM, Mexico City 14080, Mexico
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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
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34
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Li M, Gao M, Xie X, Zhang Y, Ning J, Liu P, Gu K. MicroRNA-200c reverses drug resistance of human gastric cancer cells by targeting regulation of the NER-ERCC3/4 pathway. Oncol Lett 2019; 18:145-152. [PMID: 31289483 PMCID: PMC6539893 DOI: 10.3892/ol.2019.10304] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 03/13/2019] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common types of malignant tumor. Due to the lack of effective drugs and the emergence of chemotherapy resistance, patients with GC exhibit a poor prognosis and low survival rate. MicroRNAs (miRNAs/miRs) serve an important role in drug resistance of different types of cancer. They may be suitable for use as biomarkers in the diagnosis, treatment and prognosis of tumors. The present study aimed to investigate the molecular mechanism underlying the ability of miR-200c-3p to reverse drug resistance in a SGC7901/DDP GC cell line, particularly its effects on the ERCC excision repair 3, TFIIH core complex helicase subunit (ERCC3) and ERCC excision repair 4, endonuclease catalytic subunit (ERCC4) proteins in the nucleotide excision repair (NER) pathway. Reverse transcription-quantitative polymerase chain reaction demonstrated that miR-200c-3p expression in cisplatin-resistant SGC7901/DDP cells was lower than in parental SGC7901 cells, whereas the protein expression levels of ERCC3 and ERCC4 in these cells were higher by western blot analysis. In SGC7901/DDP-derived miR-200c-3p overexpressing cells, ERCC3 expression, ERCC4 expression and cisplatin resistance were decreased compared with in parental SGC7901/DDP cells and SGC7901/DDP-derived vector control cells. In SGC7901-derived miR-200c-3p knockdown cells, ERCC3 expression, ERCC4 expression and cisplatin resistance were increased compared with in parental SGC7901 cells and SGC7901-derived vector control cells. In conclusion, overexpression of miR-200c-3p may reverse drug resistance in the SGC7901/DDP GC cell line via downregulation of ERCC3 and ERCC4, which suggested this may be part of a mechanism involving the NER pathway.
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Affiliation(s)
- Min Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Min Gao
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xiaoque Xie
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Yiyin Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Jie Ning
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Pingping Liu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Kangsheng Gu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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Zhang LQ, Lu N. Role of miR-200c in early diagnosis of gastric cancer: Current status and prospects. Shijie Huaren Xiaohua Zazhi 2019; 27:382-388. [DOI: 10.11569/wcjd.v27.i6.382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of the digestive tract, and its morbidity and mortality still rank the second among all cancers. The proportion of patients with advanced GC is higher, and their therapeutic effect is extremely poor. In recent years, numerous studies have shown that the content of miR-200c in GC patients is significantly increased, and the level of miR-200c is closely related to epithelial-mesenchymal transition and lymph node metastasis. Therefore, in-depth disclosure of the role of miR-200c in the diagnosis of GC will not only contribute to the early diagnosis of GC, but also help develop new effective treatment strategies and judge the prognosis of patients with GC. This article reviews the role of miR-200c in the early diagnosis of GC and discusses its application prospects.
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Affiliation(s)
- Ling-Qian Zhang
- Department of Oncology, Xinjiang Military Command General Hospital of PLA, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
| | - Ning Lu
- Department of Oncology, Xinjiang Military Command General Hospital of PLA, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
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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.
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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
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Corrà F, Agnoletto C, Minotti L, Baldassari F, Volinia S. The Network of Non-coding RNAs in Cancer Drug Resistance. Front Oncol 2018; 8:327. [PMID: 30211115 PMCID: PMC6123370 DOI: 10.3389/fonc.2018.00327] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/31/2018] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have been implicated in most cellular functions. The disruption of their function through somatic mutations, genomic imprinting, transcriptional and post-transcriptional regulation, plays an ever-increasing role in cancer development. ncRNAs, including notorious microRNAs, have been thus proposed to function as tumor suppressors or oncogenes, often in a context-dependent fashion. In parallel, ncRNAs with altered expression in cancer have been reported to exert a key role in determining drug sensitivity or restoring drug responsiveness in resistant cells. Acquisition of resistance to anti-cancer drugs is a major hindrance to effective chemotherapy and is one of the most important causes of relapse and mortality in cancer patients. For these reasons, non-coding RNAs have become recent focuses as prognostic agents and modifiers of chemo-sensitivity. This review starts with a brief outline of the role of most studied non-coding RNAs in cancer and then highlights the modulation of cancer drug resistance via known ncRNAs based mechanisms. We identified from literature 388 ncRNA-drugs interactions and analyzed them using an unsupervised approach. Essentially, we performed a network analysis of the non-coding RNAs with direct relations with cancer drugs. Within such a machine-learning framework we detected the most representative ncRNAs-drug associations and groups. We finally discussed the higher integration of the drug-ncRNA clusters with the goal of disentangling effectors from downstream effects and further clarify the involvement of ncRNAs in the cellular mechanisms underlying resistance to cancer treatments.
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Affiliation(s)
- Fabio Corrà
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Chiara Agnoletto
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Linda Minotti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Federica Baldassari
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano Volinia
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
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Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer. Oncotarget 2018; 9:24457-24469. [PMID: 29849953 PMCID: PMC5966259 DOI: 10.18632/oncotarget.25326] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 04/17/2018] [Indexed: 12/21/2022] Open
Abstract
In this study, we identified microRNAs (miRNAs) involved in cisplatin (CDDP) resistance in bladder cancer (BCa). After establishing CDDP-resistant BCa cell lines (T24RC and EJ138RC), TaqMan arrays revealed that members of the miR-200 family (miR-200b, miR-200a and miR-429) were downregulated in T24RC as compared to parental T24 cells. miR-200b was associated with CDDP sensitivity in BCa cells, and its downregulation was associated with CpG island hypermethylation. Pharmacological demethylation using 5-aza-2’-deoxycytidine restored miR-200b expression, and the combination of 5-aza-2’-deoxycytidine + CDDP strongly inhibited T24RC cell proliferation. Microarray analysis revealed that miR-200b + CDDP induced genes involved in CDDP sensitivity or cytotoxicity, including IGFBP3, ICAM1 and TNFSF10, in the resistant cells. Expression and DNA methylation of miR-200b were inversely associated in primary BCa, and low expression/high methylation was associated with poor overall survival. These results suggest downregulation of miR-200b is associated with CDDP resistance in BCa. Epigenetic silencing of miR-200b may be a marker of CDDP resistance and a useful therapeutic target for overcoming CDDP resistance in BCa.
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Zhang Y, Lin S, Chen Y, Yang F, Liu S. LDH-Apromotes epithelial-mesenchymal transition by upregulating ZEB2 in intestinal-type gastric cancer. Onco Targets Ther 2018; 11:2363-2373. [PMID: 29740212 PMCID: PMC5931238 DOI: 10.2147/ott.s163570] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Introduction Epithelial-mesenchymal transition (EMT) is regarded as a crucial process of invasion and metastasis, which contribute greatly to cancer-related relapse and death. Based on research results that hypoxia can trigger gastric cancer EMT and decreasing lactate production can selectively kill hypoxic cancer cells, we infer that lactate dehydrogenase A (LDH-A) transforming pyruvate into lactate is at least in part responsible for poor prognosis of gastric cancer. Materials and methods We used siRNA to knock down LDH-A in intestinal-type gastric cancer (ITGC) cell lines SGC7901 and BGC823. Western blot and RT-PCR were applied to detect mRNA and protein expression of EMT-related genes, respectively. Transwell invasion assay and migration assay were applied to study invasive and migratory abilities, respectively. Survival analysis was used to evaluate prognostic values. Results and conclusion The results of in vitro experiment demonstrated that LDH-A facilitates ITGC cells’ invasion and migration by upregulating ZEB2. The positive correlation between LDH-A and ZEB2 was verified in 371 ITGC specimens. Survival analysis indicated that co-expression of LDH-A/ZEB2 had synergetic power to predict overall survival. Thus, we conclude that the close relationship between LDH-A and ZEB2 may offer a potential therapeutic strategy for ITGC.
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Affiliation(s)
- Yongjie Zhang
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, People's Republic of China.,Department of Medical Oncology, Huai'an Hospital to Xuzhou Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Sen Lin
- Clinical Laboratory, Huai'an Hospital to Xuzhou Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Yan Chen
- Department of Medical Oncology, Huai'an Hospital to Xuzhou Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Fei Yang
- Department of Medical Oncology, Huai'an Hospital to Xuzhou Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Shenlin Liu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
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Zhou X, Men X, Zhao R, Han J, Fan Z, Wang Y, Lv Y, Zuo J, Zhao L, Sang M, Liu XD, Shan B. miR-200c inhibits TGF-β-induced-EMT to restore trastuzumab sensitivity by targeting ZEB1 and ZEB2 in gastric cancer. Cancer Gene Ther 2018; 25:68-76. [DOI: 10.1038/s41417-017-0005-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/12/2017] [Accepted: 10/20/2017] [Indexed: 02/08/2023]
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