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Li KQ, Bai X, Ke AT, Ding SQ, Zhang CD, Dai DQ. Ubiquitin-specific proteases: From biological functions to potential therapeutic applications in gastric cancer. Biomed Pharmacother 2024; 173:116323. [PMID: 38401523 DOI: 10.1016/j.biopha.2024.116323] [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: 12/04/2023] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 02/26/2024] Open
Abstract
Deubiquitination, a post-translational modification regulated by deubiquitinases, is essential for cancer initiation and progression. Ubiquitin-specific proteases (USPs) are essential elements of the deubiquitinase family, and are overexpressed in gastric cancer (GC). Through the regulation of several signaling pathways, such as Wnt/β-Catenin and nuclear factor-κB signaling, and the promotion of the expression of deubiquitination- and stabilization-associated proteins, USPs promote the proliferation, metastasis, invasion, and epithelial-mesenchymal transition of GC. In addition, the expression of USPs is closely related to clinicopathological features, patient prognosis, and chemotherapy resistance. USPs therefore could be used as prognostic biomarkers. USP targeting small molecule inhibitors have demonstrated strong anticancer activity. However, they have not yet been tested in the clinic. This article provides an overview of the latest fundamental research on USPs in GC, aiming to enhance the understanding of how USPs contribute to GC progression, and identifying possible targets for GC treatment to improve patient survival.
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Affiliation(s)
- Kai-Qiang Li
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Xiao Bai
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Ang-Ting Ke
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Si-Qi Ding
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Chun-Dong Zhang
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Dong-Qiu Dai
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China; Cancer Center, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China.
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Hu Y, Li J, Liu C, Zhang X, Wang Y, Lin J, Peng Z, Zhu L. MiR362-3p Alleviates Osteosarcoma by Regulating the IL6ST/JAK2/STAT3 Pathway in Vivo and in Vitro. Technol Cancer Res Treat 2024; 23:15330338241261616. [PMID: 39051528 PMCID: PMC11273602 DOI: 10.1177/15330338241261616] [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: 01/21/2024] [Revised: 05/06/2024] [Accepted: 05/22/2024] [Indexed: 07/27/2024] Open
Abstract
Objectives: To investigate the effects and the related signaling pathway of miR-362-3p on OS. Methods: The bioinformatics analysis approaches were employed to investigate the target pathway of miR-362-3p. After the 143B and U2OS cells and nu/nu male mice were randomly divided into blank control (BC) group, normal control (NC) group, and overexpression group (OG), the CCK-8, EdU staining, wound healing assay, Transwell assay, and TUNEL staining were adopted to respectively determine the effects of overexpressed miR-362-3p on the cell viability, proliferation, migration, invasion, and apoptosis of 143B and U2OS cells in vitro, tumor area assay and hematoxylin and eosin staining were employed to respectively determine the effects of overexpressed miR-362-3p on the growth and pathological injury of OS tissue in vivo. The qRT-PCR, Western blot, and immunohistochemical staining were applied to respectively investigate the effects of overexpressed miR-362-3p on the IL6ST/JAK2/STAT3 pathway in OS in vivo and in vitro. Results: The bioinformatics analysis approaches combined qRT-PCR indicated that the IL6ST/JAK2/STAT3 is one of the target pathways of miR-362-3p. Compared with NC, the cell viability, proliferation, migration, and invasion of 143B and U2OS cells were dramatically (P < 0.01) inhibited but the apoptosis was prominently (P <0 .0001) promoted in OG. Compared with NC, the growth of OS tissue was significantly (P < 0.05) suppressed and the pathological injury of OS tissue was substantially aggravated in OG. The gene expression levels of IL6ST, JAK2, and STAT3 and the protein expression levels of IL6ST, JAK2, p-JAK2, STAT3, and p-STAT3 in 143B and U2OS cells were memorably (P < 0.0001) lower in OG than those in NC. In addition, the positively stained areas of proteins of IL6ST, JAK2, p-JAK2, STAT3, and p-STAT3 of OS tissue in OG were markedly (P < 0.01) reduced compared with those in NC. Conclusion: The overexpression of miR362-3p alleviates OS by inhibiting the IL6ST/JAK2/STAT3 pathway in vivo and in vitro.
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Affiliation(s)
- Yunteng Hu
- Department of Spine Surgery, Zhujiang Hosptial, Southern Medical University, Guangzhou, China
| | - Jianjun Li
- Department of Spine Surgery, Zhujiang Hosptial, Southern Medical University, Guangzhou, China
| | - Chun Liu
- Department of Spine Surgery, Zhujiang Hosptial, Southern Medical University, Guangzhou, China
| | - Xue Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Gannan Medical College, Ganzhou, China
| | - Yihan Wang
- Department of Spine Surgery, Zhujiang Hosptial, Southern Medical University, Guangzhou, China
| | - Jiezhao Lin
- Department of Spine Surgery, Zhujiang Hosptial, Southern Medical University, Guangzhou, China
| | - Ziyue Peng
- Department of Spine Surgery, Zhujiang Hosptial, Southern Medical University, Guangzhou, China
| | - Lixin Zhu
- Department of Spine Surgery, Zhujiang Hosptial, Southern Medical University, Guangzhou, China
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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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Chamandi G, El-Hajjar L, El Kurdi A, Le Bras M, Nasr R, Lehmann-Che J. ER Negative Breast Cancer and miRNA: There Is More to Decipher Than What the Pathologist Can See! Biomedicines 2023; 11:2300. [PMID: 37626796 PMCID: PMC10452617 DOI: 10.3390/biomedicines11082300] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/03/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer (BC), the most prevalent cancer in women, is a heterogenous disease. Despite advancements in BC diagnosis, prognosis, and therapeutics, survival rates have drastically decreased in the metastatic setting. Therefore, BC still remains a medical challenge. The evolution of high-throughput technology has highlighted gaps in the classification system of BCs. Of particular interest is the notorious triple negative BC, which was recounted as being heterogenous itself and it overlaps with distinct subtypes, namely molecular apocrine (MA) and luminal androgen (LAR) BCs. These subtypes are, even today, still misdiagnosed and poorly treated. As such, researchers and clinicians have been looking for ways through which to refine BC classification in order to properly understand the initiation, development, progression, and the responses to the treatment of BCs. One tool is biomarkers and, specifically, microRNA (miRNA), which are highly reported as associated with BC carcinogenesis. In this review, the diverse roles of miRNA in estrogen receptor negative (ER-) and androgen receptor positive (AR+) BC are depicted. While highlighting their oncogenic and tumor suppressor functions in tumor progression, we will discuss their diagnostic, prognostic, and predictive biomarker potentials, as well as their drug sensitivity/resistance activity. The association of several miRNAs in the KEGG-reported pathways that are related to ER-BC carcinogenesis is presented. The identification and verification of accurate miRNA panels is a cornerstone for tackling BC classification setbacks, as is also the deciphering of the carcinogenesis regulators of ER - AR + BC.
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Affiliation(s)
- Ghada Chamandi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon; (G.C.); (L.E.-H.)
- Pathophysiology of Breast Cancer Team, INSERM U976, Immunologie Humaine, Pathophysiologie, Immunothérapie (HIPI), Université Paris Cité, 75010 Paris, France;
| | - Layal El-Hajjar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon; (G.C.); (L.E.-H.)
- Office of Basic/Translational Research and Graduate Studies, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon
| | - Abdallah El Kurdi
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon;
| | - Morgane Le Bras
- Pathophysiology of Breast Cancer Team, INSERM U976, Immunologie Humaine, Pathophysiologie, Immunothérapie (HIPI), Université Paris Cité, 75010 Paris, France;
| | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon; (G.C.); (L.E.-H.)
| | - Jacqueline Lehmann-Che
- Pathophysiology of Breast Cancer Team, INSERM U976, Immunologie Humaine, Pathophysiologie, Immunothérapie (HIPI), Université Paris Cité, 75010 Paris, France;
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5
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An T, Lu Y, Gong Z, Wang Y, Su C, Tang G, Hou J. Research Progress for Targeting Deubiquitinases in Gastric Cancers. Cancers (Basel) 2022; 14:cancers14235831. [PMID: 36497313 PMCID: PMC9735992 DOI: 10.3390/cancers14235831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Gastric cancers (GCs) are malignant tumors with a high incidence that threaten global public health. Despite advances in GC diagnosis and treatment, the prognosis remains poor. Therefore, the mechanisms underlying GC progression need to be identified to develop prognostic biomarkers and therapeutic targets. Ubiquitination, a post-translational modification that regulates the stability, activity, localization, and interactions of target proteins, can be reversed by deubiquitinases (DUBs), which can remove ubiquitin monomers or polymers from modified proteins. The dysfunction of DUBs has been closely linked to tumorigenesis in various cancer types, and targeting certain DUBs may provide a potential option for cancer therapy. Multiple DUBs have been demonstrated to function as oncogenes or tumor suppressors in GC. In this review, we summarize the DUBs involved in GC and their associated upstream regulation and downstream mechanisms and present the benefits of targeting DUBs for GC treatment, which could provide new insights for GC diagnosis and therapy.
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Affiliation(s)
- Tao An
- School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Yanting Lu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250353, China
| | - Zhaoqi Gong
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Yongtao Wang
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Chen Su
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen 361005, China
| | - Guimei Tang
- School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
- Correspondence: (G.T.); (J.H.)
| | - Jingjing Hou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen 361005, China
- Correspondence: (G.T.); (J.H.)
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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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Sheida A, Taghavi T, Shafabakhsh R, Ostadian A, Razaghi Bahabadi Z, Khaksary Mahabady M, Hamblin MR, Mirzaei H. Potential of natural products in the treatment of myocardial infarction: focus on molecular mechanisms. Crit Rev Food Sci Nutr 2022; 63:5488-5505. [PMID: 34978223 DOI: 10.1080/10408398.2021.2020720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although conventional drugs are widely used in the prevention and treatment of cardiovascular disease (CVD), they are being used less frequently due to concerns about possible side effects over the long term. There has been a renewed research interest in medicinal plant products, and their role in protecting the cardiovascular system and treating CVD, which are now being considered as potential alternatives to modern drugs. The most important mechanism causing damage to the myocardium after heart attack and reperfusion, is increased levels of free radicals and oxidative stress. Therefore, treatment approaches often focus on reducing free radicals or enhancing antioxidant defense mechanism. It has been previously reported that bioactive natural products can protect the heart muscle in myocardial infarction (MI). Since these compounds are readily available in fruits and vegetables, they could prevent the risk of MI if they are consumed daily. Although the benefits of a healthy diet are well known, many scientific studies have focused on whether pure natural compounds can prevent and treat MI. In this review we summarize the effects of curcumin, resveratrol, quercitin, berberine, and tanshinone on MI and CVD, and focus on their proposed molecular mechanisms of action.
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Affiliation(s)
- Amirhossein Sheida
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Rana Shafabakhsh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirreza Ostadian
- Department of Laboratory Medicine, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Razaghi Bahabadi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - 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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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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NF-κB in Gastric Cancer Development and Therapy. Biomedicines 2021; 9:biomedicines9080870. [PMID: 34440074 PMCID: PMC8389569 DOI: 10.3390/biomedicines9080870] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/09/2021] [Accepted: 07/20/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is considered one of the most common causes of cancer-related death worldwide and, thus, a major health problem. A variety of environmental factors including physical and chemical noxae, as well as pathogen infections could contribute to the development of gastric cancer. The transcription factor nuclear factor kappa B (NF-κB) and its dysregulation has a major impact on gastric carcinogenesis due to the regulation of cytokines/chemokines, growth factors, anti-apoptotic factors, cell cycle regulators, and metalloproteinases. Changes in NF-κB signaling are directed by genetic alterations in the transcription factors themselves, but also in NF-κB signaling molecules. NF-κB actively participates in the crosstalk of the cells in the tumor micromilieu with divergent effects on the heterogeneous tumor cell and immune cell populations. Thus, the benefits/consequences of therapeutic targeting of NF-κB have to be carefully evaluated. In this review, we address recent knowledge about the mechanisms and consequences of NF-κB dysregulation in gastric cancer development and therapy.
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Inhibitory feedback control of NF-κB signalling in health and disease. Biochem J 2021; 478:2619-2664. [PMID: 34269817 PMCID: PMC8286839 DOI: 10.1042/bcj20210139] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/14/2021] [Accepted: 06/16/2021] [Indexed: 12/14/2022]
Abstract
Cells must adapt to changes in their environment to maintain cell, tissue and organismal integrity in the face of mechanical, chemical or microbiological stress. Nuclear factor-κB (NF-κB) is one of the most important transcription factors that controls inducible gene expression as cells attempt to restore homeostasis. It plays critical roles in the immune system, from acute inflammation to the development of secondary lymphoid organs, and also has roles in cell survival, proliferation and differentiation. Given its role in such critical processes, NF-κB signalling must be subject to strict spatiotemporal control to ensure measured and context-specific cellular responses. Indeed, deregulation of NF-κB signalling can result in debilitating and even lethal inflammation and also underpins some forms of cancer. In this review, we describe the homeostatic feedback mechanisms that limit and ‘re-set’ inducible activation of NF-κB. We first describe the key components of the signalling pathways leading to activation of NF-κB, including the prominent role of protein phosphorylation and protein ubiquitylation, before briefly introducing the key features of feedback control mechanisms. We then describe the array of negative feedback loops targeting different components of the NF-κB signalling cascade including controls at the receptor level, post-receptor signalosome complexes, direct regulation of the critical ‘inhibitor of κB kinases’ (IKKs) and inhibitory feedforward regulation of NF-κB-dependent transcriptional responses. We also review post-transcriptional feedback controls affecting RNA stability and translation. Finally, we describe the deregulation of these feedback controls in human disease and consider how feedback may be a challenge to the efficacy of inhibitors.
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Malczewska A, Frampton AE, Mato Prado M, Ameri S, Dabrowska AF, Zagorac S, Clift AK, Kos-Kudła B, Faiz O, Stebbing J, Castellano L, Frilling A. Circulating MicroRNAs in Small-bowel Neuroendocrine Tumors: A Potential Tool for Diagnosis and Assessment of Effectiveness of Surgical Resection. Ann Surg 2021; 274:e1-e9. [PMID: 31373926 DOI: 10.1097/sla.0000000000003502] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.
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Affiliation(s)
- Anna Malczewska
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Adam E Frampton
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
| | - Mireia Mato Prado
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
| | - Shima Ameri
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
| | - Aleksandra F Dabrowska
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
| | - Sladjana Zagorac
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
| | - Ashley K Clift
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
| | - Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Omar Faiz
- St. Mark's Hospital, Harrow, Middlesex, UK
| | - Justin Stebbing
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
| | - Leandro Castellano
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
- University of Sussex, School of Life Sciences, John Maynard Smith Building, Falmer, Brighton, UK
| | - Andrea Frilling
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK
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12
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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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13
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Chen R, Yang M, Huang W, Wang B. Cascades between miRNAs, lncRNAs and the NF-κB signaling pathway in gastric cancer (Review). Exp Ther Med 2021; 22:769. [PMID: 34055068 PMCID: PMC8145527 DOI: 10.3892/etm.2021.10201] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 04/28/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is a common digestive tract malignancy that is mainly treated with surgery combined with perioperative adjuvant chemoradiotherapy and biological targeted therapy. However, the diagnosis rate of early gastric cancer is low and both postoperative recurrence and distant metastasis are thorny problems. Therefore, it is essential to study the pathogenesis of gastric cancer and search for more effective means of treatment. The nuclear factor-κB (NF-κB) signaling pathway has an important role in the occurrence and development of gastric cancer and recent studies have revealed that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are able to regulate this pathway through a variety of mechanisms. Understanding these interrelated molecular mechanisms is helpful in guiding improvements in gastric cancer treatment. In the present review, the functional associations between miRNAs, lncRNAs and the NF-κB signaling pathway in the occurrence, development and prognosis of gastric cancer were discussed. It was concluded that miRNAs and lncRNAs have complex relations with the NF-κB signaling pathway in gastric cancer. miRNAs/target genes/NF-κB/target proteins, signaling molecules/NF-κB/miRNAs/target genes, lncRNAs/miRNAs/NF-κB/genes or mRNAs, lncRNAs/target genes/NF-Κb/target proteins, and lncRNAs/NF-κB/target proteins cascades are all important factors in the occurrence and development of gastric cancer.
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Affiliation(s)
- Risheng Chen
- Department of Anesthesiology, Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Mingxiu Yang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology (2016TP1015), Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Weiguo Huang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology (2016TP1015), Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Baiyun Wang
- Department of Anesthesiology, Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
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14
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Li B, Zhang H. Knockdown of microRNA-130b improves doxorubicin sensitivity in bladder urothelial carcinoma by negatively regulating cylindromatosis expression. Arch Med Sci 2021; 17:1038-1043. [PMID: 34336031 PMCID: PMC8314415 DOI: 10.5114/aoms.2019.86622] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 07/25/2018] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Chemotherapeutic resistance reduces the sensitivity of bladder urothelial carcinoma (BUC) to chemotherapeutic drugs and contributes a barrier leading to treatment failure. The purpose of this research project is to investigate the regulatory effects of miR-130b on chemotherapeutic drug resistance of BUC and its mechanism. MATERIAL AND METHODS The relative expression of miRNA-130b and cylindromatosis (CYLD) was examined using real-time quantitative PCR. The cell proliferation and doxorubicin sensitivity were detected with the enhanced CCK-8 assay. The specific combination of miR-130b and CYLD was verified with the luciferase reporter gene assay. Protein expression was detected by Western blot. RESULTS Our study found that miR-130b was up-regulated in doxorubicin-insensitive BUC tissues and cell lines, and its high expression was negatively related to doxorubicin sensitivity in BUC. The miR-130b knockdown reduced the IC50 of doxorubicin and improved doxorubicin sensitivity of J82/Dox and T24/Dox cells. For the regulation mechanism analysis of miR-130b, bioinformatics analysis software was used to predict the potential targets of miR-130b, including the CYLD gene. The following luciferase activities assay, quantitative real time-PCR and western blot identified the CYLD gene as a target of miR-130b. Knockdown of CYLD reversed miR-130b's regulatory roles in doxorubicin sensitivity in J82/Dox and T24/Dox cells. CONCLUSIONS High expression of miR-130b is negatively related to doxorubicin sensitivity in BUC, and knockdown of miR-130b improves doxorubicin sensitivity in BUC by negatively regulating CYLD expression. Our findings will provide guidance for the clinical chemotherapy of BUC.
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Affiliation(s)
- Bo Li
- China Medical University, Shenyang, China
| | - Hui Zhang
- China Medical University, Shenyang, China
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15
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Cheng HP, Huang CJ, Tsai ML, Ong HT, Cheong SK, Choo KB, Chiou SH. MicroRNA-362 negatively and positively regulates SMAD4 expression in TGF-β/SMAD signaling to suppress cell migration and invasion. Int J Med Sci 2021; 18:1798-1809. [PMID: 33746597 PMCID: PMC7976584 DOI: 10.7150/ijms.50871] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 01/23/2021] [Indexed: 11/05/2022] Open
Abstract
Cell migration and invasion are modulated by epithelial-to-mesenchymal transition (EMT) and the reverse MET process. Despite the detection of microRNA-362 (miR-362, both the miR-362-5p and -3p species) in cancers, none of the identified miR-362 targets is a mesenchymal or epithelial factor to link miR-362 with EMT/MET and metastasis. Focusing on the TGF-β/SMAD signaling pathway in this work, luciferase assays and western blot data showed that miR-362 targeted and negatively regulated expression of SMAD4 and E-cadherin, but not SNAI1, which is regulated by SMAD4. However, miR-362 knockdown also down-regulated SMAD4 and SNAI1, but up-regulated E-cadherin expression. Wound-healing and transwell assays further showed that miR-362 knockdown suppressed cell migration and invasion, effects which were reversed by over-expressing SMAD4 or SNAI1, or by knocking down E-cadherin in the miR-362 knockdown cells. In orthotopic mice, miR-362 knockdown inhibited metastasis, and displayed the same SMAD4 and E-cadherin expression profiles in the tumors as in the in vitro studies. A scheme is proposed to integrate miR-362 negative regulation via SMAD4, and to explain miR-362 positive regulation of SMAD4 via miR-362 targeting of known SMAD4 suppressors, BRK and DACH1, which would have resulted in SMAD4 depletion and annulment of subsequent involvement in TGF-β signaling actions. Hence, miR-362 both negatively and positively regulates SMAD4 expression in TGF-β/SMAD signaling pathway to suppress cell motility and invasiveness and metastasis, and may explain the reported clinical association of anti-miR-362 with suppressed metastasis in various cancers. MiR-362 knockdown in miR-362-positive cancer cells may be used as a therapeutic strategy to suppress metastasis.
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Affiliation(s)
- Han Ping Cheng
- Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia.,Postgraduate Program, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia.,Institutes of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Chiu-Jung Huang
- Department of Animal Science & Graduate Institute of Biotechnology, Chinese Culture University, Taipei, Taiwan
| | - Ming-Long Tsai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hooi Tin Ong
- Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Soon Keng Cheong
- Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia.,Dean's Office, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Kong Bung Choo
- Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia.,Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.,Institutes of Pharmacology, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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16
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Martins JRB, de Moraes LN, Cury SS, Dadalto J, Capannacci J, Carvalho RF, Nogueira CR, Hokama NK, Hokama PDOM. Comparison of microRNA Expression Profile in Chronic Myeloid Leukemia Patients Newly Diagnosed and Treated by Allogeneic Hematopoietic Stem Cell Transplantation. Front Oncol 2020; 10:1544. [PMID: 33014798 PMCID: PMC7500210 DOI: 10.3389/fonc.2020.01544] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 07/20/2020] [Indexed: 01/07/2023] Open
Abstract
Chronic myeloid leukemia (CML) results from a translocation between chromosomes 9 and 22, which generates the Philadelphia chromosome. This forms BCR/ABL1, an active tyrosine kinase protein that promotes cell growth and replication. Despite great progress in CML treatment in the form of tyrosine kinase inhibitors, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) is currently used as an important treatment alternative for patients resistant to these inhibitors. Studies have shown that unregulated expression of microRNAs, which act as oncogenes or tumor suppressors, is associated with human cancers. This contributes to tumor formation and development by stimulating proliferation, angiogenesis, and invasion. Research has demonstrated the potential of microRNAs as biomarkers for cancer diagnosis, prognosis, and therapeutic targets. In the present study, we compared the circulating microRNA expression profiles of 14 newly diagnosed patients with chronic phase-CML and 14 Philadelphia chromosome-negative patients after allo-HSCT. For each patient, we tested 758 microRNAs by reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis. The global expression profile of microRNAs revealed 16 upregulated and 30 downregulated microRNAs. Target genes were analyzed, and key pathways were extracted and compared. Bioinformatics tools were used to analyze data. Among the downregulated miRNA target genes, some genes related to cell proliferation pathways were identified. These results reveal the comprehensive microRNA profile of CML patients and the main pathways related to the target genes of these miRNAs in cytogenetic remission after allo-HSCT. These results provide new resources for exploring stem cell transplantation-based CML treatment strategies.
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Affiliation(s)
| | | | - Sarah Santiloni Cury
- Department of Structural and Functional Biology, São Paulo State University (UNESP-IBB), Botucatu, Brazil
| | - Juliane Dadalto
- Department of Internal Medicine, São Paulo State University (UNESP-FMB), Botucatu, Brazil
| | - Juliana Capannacci
- Department of Internal Medicine, São Paulo State University (UNESP-FMB), Botucatu, Brazil
| | - Robson Francisco Carvalho
- Department of Structural and Functional Biology, São Paulo State University (UNESP-IBB), Botucatu, Brazil
| | - Célia Regina Nogueira
- Department of Internal Medicine, São Paulo State University (UNESP-FMB), Botucatu, Brazil
| | - Newton Key Hokama
- Department of Internal Medicine, São Paulo State University (UNESP-FMB), Botucatu, Brazil
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17
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Barraclough JY, Joglekar MV, Januszewski AS, Martínez G, Celermajer DS, Keech AC, Hardikar AA, Patel S. A MicroRNA Signature in Acute Coronary Syndrome Patients and Modulation by Colchicine. J Cardiovasc Pharmacol Ther 2020; 25:444-455. [PMID: 32356454 DOI: 10.1177/1074248420922793] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Circulating microRNAs (miRNAs) may play a pathogenic role in acute coronary syndromes (ACS). It is not yet known if miRNAs dysregulated in ACS are modulated by colchicine. We profiled miRNAs in plasma samples simultaneously collected from the aorta, coronary sinus, and right atrium in patients with ACS. METHODS A total of 396 of 754 miRNAs were detected by TaqMan real-time polymerase chain reaction from EDTA-plasma in a discovery cohort of 15 patients (n = 3 controls, n = 6 ACS standard therapy, n = 6 ACS standard therapy plus colchicine). Fifty-one significantly different miRNAs were then measured in a verification cohort of 92 patients (n = 13 controls, n = 40 ACS standard therapy, n = 39 ACS standard therapy plus colchicine). Samples were simultaneously obtained from the coronary sinus, aortic root, and right atrium. RESULTS Circulating levels of 30 of 51 measured miRNAs were higher in ACS standard therapy patients compared to controls. In patients with ACS, levels of 12 miRNAs (miR-17, -106b-3p, -191, -106a, -146a, -130a, -223, -484, -889, -425-3p, -629, -142-5p) were lower with colchicine treatment. Levels of 7 of these 12 miRNA were higher in ACS standard therapy patients compared to controls and returned to levels seen in control individuals after colchicine treatment. Three miRNAs suppressed by colchicine (miR-146a, miR-17, miR-130a) were identified as regulators of inflammatory pathways. MicroRNAs were comparable across sampling sites with select differences in the transcoronary gradient of 4 miRNA. CONCLUSION The levels of specific miRNAs elevated in ACS returned to levels similar to control individuals following colchicine. These miRNAs may mediate ACS (via inflammatory pathways) or increase post-ACS risk, and could be potentially used as biomarkers of treatment efficacy.
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Affiliation(s)
- Jennifer Y Barraclough
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.,Sydney Medical School, The University of Sydney, Australia.,Heart Research Institute Sydney, Australia
| | - Mugdha V Joglekar
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Australia
| | - Andrzej S Januszewski
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Australia
| | - Gonzalo Martínez
- Heart Research Institute Sydney, Australia.,Division of Cardiovascular Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - David S Celermajer
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.,Sydney Medical School, The University of Sydney, Australia.,Heart Research Institute Sydney, Australia
| | - Anthony C Keech
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.,NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Australia
| | - Anandwardhan A Hardikar
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Australia
| | - Sanjay Patel
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.,Sydney Medical School, The University of Sydney, Australia.,Heart Research Institute Sydney, Australia
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18
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Comparing MicroRNA Profilings of Purified HER-2-Negative and HER-2-Positive Cells Validates miR-362-5p/Sema3A as Characteristic Molecular Change in Triple-Negative Breast Cancers. DISEASE MARKERS 2019; 2019:6057280. [PMID: 31929841 PMCID: PMC6935799 DOI: 10.1155/2019/6057280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 09/11/2019] [Accepted: 09/28/2019] [Indexed: 12/20/2022]
Abstract
Background HER-2 is a key molecule serving as the therapeutic target, prognostic biomarker, and classification marker in breast cancer. Accurate microRNA profilings had not been conducted in purified tumor cells of HER-2-negative and HER-2-positive tissue specimens obtained from breast cancer patients. Methods (i) Differential expression microRNA discovery using laser capture microdissection- (LCM-) assisted specimen preparation and microRNA array chips on HER-2 overexpressing and triple-negative breast carcinoma (TNBC) subtype tissues, (ii) differential expression microRNA validation by quantitative real-time PCR, and (iii) independent validation on tissue microarray. Results Five microRNAs (miR-20a-5p, miR-221-3p, miR-362-5p, miR-502-3p, and miR-222-3p) were screened and validated as upregulated microRNAs in TNBC cells comparing to HER-2 overexpressing cells using a microRNA array (5 cases in each group) and quantitative real-time PCR (20 cases in each group). The expression difference of miR-362-5p had the most significant statistical significance (p = 0.0016) among the five microRNAs. The expression of miR-362-5p and its target gene Sema3A was further analyzed using in situ hybridization (ISH) and immunohistochemistry on standard tissue sections (n = 150). 70.8% of HER-2-negative cells showed moderate expression of miR-362-5p whereas 20.4% HER-2-negative cells correlated with strong expression of miR-362-5p (p < 0.0001). The proportion of patients with moderate/strong miR-362-5p expression in luminal, HER-2 overexpressing, and TNBC subtypes were 53.2%, 22.2%, and 74.3%, respectively (p = 0.0002). High miR-362-5p expressers had shorter overall survival in the univariate analysis (p = 0.046). There was a significant negative correlation between miR-362-5p and Sema3A expression (p < 0.0001). The patients with negative/weak Sema3A protein expression had poorer prognosis than those with moderate (HR: 3.723, p = 0.021) or strong (HR: 3.966, p = 0.013) Sema3A protein expression in the multivariate analysis. Conclusions miR-362-5p/Sema3A might provide a promising therapeutic pathway and represents a candidate therapeutic target of the TNBC subtype.
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19
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Calabrese G, Dolcimascolo A, Caruso G, Forte S. miR-19a Is Involved In Progression And Malignancy Of Anaplastic Thyroid Cancer Cells. Onco Targets Ther 2019; 12:9571-9583. [PMID: 32009794 PMCID: PMC6859471 DOI: 10.2147/ott.s221733] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 08/13/2019] [Indexed: 12/15/2022] Open
Abstract
Background MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding RNAs acting as negative regulators of gene expression involved in a number of physiological processes. MiRNAs' expression is commonly dysregulated in many types of human tumor diseases and cancers, including thyroid cancers, and is often involved in tumor initiation and progression. miR-19a, a member of miR-17-92 cluster, has been demonstrated to promote cell growth in anaplastic thyroid cancer (ATC), the most advanced and aggressive thyroid cancer. Purpose In this work, we investigate the potential contribution of miR-19a in thyroid cancer cells poor prognosis and de-differentiation. Methods We directly modulated the expression of miR-19a in papillary (PTC) and anaplastic thyroid carcinoma cell lines through transfection of specific miR-19a mimic or inhibitor. Further, we performed gene expression analysis of specific genes to evaluate miR-19a association with cell cycle, differentiation, and poor prognosis. Results Our data indicate that miR-19a overexpression in PTC cells significantly promotes cell growth, decreases the expression of differentiation genes and activates poor prognosis genes. Its inhibition in ATC cells reduces cell proliferation and the expression of genes related to poor prognosis but does not affect differentiation. Conclusion Our findings reveal the existence of functional associations between miR-19a expression and thyroid cancer progression and malignancy suggesting miR-19a as a novel candidate therapeutic target for ATC.
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Affiliation(s)
- Giovanna Calabrese
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy
| | - Anna Dolcimascolo
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy
| | - Giuseppe Caruso
- Department of Laboratories, Oasi Research Institute, IRCCs, Troina, EN 94018, Italy
| | - Stefano Forte
- Molecular Biology Unit, IOM Ricerca, Viagrande, CT 95029, Italy
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20
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Sun J, Shi X, Mamun MAA, Gao Y. The role of deubiquitinating enzymes in gastric cancer. Oncol Lett 2019; 19:30-44. [PMID: 31897112 PMCID: PMC6924028 DOI: 10.3892/ol.2019.11062] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 10/22/2019] [Indexed: 12/24/2022] Open
Abstract
The epigenetic regulation of gene expression (via DNA methylation, histone modification and microRNA interference) contributes to a variety of diseases, particularly cancer. Protein deubiquitination serves a key role in the mechanism underlying histone modification, and consequently influences tumor development and progression. Improved characterization of the role of ubiquitinating enzymes has led to the identification of numerous deubiquitinating enzymes (DUBs) with various functions. Gastric cancer (GC) is a highly prevalent cancer type that exhibits a high mortality rate. Latest analysis about cancer patient revealed that GC is sixth deadliest cancer type, which frequently occur in male (7.2%) than female (4.1%). Complex associations between DUBs and GC progression have been revealed in multiple studies; however, the molecular mechanism underpinning the metastasis and recurrence of GC is yet to be elucidated. Generally, DUBs were upregulated in gastric cancer. The relation of DUBs and tumor size, classification and staging was observed in GC. Besides, 5-yar survival rate of patients with GC is effeccted by expression level of DUBs. Among the highly expressed DUBs, specifically six DUBs namely UCHs, USPs, OTUs, MJDs, JAMMs and MCPIPs effect on this survival rate. Consequently, the association between GC and DUBs has received increasing attention in recent years. Therefore, in the present review, literature investigating the association between DUBs and GC pathophysiology was analyzed and critically appraised.
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Affiliation(s)
- Jiangang Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xiaojing Shi
- Zhengzhou University School of Pharmaceutical Science, Zhengzhou, Henan 450001, P.R. China
| | - M A A Mamun
- Zhengzhou University School of Pharmaceutical Science, Zhengzhou, Henan 450001, P.R. China
| | - Yongshun Gao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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21
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Zeng Z, Pan Y, Wu W, Li L, Wu Z, Zhang Y, Deng B, Wei S, Zhang W, Lin F, Song Y. Myocardial hypertrophy is improved with berberine treatment via long non-coding RNA MIAT-mediated autophagy. J Pharm Pharmacol 2019; 71:1822-1831. [PMID: 31612504 DOI: 10.1111/jphp.13170] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 09/01/2019] [Indexed: 01/01/2023]
Abstract
Abstract
Objectives
This study aimed to evaluate berberine (BBR) effects on myocardial hypertrophy (MH) and associated mechanisms.
Methods
BBR effects on MH were evaluated in rats with constriction of abdominal aorta (CAA). qRT-PCR assay was used to measure MH-related genes, long non-coding RNAs (lncRNAs) and autophagy-related genes expressions. Western blot was performed to detect autophagy markers expression. Filamentous actin and phalloidin expressions were detected using immunofluorescence assay.
Key findings
BBR significantly attenuated CAA-induced MH and cardiomyocyte enlargement. CAA upregulated β myosin heavy chain and atrial natriuretic peptide expressions in heart tissues, which was attenuated by BBR. BBR suppressed myocardial infarction associated transcript (MIAT) expression in rats with CAA. p62 mRNA expression was upregulated and beclin1 and autophagy related 5 were downregulated in CAA versus control groups. The effects were abolished by BBR. In vitro studies showed that BBR ameliorated angiotensin II-induced MH and attenuated Ang II-induced MIAT expression in H9C2 cells. Expressions of phosphorylated mTOR, phosphorylated AMPK and LC3 were upregulated in H9C2 cells after Ang II stimulation, and the effects were abolished by BBR.
Conclusions
BBR exerted beneficial effects on MH induced by CCA, and the mechanisms were associated with decreased MIAT expression and enhanced autophagy.
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Affiliation(s)
- Zhicong Zeng
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
| | - Yan Pan
- Diabetes Department, Bao'an TCM Hospital Group, Shenzhen, China
| | - Wei Wu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liang Li
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
- Graduate School, Guangzhou University of TCM, Guangzhou, China
| | - Zijun Wu
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
| | - Yuangui Zhang
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
| | - Bin Deng
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
| | - Shanyan Wei
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
| | - Weiwei Zhang
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
| | - Fengxia Lin
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
| | - Yinzhi Song
- Cardiology Department, Bao'an TCM Hospital Group, Shenzhen, China
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22
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Jiao J, Zhang S. Long non‑coding RNA MEG‑3 suppresses gastric carcinoma cell growth, invasion and migration via EMT regulation. Mol Med Rep 2019; 20:2685-2693. [PMID: 31524253 PMCID: PMC6691256 DOI: 10.3892/mmr.2019.10515] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 10/29/2018] [Indexed: 12/20/2022] Open
Abstract
Gastric carcinoma is one of the most frequently diagnosed gastrointestinal tumors. Long non-coding RNAs (lncRNAs) are broadly defined as endogenous cellular non-coding RNA molecules. Studies have demonstrated that they may be associated with human cancer progression. In the present study, the role of lncRNA-maternally expressed gene 3 (MEG3) in the progression of gastric carcinoma cells was investigated in vitro and in vivo. It was demonstrated that lncRNA-MEG3 expression was downregulated in gastric carcinoma cells compared with normal gastric cells. lncRNA-MEG3 transfection increased E-cadherin expression and markedly inhibited gastric carcinoma cell growth, migration and invasion. Flow cytometric analysis revealed that lncRNA-MEG3 transfection promoted the apoptosis of gastric carcinoma cells. Western blot analysis demonstrated that lncRNA-MEG3 transfection inhibited the expression of anti-apoptotic proteins B cell lymphoma-2 (Bcl-2) and Bcl-2-like protein 2 and increased the expression of pro-apoptotic proteins caspase-3 and caspase-9 in gastric carcinoma cells. lncRNA-MEG3 transfection upregulated the expression of epithelial marker E-cadherin and inhibited the expression of mesenchymal markers vimentin and fibronectin in gastric carcinoma cells, which suggested that lncRNA-MEG3 inhibited epithelial-mesenchymal transition (EMT), which may subsequently inhibit progression in gastric carcinoma cells. The present study also revealed that lncRNA-MEG3 transfection suppressed tumor growth mainly by decreasing the expression of vascular endothelial growth factor and increasing the expression of Bcl-2 in vivo. In conclusion, these results indicated that lncRNA-MEG3 may regulate EMT-associated signaling pathways and has the potential as a therapeutic target in gastric carcinoma.
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Affiliation(s)
- Junquan Jiao
- Center for Cancer Diagnosis and Treatment, Shangluo Central Hospital, Shangluo, Shaanxi 72600, P.R. China
| | - Shaobo Zhang
- Department of General Surgery, Hong Hui Hospital, Xi'an Jiao Tong University, Xi'an, Shaanxi 710049, P.R. China
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23
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Tijhuis AE, Johnson SC, McClelland SE. The emerging links between chromosomal instability (CIN), metastasis, inflammation and tumour immunity. Mol Cytogenet 2019; 12:17. [PMID: 31114634 PMCID: PMC6518824 DOI: 10.1186/s13039-019-0429-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 04/15/2019] [Indexed: 02/06/2023] Open
Abstract
Many cancers possess an incorrect number of chromosomes, a state described as aneuploidy. Aneuploidy is often caused by Chromosomal Instability (CIN), a process of continuous chromosome mis-segregation. CIN is believed to endow tumours with enhanced evolutionary capabilities due to increased intratumour heterogeneity, and facilitating adaptive resistance to therapies. Recently, however, additional consequences and associations with CIN have been revealed, prompting the need to understand this universal hallmark of cancer in a multifaceted context. This review is focused on the investigation of possible links between CIN, metastasis and the host immune system in cancer development and treatment. We specifically focus on these links since most cancer deaths are due to the consequences of metastasis, and immunotherapy is a rapidly expanding novel avenue of cancer therapy.
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Affiliation(s)
- Andréa E. Tijhuis
- Barts Cancer Institute, Queen Mary University of London, EC1M 6BQ, London, UK
| | - Sarah C. Johnson
- Barts Cancer Institute, Queen Mary University of London, EC1M 6BQ, London, UK
| | - Sarah E. McClelland
- Barts Cancer Institute, Queen Mary University of London, EC1M 6BQ, London, UK
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24
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Song L, Liu S, Yao H, Zhang L, Li Y, Xu D, Li Q. MiR-362-3p is downregulated by promoter methylation and independently predicts shorter OS of cervical squamous cell carcinoma. Biomed Pharmacother 2019; 115:108944. [PMID: 31082771 DOI: 10.1016/j.biopha.2019.108944] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/16/2019] [Accepted: 04/29/2019] [Indexed: 10/26/2022] Open
Abstract
The current study was undertaken to investigate the potential influence of methylation on miR-362-5p/3p expression and further analyzed their independent prognostic value in cervical adenocarcinoma (ADC) and squamous cell carcinoma (SCC) respectively. SiHa and CaSki cells were used as the in vitro cell model. In silico bioinformatic analysis was conducted via the combined use of the Cancer Genome Atlas-Cervical Cancer (TCGA-CESC), Starbase 3.0 and String 10.5. Results revealed that the downregulation of miR-362-5p/3p was accompanied by the infection of high-risk human papillomavirus (HR-HPV) and their expression was further decreased in HR-HPV cancer tissues. Demethylation could restore their expression. By performing Methylation-specific PCR (MSP) based on methylated or unmethylated specific primers, we confirmed that the proximal promoter region was methylated in both cell lines. Higher miR-362-3p expression might independently predict favorable overall survival (OS) in SCC patients (HR: 0.561, 95%CI: 0.354-0.889, p = 0.014), after adjustment of clinical stages, lymphovascular invasion and miR-362-5p expression. However, no prognostic value of miR-362-5p or miR-362-3p expression was observed in terms of OS in patients with ADC. Via bioinformatic analysis, we found that miR-362-3p might have an entirely different regulatory network in cervical ADC and SCC, which might help to explain the distinct prognostic value of miR-362-3p in these two histological subtypes. In summary, we infer that the methylation level of the proximal promoter region of pre-miR-362 would influence the expression of miR-362-5p/3p in cervical cancer. MiR-362-3p expression might be a specific prognostic biomarker in cervical SCC, but not in ADC.
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Affiliation(s)
- Lili Song
- Department of Obstetrics & Gynecology, Cangzhou Central Hospital, Hebei, 061001, China
| | - Shikai Liu
- Department of Obstetrics & Gynecology, Cangzhou Central Hospital, Hebei, 061001, China.
| | - Hairong Yao
- Department of Obstetrics & Gynecology, Cangzhou Central Hospital, Hebei, 061001, China
| | - Liang Zhang
- Department of Obstetrics & Gynecology, Cangzhou Central Hospital, Hebei, 061001, China
| | - Ying Li
- Department of Obstetrics & Gynecology, Cangzhou Central Hospital, Hebei, 061001, China
| | - Dongkui Xu
- Department of Obstetrics & Gynecology, Cangzhou Central Hospital, Hebei, 061001, China
| | - Qian Li
- Department of Obstetrics & Gynecology, Cangzhou Central Hospital, Hebei, 061001, China
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25
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Wan J, Yang J, Qiao C, Sun X, Di A, Zhang L, Wang D, Zhao G. MicroRNA-362 Inhibits Cell Proliferation and Invasion by Directly Targeting SIX1 in Colorectal Cancer. Yonsei Med J 2019; 60:414-422. [PMID: 31016902 PMCID: PMC6479121 DOI: 10.3349/ymj.2019.60.5.414] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/27/2019] [Accepted: 03/07/2019] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Colorectal cancer (CRC) is the third most common cancer in China and poses high morbidity and mortality. In recent years, increasing evidence has indicated that microRNAs played important functions in the occurrence and development of tumors. The purpose of this study was to identify the biological mechanisms of miR-362 in CRC. MATERIALS AND METHODS Quantitative real-time PCR was carried out to assess the expression of miR-362 and SIX1. The Kaplan-Meier method was employed to evaluate the 5-year overall survival of CRC patients. The proliferative and invasive abilities of CRC cells were assessed by MTT and transwell assays. RESULTS miR-362 was significantly decreased in CRC tissues and cell lines, compared to the normal tissues and normal cells. A significant connection was confirmed between the overall survival of 53 CRC patients and low expression of miR-362. Downregulation of miR-362 inhibited the proliferation and invasion through binding to the 3'-UTR of SIX1 mRNA in CRC. Additionally, we discovered that SIX1 was a direct target gene of miR-362 and that the expression of miR-362 had a negative connection with SIX1 expression in CRC. SIX1 could reverse partial functions in the proliferation and invasion in CRC cells. CONCLUSION miR-362 may be a prognostic marker in CRC and suppress CRC cell proliferation and invasion in part through targeting the 3'-UTR of SIX1 mRNA. The newly identified miR-362/SIX1 axis provides insight into the progression of CRC.
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Affiliation(s)
- Jin'e Wan
- Department of Hyperbaric Oxygen, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jian Yang
- Department of Oncology, Zouping Centre Hospital, Binzhou, China
| | - Cuixia Qiao
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaomei Sun
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Aiting Di
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lize Zhang
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dandan Wang
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Gang Zhao
- Department of Anorectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
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26
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Gu B, Liu H, Han Y, Chen Y, Jiang H. Integrated analysis of miRNA and mRNA expression profiles in 2-, 6-, and 12-month-old Small Tail Han Sheep ovaries reveals that oar-miR-432 downregulates RPS6KA1 expression. Gene 2019; 710:76-90. [PMID: 30898702 DOI: 10.1016/j.gene.2019.02.095] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/23/2019] [Accepted: 02/28/2019] [Indexed: 01/08/2023]
Abstract
Small Tail Han Sheep are an excellent local sheep breed in China, and their outstanding reproductive performance is one of their very important biological characteristics. Clarifying the ovary development process of these ewes should provide a theoretical basis for improving their reproductive efficiency. In this study, we identified the differentially expressed (DE) microRNAs (miRNAs) in 2-, 6-, and 12-month-old small-tail Han sheep ovaries by constructing and analyzing the miRNA expression profiles. These findings clarify the molecular mechanisms regulating the excellent reproductive performance of small-tail Han ewes. We used RNA-Seq technology and bioinformatic to analyze these profiles. Eleven, 13, and 19 DE miRNAs were identified in the 2- vs 6-, 6- vs 12-, and 2- vs 12-month-old ovaries, respectively. In total, 54, 37, and 198 predicted target genes of these DE miRNAs were identified in these three groups, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that in the 2- vs 6-month-old ovaries, the target genes of DE known sheep miRNAs were involved in 102 GO terms and seven signaling pathways; in the 6- vs 12-month-old ovaries, the target genes of DE known sheep miRNAs were involved in 52 GO terms and three signaling pathways; and in the 2- vs 12-month-old ovaries, the target genes of DE known sheep miRNAs were involved in 88 GO terms and six signaling pathways. Three miRNA-target regulatory networks were constructed based on these DE miRNA-target interactions. Nine miRNAs were selected to confirm to the accuracy of the miRNA sequencing data with qRT-PCR. The site at which oar-miR-432 binds RPS6KA1 was determined with a dual-luciferase system. This is the first integrated analysis the expression profiles of miRNAs and their targets during ovarian development in small-tail Han sheep. These data clarify the molecular regulatory mechanisms underlying sheep ovarian development and identify biomarkers that influence the reproductive performance of small-tail Han ewes.
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Affiliation(s)
- Bo Gu
- College of Animal Science and Technology, Jinlin Agricultural University, Changchun, Jilin, China
| | - Hang Liu
- College of Animal Science and Technology, Jinlin Agricultural University, Changchun, Jilin, China
| | - Yue Han
- College of Animal Science and Technology, Jinlin Agricultural University, Changchun, Jilin, China
| | - Yang Chen
- College of Animal Science and Technology, Jinlin Agricultural University, Changchun, Jilin, China
| | - Huaizhi Jiang
- College of Animal Science and Technology, Jinlin Agricultural University, Changchun, Jilin, China.
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27
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Wu X, Shen J, Xiao Z, Li J, Zhao Y, Zhao Q, Cho CH, Li M. An overview of the multifaceted roles of miRNAs in gastric cancer: Spotlight on novel biomarkers and therapeutic targets. Biochem Pharmacol 2019; 163:425-439. [PMID: 30857828 DOI: 10.1016/j.bcp.2019.03.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 03/07/2019] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs that have displayed strong association with gastric cancer (GC). Through the repression of target mRNAs, miRNAs regulate many biological pathways that are involved in cell proliferation, apoptosis, migration, invasion, metastasis as well as drug resistance. The detection of miRNAs in tissues and in body fluids emerges as a promising method in the diagnosis and prognosis of GC, due to their unique expression pattern in correlation with GC. Notably, miRNAs are also identified as potential therapeutic targets for GC therapy. The present review is thus to highlight the multifaceted roles of miRNAs in GC and in GC therapies, which would give indications for future research.
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Affiliation(s)
- Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Li
- Department of Oncology and Hematology, Hospital (T.C.M.) Affiliated to Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qijie Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.
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28
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Yang Y, Dong K, Shao S. The effect of Helicobacter pylori on the expression of FRA-1 in gastric epithelial cells and its mechanism. Microb Pathog 2019; 129:257-265. [PMID: 30807813 DOI: 10.1016/j.micpath.2019.02.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/21/2018] [Accepted: 02/18/2019] [Indexed: 02/08/2023]
Abstract
Gastric cancer is a major global health threat and is often related with Helicobacter pylori (H. pylori) infection. FRA-1 is a subunit of the activator protein-1 transcription factor complex, which played a central role in cell proliferation and migration. It has also been implicated in stomach inflammation and malignancy. The present study aimed to clarify the relationship between H. pylori infection and production of FRA-1 in controlling cell proliferation and migration and its molecular mechanisms. Cell proliferation was measured by colony formation assay. Cell migration was monitored by transwell migration assay. Gastric mucosal epithelial cells were treated with FRA-1-specific siRNA with or without H. pylori infection in vitro, and RNA and proteins were extracted. The expression of FRA-1 and indicators in cells was determined by RT-PCR and western blot analysis. β-Catenin and TGF-β activities were then assessed by western blotting and immunofluorescence. The expression of FRA-1 increased after H. pylori infection. Additional analysis identified that knockdown of FRA-1 attenuated the H. pylori-induced proliferative activity and migration of gastric cancer cells. Furthermore, upregulation of FRA-1 by H. pylori led to increase in Wnt/β-Catenin levels and TGF-β dependent signaling events. These results demonstrate that the upregulation of FRA-1 in H. pylori-infected gastric epithelial cells plays a key role in the carcinogenic process.
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Affiliation(s)
- Yang Yang
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, PR China.
| | - Ke Dong
- College of Natural Sciences, Kyonggi University, South Korea.
| | - Shihe Shao
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, PR China.
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29
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Liu C, Jian M, Qi H, Mao WZ. MicroRNA 495 Inhibits Proliferation and Metastasis and Promotes Apoptosis by Targeting Twist1 in Gastric Cancer Cells. Oncol Res 2019; 27:389-397. [PMID: 29615148 PMCID: PMC7848466 DOI: 10.3727/096504018x15223159811838] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Recently, microRNAs (miRNAs) have been reported to participate in multiple biological processes. However, the effects of miR-495 on gastric cancer (GC) remain unclear. The purpose of this study was to explore the functions of miR-495 in GC cell proliferation, metastasis, and apoptosis. SGC-7901 and BGC-823 cell lines were transfected with miR-495 mimic, miR-495 inhibitor, and negative controls (mimic control and inhibitor control). The expressions of miR-495, cell viability, migration, apoptosis, and apoptosis-related factors were examined by qRT-PCR, trypan blue staining, Transwell, flow cytometry, and Western blot, respectively. Simultaneously, key factor expression levels of EMT were detected by qRT-PCR and Western blot. The direct target of miR-495 was confirmed by dual-luciferase assay. Additionally, sh-Twist1, pc-Twist1, and corresponding controls were transfected into SGC-7901 and BGC-823 cells, and the protein levels of EMT-associated factors were detected by Western blot. miR-495 was downregulated in GC cells. miR-495 expression level was effectively overexpressed or suppressed in SGC-7901 and BGC-823 cells. Overexpression of miR-495 significantly decreased cell viability and migration, increased apoptosis, and inhibited the EMT process. Suppression of miR-495 showed contrary results. Twist1 was clarified as a target gene of miR-495, and Twist1 silencing obviously reduced the promoting effect of miR-495 suppression on these biological processes. Twist1 silencing significantly blocked the EMT process in both SGC-7901 and BGC-823 cells. miR-495 inhibited proliferation and metastasis and promoted apoptosis by targeting Twist1 in GC cells. These data indicated that miR-495 might be a novel antitumor factor of GC and provide a new method for the treatment of GC.
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Affiliation(s)
- Chao Liu
- *Qingdao University, Qingdao, P.R. China
- †Department of General Surgery, Qingdao Municipal Hospital, Qingdao, P.R. China
| | - Min Jian
- ‡Department of Laboratory Medicine, Qingdao Women and Children’s Hospital, Qingdao, P.R. China
| | - Hong Qi
- †Department of General Surgery, Qingdao Municipal Hospital, Qingdao, P.R. China
| | - Wei-Zheng Mao
- †Department of General Surgery, Qingdao Municipal Hospital, Qingdao, P.R. China
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30
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Calabrese G, Dolcimascolo A, Torrisi F, Zappalà A, Gulino R, Parenti R. MiR-19a Overexpression in FTC-133 Cell Line Induces a More De-Differentiated and Aggressive Phenotype. Int J Mol Sci 2018; 19:ijms19123944. [PMID: 30544640 PMCID: PMC6320980 DOI: 10.3390/ijms19123944] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 11/29/2018] [Accepted: 12/06/2018] [Indexed: 02/07/2023] Open
Abstract
In recent years, microRNAs (miRNAs) have received increasing attention for their important role in tumor initiation and progression. MiRNAs are a class of endogenous small non-coding RNAs that negatively regulate the expression of several oncogenes or tumor suppressor genes. MiR-19a, a component of the oncogenic miR-17-92 cluster, has been reported to be highly expressed only in anaplastic thyroid cancer, the most undifferentiated, aggressive and lethal form of thyroid neoplasia. In this work, we evaluated the putative contribution of miR-19a in de-differentiation and aggressiveness of thyroid tumors. To this aim, we induced miR-19a expression in the well-differentiated follicular thyroid cancer cell line and evaluated proliferation, apoptosis and gene expression profile of cancer cells. Our results showed that miR-19a overexpression stimulates cell proliferation and alters the expression profile of genes related to thyroid cell differentiation and aggressiveness. These findings not only suggest that miR-19a has a possible involvement in de-differentiation and malignancy, but also that it could represent an important prognostic indicator and a good therapeutic target for the most aggressive thyroid cancer.
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Affiliation(s)
- Giovanna Calabrese
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy.
| | - Anna Dolcimascolo
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy.
| | - Filippo Torrisi
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy.
| | - Agata Zappalà
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy.
| | - Rosario Gulino
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy.
| | - Rosalba Parenti
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy.
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Fang Z, Zhong M, Wang Y, Yuan X, Guo H, Yao Y, Feng M, Chen J, Xiong J, Xiang X. miR‑381 and miR‑489 suppress cell proliferation and invasion by targeting CUL4B via the Wnt/β‑catenin pathway in gastric cancer. Int J Oncol 2018; 54:733-743. [PMID: 30483755 DOI: 10.3892/ijo.2018.4646] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 11/05/2018] [Indexed: 11/05/2022] Open
Abstract
Accumulating evidence has highlighted the critical role of cullin 4B (CUL4B) in driving tumourigenesis in several malignancies, including gastric cancer (GC); however, the mechanisms underlying CUL4B upregulation remain unclear. The dysregulation of microRNAs (miRNAs or miRs) is known to be involved in tumourigenesis. In this study, we report that the expression of miR‑381 and miR‑489 is downregulated and is negatively correlated with that of CUL4B in GC tissues and cell lines. Further analysis verified that miR‑381 and miR‑489 directly targeted CUL4B. CUL4B silencing inhibited cell proliferation, migration and invasion by inactivating the Wnt/β‑catenin pathway. miR‑381/miR‑489 overexpression recapitulated the effects of CUL4B silencing, while CUL4B restoration negated the suppressive effects induced by the ectopic expression of miR‑381/miR‑489. Furthermore, miR‑381/miR‑489 exerted tumour suppressive functions by inactivating the Wnt/β‑catenin pathway through the targeting of CUL4B. Taken together, the findings of this study suggest that the miR‑381/miR‑489‑mediated expression of CUL4B modulates the proliferation and invasion of GC cells via the Wnt/β‑catenin pathway, which indicates that the miR‑381/miR‑489‑CUL4B axis is critical in the control of GC tumourigenesis.
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Affiliation(s)
- Ziling Fang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Min Zhong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yi Wang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiang Yuan
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Hui Guo
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yangyang Yao
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Miao Feng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jun Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiaojun Xiang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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32
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Ouyang Y, Li Y, Huang Y, Li X, Zhu Y, Long Y, Wang Y, Guo X, Gong K. CircRNA circPDSS1 promotes the gastric cancer progression by sponging miR-186-5p and modulating NEK2. J Cell Physiol 2018; 234:10458-10469. [PMID: 30417526 DOI: 10.1002/jcp.27714] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 10/15/2018] [Indexed: 12/17/2022]
Abstract
The aim of this study is to investigate the regulatory mechanism of circPDSS1/miR-186-5p/NEK2 axis on the viability and proliferation in gastric cancer (GC) cell line. Differentially expressed circRNAs, miRNAs, and mRNAs in GC tissues and paracarcinoma tissues were analyzed using gene chips GSE83521, GSE89143, and GSE93415. Then, the expression of circPDSS1, miR-186-5p, and NEK2 was analyzed via quantitative real-time polymerase chain reaction (qRT-PCR). Survival analysis was adopted to explore the association between the circPDSS1 expression and the prognosis of GC. The effect of circPDSS1 on GC cell cycle and apoptosis was verified with the flow cytometry. Targeting relationships among circPDSS1, miR-186-5p, and NEK2 were predicted via bioinformatics analysis and demonstrated by the dual-luciferase reporter assay. Our results showed that circPDSS1 and NEK2 were high-expressed whereas miR-186-5p was low-expressed in GC tissues and cells. CircPDSS1 promoted GC cell cycle and inhibited apoptosis by sponging miR-186-5p, while miR-186-5p inhibited cell cycle and promoted apoptosis by targeting NEK2. Thus, circPDSS1 acts as a tumor promoter by regulating miR-186-5p and NEK2, which could be a potential biomarker and therapeutic target for the management of GC.
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Affiliation(s)
- Yiming Ouyang
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
| | - Yuejin Li
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
| | - Yingguang Huang
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
| | - Xing Li
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
| | - Yu Zhu
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
| | - Yaxin Long
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
| | - Yongzhi Wang
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
| | - Xiaodong Guo
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
| | - Kunmei Gong
- Department of General Surgery, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China
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Let-7b attenuates cisplatin resistance and tumor growth in gastric cancer by targeting AURKB. Cancer Gene Ther 2018; 25:300-308. [PMID: 30237418 DOI: 10.1038/s41417-018-0048-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 08/12/2018] [Accepted: 08/25/2018] [Indexed: 12/14/2022]
Abstract
Platinum-based chemotherapy is currently a standard treatment strategy for patients with gastric cancer. Eventhough it has been widely shown that microRNAs (miRNAs) are involved in tumor development, whether miRNAs have a role in chemosensitivity of gastric cancer cells to platinum-based treatment remain largely undefined. In this study, a cisplatin-resistant gastric cancer cell line (SGC7901/DDP) with stable enhanced expression or knockdown of let-7b was generated. MTT and TUNEL assays were carried out to assess whether miR-let-7 is crucial for cell viability and apoptosis, respectively. In vitro luciferase reporter assay was performed to explore target genes of let-7b. Further, a subcutaneously transplanted tumor model in BALB/c nude mice was used to determine the impacts of let-7b on tumor growth in vivo. We observed that the let-7b-expression level of SGC7901/DDP cells was significantly lower than for its parental SGC7901 cells. Transfection of let-7b mimics was found to increase the cytotoxicity of DDP to SGC7901/DDP cells by inducing apoptosis. However, reversed cytotoxicity of DDP was observed in SGC7901/DDP cells with knockdown of let-7b. Luciferase reporter assay indicated that let-7b targeted AURKB in SGC7901/DDP cells. Knockdown of AURKB imitated the effect of let-7b overexpression on the sensitivity of SGC7901/DDP cells to DDP. Further investigation demonstrated that the SGC7901/DDP primary tumor growth was significantly reduced by let-7b mimic transfection. These findings indicate that overexpression of let-7b might provide a potential strategic approach for attenuating DDP resistance in SGC7901/DDP human gastric cancer cells.
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Zeng L, Qian J, Luo X, Zhou A, Zhang Z, Fang Q. CHSY1 promoted proliferation and suppressed apoptosis in colorectal cancer through regulation of the NFκB and/or caspase-3/7 signaling pathway. Oncol Lett 2018; 16:6140-6146. [PMID: 30344756 DOI: 10.3892/ol.2018.9385] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 07/30/2018] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer is a commonly observed malignant cancer. However, the limited therapies for colorectal cancer do not bring much benefit for patients. Chondroitin synthase-1 (CHSY1) is an enzyme responsible for the biosynthesis of chondroitin sulfate and has been implicated in the tumorigenesis of several cancer types; however, there is limited information regarding the role of CHSY1 in colorectal cancer. In the present study, CHSY1 was demonstrated to be highly expressed in colorectal cancer tissues and in cell lines, and the CHSY1 expression level was associated with the 5-year survival rate of patients with colorectal cancer. Following CHSY1 knockdown, the proliferation of colorectal cancer cells was significantly decreased. The number of RKO cells decreased by 50% following CHSY1 knockdown compared with that in the control after culture for 5 days. However, the apoptosis rate of RKO cells increased to 14.15% after CHSY1 knockdown. In addition, the activity of caspase-3/7 was also enhanced. Furthermore, the expression of B-cell lymphoma 2 (Bcl-2) was reduced, whereas the levels of Bcl-2-associated X protein (Bax) and truncated caspase-3/7 were increased following CHSY1 knockdown. Additionally, the phosphorylation level of IκB and the expression of nuclear factor (NF)κB also decreased. In contrast, forced expression of CHSY1 increased the level of Bcl-2, NFκB, and phosphorylated IκB, whereas the level of bax and truncated caspase-3/7 decreased. Therefore, the data of the present study suggest that CHSY1 promoted cell proliferation by regulating NFκB signaling and suppressed cell apoptosis by regulating/caspase-3/7 signaling in colorectal cancer. The present study also suggests that CHSY1 may be a potential target for colorectal cancer therapy.
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Affiliation(s)
- Lifeng Zeng
- Department of Clinical Laboratory, Jiangxi Province People's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Jinrong Qian
- Department of Health Care of Cadre, Jiangxi Province People's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Xiaojiang Luo
- Department of Gastrointestinal Surgery, Jiangxi Province People's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Aiqun Zhou
- Department of Clinical Laboratory, Jiangxi Province People's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Zhiyong Zhang
- Department of Clinical Laboratory, Jiangxi Province People's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Quangang Fang
- Department of Clinical Laboratory, Jiangxi Province People's Hospital, Nanchang, Jiangxi 330006, P.R. China
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Aberrant Expression of miR-362 Promotes Lung Cancer Metastasis through Downregulation of Sema3A. J Immunol Res 2018; 2018:1687097. [PMID: 30155491 PMCID: PMC6093061 DOI: 10.1155/2018/1687097] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 06/07/2018] [Indexed: 01/24/2023] Open
Abstract
miR-362 is a recently discovered member of the microRNA family, and it modulates a variety of physical activities and plays an important role in the occurrence and development of many tumors. However, the biological functions of hsa-miR-362-5p in non-small-cell lung carcinoma (NSCLC) are unknown. Transwell assay and colony formation were used to determine the migration, invasion, and proliferation of NSCLC cells in vitro. A subcutaneous tumor model in nude mice was established to detect NSCLC tumor growth in vivo. The direct binding of miR-362 to the 3'UTR of Semaphorin 3A (Sema3A) was confirmed by luciferase reporter assay. In this study, we found that the level of miR-362 was higher in NSCLC tissues than in adjacent normal tissues and that the level of miR-362 expression was also elevated in five NSCLC cell lines (A549, 95-D, H1299, H292, and H460) relative to a human normal lung epithelial cell line (BEAS2B). Furthermore, miR-362 promoted NSCLC cell invasion, migration, and colony formation in vitro and tumor formation in vivo. Next, we identified the miR-362 target gene Sema3A, which is significantly correlated with metastasis. Sema3A expression was increased in normal tissues relative to NSCLC tissues. This result is consistent with the fact that miR-362 expression is negatively correlated with Sema3A expression in clinical tissue samples and indicated that miR-362 can regulate Sema3A expression in NSCLC cells and consequently affect NSCLC invasion, migration, and colony formation. Taken together, these findings on the newly identified miR-362/Sema3A axis elucidate the molecular mechanism of NSCLC invasion and migration and could lead to a potential therapeutic target in NSCLC treatment.
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Wang D, Wang H, Li Y, Li Q. MiR-362-3p functions as a tumor suppressor through targeting MCM5 in cervical adenocarcinoma. Biosci Rep 2018; 38:BSR20180668. [PMID: 29871972 PMCID: PMC6013705 DOI: 10.1042/bsr20180668] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 05/29/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023] Open
Abstract
Our previous study suggested that minichromosome maintenance protein 5 (MCM5) overexpression was observed in cervical adenocarcinoma and closely associated with advanced clinical stage, more metastatic lymph nodes, present distant metastasis, low histological grade, and poor prognosis. Down-regulation of MCM5 inhibited cervical adenocarcinoma cell proliferation. The purpose of the present study is to search and confirm valuable microRNAs (miRNAs), which target MCM5 to modulate cervical adenocarcinoma cell proliferation. In our results, we found that levels of miR-362-3p expression were reduced in cervical adenocarcinoma tissues and cell lines. Moreover, 3'-UTR of MCM5 had binding site of miR-362-3p through analyzing Targetscan database and miRanda database, and there were an inverse association between miR-362-3p and MCM5 in cervical adenocarcinoma tissues. Furthermore, we verified miR-362-3p directly targeted to 3'-UTR of DCLK1 by luciferase reporter assay, and negatively regulated mRNA and protein expressions of MCM5 by qPCR and Western blot. Then, we conducted gain-of-function study and rescued-function study, and found that miR-362-3p served as a tumor suppressive miRNA to modulate cervical adenocarcinoma cell proliferation through regulating the functional target MCM5. Finally, we analyzed correlations between miR-362-3p expression and clinicopathological characteristics and observed that miR-362-3p low expression was associated with advanced clinical stage and poor prognosis. In conclusion, miR-362-3p is a tumor suppressive miRNA in cervical adenocarcinoma.
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Affiliation(s)
- Dan Wang
- Department of Gynecology, Jining No.1 People's Hospital, Jining 272000, Shandong, China
| | - Hongyan Wang
- Department of Gynecology, Jining No.1 People's Hospital, Jining 272000, Shandong, China
| | - Yichun Li
- Department of Hepatobiliary Surgery, Jining No.1 People's Hospital, Jining 272000, Shandong, China
| | - Qian Li
- Department of Gynecology, Jining No.1 People's Hospital, Jining 272000, Shandong, China
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Wang H, Fang ZL, Zhang GH, Ma X. TRIM44, a crucial target of miR-410, functions as a potential oncogene in osteosarcoma. Onco Targets Ther 2018; 11:3637-3647. [PMID: 29950867 PMCID: PMC6016597 DOI: 10.2147/ott.s163163] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Purpose Mounting evidence highlights the essential role of TRIM44 in tumor initiation and malignant progression in several cancers; however, the function of TRIM44 in osteosarcoma (OS) remains unknown. In this study, we aim to investigate the role of TRIM44 and reveal its regulation by deregulated miRNAs in OS. Materials and methods The expression profiles of TRIM44 were examined by immunohistochemistry, Western blotting, and qRT-PCR. The biological functions of TRIM44 were investigated through siRNA-mediated knockdown experiments. The regulation of TRIM44 by miR-410 was confirmed by Western blotting, dual luciferase reporter assays, and rescue experiments. Results TRIM44 was upregulated in OS tissues and cell lines, and its overexpression was positively correlated with TNM stage, metastasis, and recurrence. Knockdown of TRIM44 in OS cells suppressed cell proliferation, migration, invasion, and epithelial–mesenchymal transition. In addition, we identified TRIM44 as a novel target gene of miR-410 and miR-410 was remarkably downregulated in OS. Moreover, overexpression of miR-410 suppressed proliferation, migration, invasion, and epithelial–mesenchymal transition of OS cells by directly targeting TRIM44 expression. Furthermore, reintroduction of TRIM44 partially reversed miR-410-induced inhibitory effects on OS cells. Conclusion Collectively, our findings indicate that the miR-410/TRIM44 link is critical in the control of OS progression.
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Affiliation(s)
- Heng Wang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zi-Ling Fang
- Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Gong-Hao Zhang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xin Ma
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
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The upregulation of TMPRSS4, partly ascribed to the downregulation of miR‑125a‑5p, promotes the growth of human lung adenocarcinoma via the NF‑κB signaling pathway. Int J Oncol 2018; 53:148-158. [PMID: 29750426 PMCID: PMC5958727 DOI: 10.3892/ijo.2018.4396] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 04/20/2018] [Indexed: 12/13/2022] Open
Abstract
In this study, with the aid of microarray technology, transmembrane protease serine 4 (TMPRSS4), a novel member of the serine protease family, was found to be upregulated in the majority of lung adenocarcinoma (LUAD) tissues compared to normal lung tissues. Of note, the clinical significance of TMPRSS4 in LUAD has not yet been reported, at least to the best of our knowledge. Through immunohistochemistry assays, we found that TMPRSS4 was overexpressed in LUAD tissues and that the TMPRSS4 expression level was also proportionally associated with the AJCC clinical stage, T stage and pathological grade. Moreover, a high expression of TMPRSS4 was found to be associated with adverse outcomes and was a significant independent factors predicting a poor prognosis. To elucidate the possible mechanisms responsible for the overexpression of TMPRSS4, we examined at microRNAs (miRNAs or miRs), which are small non-coding RNAs commonly dysregulated in human malignancies and are known to promote carcinogenesis by interacting with other types of RNAs. By means of bioinformatics analysis, a miRNA potentially targeting TMPRSS4 mRNA, namely miR-125a-5p, was selected. Dual luciferase reporter gene assays were then performed to verify the interaction. The results of MTT assays and apoptotic assays revealed that miR-125a-5p significantly inhibited cell growth and enhanced apoptosis, and the silencing of TMPRSS4 had similar effects. Furthermore, we observed that either the overexpression of miR-125a-5p or the silencing of TMPRSS4 prevented the activation of the nuclear factor (NF)-κB signaling pathway. On the whole, our findings illustrate that TMPRSS4 may be a candidate oncogene and may thus serve as a prognostic biomarker for LUAD, and its overexpression may be partly ascribed to the downregulation of miR-125a-5p. The dysregulation of miR-125a-5p and TMPRSS4 affect the biological function of LUAD cells via the NF-κB signaling pathway. The miR-125a-5p/TMPRSS4/NF-κB axis may thus provide novel insight into the pathogenic mechanisms of LUAD and may be used in the development of novel treatment strategies for LUAD.
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Ma QL, Wang JH, Yang M, Wang HP, Jin J. MiR-362-5p as a novel prognostic predictor of cytogenetically normal acute myeloid leukemia. J Transl Med 2018. [PMID: 29540187 PMCID: PMC5853092 DOI: 10.1186/s12967-018-1445-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background MicroRNAs are of special interest in cancer research and hold significant promise as diagnostic and prognostic biomarkers for malignant disease. MiR-362-5p have been found to exert both oncogenic and tumor suppressive effects depending highly on the cellular context. The aim of this study was to determine whether the expression of miR-362-5p can be served as a prognostic factor for patients with cytogentically normal acute myeloid leukemia (CN-AML). Methods We enrolled 224 patients with CN-AML and measured the expression of miR-362-5p by quantitative real time PCR analysis. We classified patients into high and low expression based on the median value. The Cox regression analyses were carried out to assess the prognostic significance of miR-362-5p expression in the context of the well-established predictors. Additionally, microRNA expression profiling were conducted to identify the biological insights between high and low group. Results High expressers had older age. High expressers obtained shorter overall survival in the univariate analysis. The independent prognostic value of miR-362-5p remained in the context of the well-established clinical and cytogenetic predictors. Moreover, the prognostic value of miR-362-5p was also validated in an independent cohort of CN-AML. Notably, numerous oncomiRs were also high expressed in high miR-362-5p group. Conclusion High miR-362-5p expression was associated with poorer overall survival implicating the oncogenic function in AML development.
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Affiliation(s)
- Qiu-Ling Ma
- Department of Hematology, The First Affiliated Hospital, Zhejiang University of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Hematopoietic Malignancies, Hangzhou, Zhejiang Province, People's Republic of China.,Department of Hematology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, People's Republic of China
| | - Jing-Han Wang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Hematopoietic Malignancies, Hangzhou, Zhejiang Province, People's Republic of China
| | - Min Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, Zhejiang, People's Republic of China
| | - Huan-Ping Wang
- Key Laboratory of Hematopoietic Malignancies, Hangzhou, Zhejiang Province, People's Republic of China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, Zhejiang, People's Republic of China. .,Key Laboratory of Hematopoietic Malignancies, Hangzhou, Zhejiang Province, People's Republic of China.
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Blood and lung microRNAs as biomarkers of pulmonary tumorigenesis in cigarette smoke-exposed mice. Oncotarget 2018; 7:84758-84774. [PMID: 27713172 PMCID: PMC5341294 DOI: 10.18632/oncotarget.12475] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 09/22/2016] [Indexed: 12/28/2022] Open
Abstract
Cigarette smoke (CS) is known to dysregulate microRNA expression profiles in the lungs of mice, rats, and humans, thereby modulating several pathways involved in lung carcinogenesis and other CS-related diseases. We designed a study aimed at evaluating (a) the expression of 1135 microRNAs in the lung of Swiss H mice exposed to mainstream CS during the first 4 months of life and thereafter kept in filtered air for an additional 3.5 months, (b) the relationship between lung microRNA profiles and histopathological alterations in the lung, (c) intergender differences in microRNA expression, and (d) the comparison with microRNA profiles in blood serum. CS caused multiple histopathological alterations in the lung, which were almost absent in sham-exposed mice. An extensive microRNA dysregulation was detected in the lung of CS-exposed mice. Modulation of microRNA profiles was specifically related to the histopathological picture, no effect being detected in lung fragments with non-neoplastic lung diseases (emphysema or alveolar epithelial hyperplasia), whereas a close association occurred with the presence and multiplicity of preneoplastic lesions (microadenomas) and benign lung tumors (adenomas). Three microRNAs regulating estrogen and HER2-dependent mechanisms were modulated in the lung of adenoma-bearing female mice. Blood microRNAs were also modulated in mice affected by early neoplastic lesions. However, there was a poor association between lung microRNAs and circulating microRNAs, which can be ascribed to an impaired release of mature microRNAs from the damaged lung. Studies in progress are evaluating the feasibility of analyzing blood microRNAs as a molecular tool for lung cancer secondary prevention.
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Zhang K, Guo L. MiR-767 promoted cell proliferation in human melanoma by suppressing CYLD expression. Gene 2018; 641:272-278. [DOI: 10.1016/j.gene.2017.10.055] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 09/21/2017] [Accepted: 10/16/2017] [Indexed: 12/27/2022]
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Li Y, Bai W, Zhang X. Identifying heterogeneous subtypes of gastric cancer and subtype‑specific subpaths of microRNA‑target pathways. Mol Med Rep 2017; 17:3583-3590. [PMID: 29286091 PMCID: PMC5802161 DOI: 10.3892/mmr.2017.8329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 11/15/2017] [Indexed: 01/13/2023] Open
Abstract
The present study aimed to classify gastric cancer (GC) into subtypes and to screen the subtype-specific genes, their targeted microRNAs (miRNAs) and enriched pathways to explore the putative mechanism of each GC subtypes. The GSE13861 data set was downloaded from the Gene Expression Omnibus and used to screen differential expression genes (DEGs) in GC samples based on the detection of imbalanced differential signal algorithm. The specific genes in each subtype were identified with the cut-off criterion of U>0.04, pathway enrichment analysis was performed and the subtype-specific subpaths of miRNA-target pathway were determined. A total of 1,263 DEGs were identified in the primary gastric adenocarcinoma (PGD) samples, which were subsequently divided into four subtypes, according to the hierarchy cluster analysis. Identification of the subpaths of each subtype indicated that the subpath related to subtype 1 was miRNA (miR)-202/calcium voltage-gated channel subunit α1 (CACNA1E)/type II diabetes mellitus. The nuclear factor-κB signaling pathway was the most significantly specific pathway and subpath identified for subtype 2, which was regulated by miR-338-targeted suppression of C-C motif chemokine ligand 21 (CCL21). For subtype 3, significant related pathways included ubiquitin-mediated proteolysis and proteasome, and the important subpath was miR-146B/proteasome 26S subunit, non-ATPase 3 (PSMD3)/proteasome; focal adhesion was the significant pathway indicated for subtype 4, and the subpaths were miR-34A/vinculin (VCL)/focal adhesion and miR-34C/VCL/focal adhesion. In addition, Helicobacter pylori infection was higher in GC subtype 1 than in other subtypes. Specific genes, such as CACNA1E, CCL21, PSMD3 and VCL, may be used as potential feature genes to identify different subtypes of GC, and their associated subpaths may partially explain the pathogenetic mechanism of each GC subtype.
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Affiliation(s)
- Yuanhang Li
- Medical Department, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
| | - Weijun Bai
- Medical Department, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
| | - Xu Zhang
- Radiotherapy Department, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
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Kheirollahi M, Moodi M, Ashouri S, Nikpour P, Kazemi M. Evaluation of miR-362 Expression in Astrocytoma of Human Brain Tumors. Adv Biomed Res 2017; 6:129. [PMID: 29142892 PMCID: PMC5672651 DOI: 10.4103/2277-9175.216782] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Background: Patients affected by gliomas have a poor prognosis. Astrocytoma is a subtype of glioma. Identification of biomarkers could be an effective way to an early diagnosis of tumor or to distinguish more aggressive tumors that need more intensive therapy. In this study, we investigated whether the expression of miR-362 was increased or decreased in patients with different grades of astrocytoma. Materials and Methods: miR-362 expression was compared in 25 patients with astrocytoma with that of 4 normal nonneoplastic brain tissues. Results: In all tumor tissues, the expression of miR-362 was significantly decreased relative to its expression in normal brain tissues. However, there was no significant difference between miR-362 expressions in high and low grades of astrocytoma. Conclusions: In conclusion, miR-362 showed a down-regulation pattern in astrocytoma tissues that was different from the pattern obtained from previously published microarray studies.
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Affiliation(s)
- Majid Kheirollahi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahdiye Moodi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saeideh Ashouri
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvaneh Nikpour
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Applied Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Kazemi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Chen EG, Zhang JS, Xu S, Zhu XJ, Hu HH. Long non-coding RNA DGCR5 is involved in the regulation of proliferation, migration and invasion of lung cancer by targeting miR-1180. Am J Cancer Res 2017; 7:1463-1475. [PMID: 28744397 PMCID: PMC5523028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 05/23/2017] [Indexed: 06/07/2023] Open
Abstract
Accumulating studies have demonstrated that non-coding RNAs (ncRNAs), including small non-coding RNAs (small ncRNAs) and long non-coding RNAs (lncRNAs), are involved in tumor growth in lung cancer (LC). However, the specific role of DGCR5 in LC progression is not yet clear. In the present study, we found that DGCR5 was downregulated and miR-1180 was upregulated in the sera and tissues of LC patients and was correlated with poor prognosis. We also found that DGCR5 suppressed proliferation, migration and invasion of LC cell lines H520 and H1299. In addition, a luciferase reporter gene assay was used to investigate the regulatory relationship between DGCR5 and miR-1180. Furthermore, we suggested that DGCR5 inhibited the expression of AKT, GSK-3β, and β-catenin by targeting miR-1180. Based on these findings, DGCR5 might serve as a potential target for the development of effective anti-neoplastic therapies in lung cancer.
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Affiliation(s)
- En-Guo Chen
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| | - Ji-Song Zhang
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| | - Shan Xu
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| | - Xiao-Jing Zhu
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| | - Hui-Hui Hu
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
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Li M, Guan H. Noncoding RNAs Regulating NF-κB Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 927:317-36. [PMID: 27376741 DOI: 10.1007/978-981-10-1498-7_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
As transcription factors that regulate expression of a variety of genes essential for diverse physiological and pathological processes, nuclear factor kappa B (NF-κB) family molecules play important roles in the development and progression of malignant tumor, and constitutive activation of NF-κB has been evidenced in various types of tumor tissues. Underlying its pathologic role, deregulated expression and/or transactivating activity of NF-κB usually involves multiple layers of molecular mechanisms. Noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are known to modulate expression and biological functions of regulatory proteins in a variety of cancer contexts. In this chapter, the regulatory role of miRNAs and lncRNAs in NF-κB signaling in malignant diseases will be discussed.
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Affiliation(s)
- Mengfeng Li
- Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, China.
| | - Hongyu Guan
- Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, China
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46
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Sokolova O, Naumann M. NF-κB Signaling in Gastric Cancer. Toxins (Basel) 2017; 9:toxins9040119. [PMID: 28350359 PMCID: PMC5408193 DOI: 10.3390/toxins9040119] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 03/14/2017] [Accepted: 03/22/2017] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a leading cause of cancer death worldwide. Diet, obesity, smoking and chronic infections, especially with Helicobacter pylori, contribute to stomach cancer development. H. pylori possesses a variety of virulence factors including encoded factors from the cytotoxin-associated gene pathogenicity island (cagPAI) or vacuolating cytotoxin A (VacA). Most of the cagPAI-encoded products form a type 4 secretion system (T4SS), a pilus-like macromolecular transporter, which translocates CagA into the cytoplasm of the host cell. Only H. pylori strains carrying the cagPAI induce the transcription factor NF-κB, but CagA and VacA are dispensable for direct NF-κB activation. NF-κB-driven gene products include cytokines/chemokines, growth factors, anti-apoptotic factors, angiogenesis regulators and metalloproteinases. Many of the genes transcribed by NF-κB promote gastric carcinogenesis. Since it has been shown that chemotherapy-caused cellular stress could elicit activation of the survival factor NF-κB, which leads to acquisition of chemoresistance, the NF-κB system is recommended for therapeutic targeting. Research is motivated for further search of predisposing conditions, diagnostic markers and efficient drugs to improve significantly the overall survival of patients. In this review, we provide an overview about mechanisms and consequences of NF-κB activation in gastric mucosa in order to understand the role of NF-κB in gastric carcinogenesis.
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Affiliation(s)
- Olga Sokolova
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, Magdeburg 39120, Germany.
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, Magdeburg 39120, Germany.
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Biersack B. Interactions between anticancer active platinum complexes and non-coding RNAs/microRNAs. Noncoding RNA Res 2017; 2:1-17. [PMID: 30159416 PMCID: PMC6096430 DOI: 10.1016/j.ncrna.2016.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 10/07/2016] [Accepted: 10/07/2016] [Indexed: 12/13/2022] Open
Abstract
Platinum(II) complexes such as cisplatin, carboplatin and oxaliplatin are clinically approved for the therapy of various solid tumors. Challenging pathogenic properties of cancer cells and the response of cancers towards platinum-based drugs are strongly influenced by non-coding small RNA molecules, the microRNAs (miRNAs). Both increased platinum activity and formation of tumor resistance towards platinum drugs are controlled by miRNAs. This review gives an overview of the interactions between platinum-based drugs and miRNAs, and their influence on platinum activity in various cancer types is discussed.
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Key Words
- 5-FU, 5-fluorouracil
- Anticancer drugs
- CBDCA, cyclobutane-1,1-dicarboxylate
- Carboplatin
- Cisplatin
- DACH, 1,2-diaminocyclohexane
- DDP, cisplatin
- EGCG, (−)-epigallocatechin-3-gallate
- EOX, epirubicin/oxaliplatin/xeloda
- FOLFOX, folinate/5-FU/oxaliplatin
- GC, gemcitabine/cisplatin, gastric cancer
- LNA, locked nucleic acid
- MVAC, methotrexate/vinblastine/adriamycin/cisplatin
- MicroRNA
- Oxaliplatin
- Platinum complexes
- XELOX, xeloda/oxaliplatin
- dTTP, deoxythymidine triphosphate
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Gao HY, Huo FC, Wang HY, Pei DS. MicroRNA-9 inhibits the gastric cancer cell proliferation by targeting TNFAIP8. Cell Prolif 2017; 50. [PMID: 28127811 DOI: 10.1111/cpr.12331] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 12/16/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND OBJECTIVES MicroRNA-9 is frequently dysregulated in many human carcinoma types, including gastric cancer (GC). Previous studies demonstrated that the expression of TNFAIP8 in GC is correlated with tumour occurrence, development, invasion, metastasis and prognosis. However, till now, the relationship between MicroRNA-9 and TNFAIP8 in GC has not been reported. MATERIALS AND METHODS Levels of miR-9 and TNFAIP8 expression in GC tissues and in human GC cell lines were studied using qualitative real-time PCR (qRT-PCR) and Western blotting. Cell viability was detected using the CCK-8 and clone formation assays. A dual-luciferase reporter system was used to confirm the target gene of miR-9. RESULTS We found that the expression level of MicroRNA-9 in GC tissues and cell lines was significantly lower than that in adjacent non-cancerous tissues and human immortalized gastric epithelial cell (GES) line, respectively. In addition, overexpression of MicroRNA-9 markedly inhibited GC cell proliferation in vitro and tumour growth in vivo. Further experiments revealed that TNFAIP8 was a direct and functional target of MicroRNA-9 in GC and overexpression of MicroRNA-9 obviously down-regulated the expression of TNFAIP8, which was involved in the gastric carcinogenesis and cancer progression. CONCLUSION Our results suggested that MicroRNA-9-TNFAIP8 might represent a promising diagnostic biomarker for GC patients and could be a potential therapeutic target in the prevention and treatment of GC.
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Affiliation(s)
- Hong-Yu Gao
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, China
| | - Fu-Chun Huo
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, China
| | - Hai-Yan Wang
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, China.,Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Dong-Sheng Pei
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, China.,Department of Pathology, Xuzhou Medical University, Xuzhou, China
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Fang Z, Zhang L, Liao Q, Wang Y, Yu F, Feng M, Xiang X, Xiong J. Regulation of TRIM24 by miR-511 modulates cell proliferation in gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:17. [PMID: 28114950 PMCID: PMC5259882 DOI: 10.1186/s13046-017-0489-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 01/05/2017] [Indexed: 12/20/2022]
Abstract
Background Increasing evidence highlights the important roles of tripartite motif containing 24 (TRIM24) in tumor initiation and malignant progression in many tumors, including gastric cancer (GC). Although TRIM24 expression is remarkably upregulated during GC carcinogenesis, the molecular mechanisms underlying TRIM24 dysregulation remain unexplored. Methods In this study, miRNA target prediction tools were applied to explore miRNAs that potentially target TRIM24. Western blot and quantitative reverse-transcriptase PCR (qRT-PCR) were performed to detected TRIM24 and miR-511 expression in GC tissues and cell lines. Dual-luciferase reporter assay was utilized to validate if TRIM24 is a direct target gene of miR-511. CCK-8 assay, cell colony formation assay, EdU incorporation assay and cell cycle analysis were performed to determine whether miR-511-mediated regulation of TRIM24 could affect GC progression. Results In our study, miR-511 was found to be downregulated in GC and an inverse correlation was observed between TRIM24 and miR-511 expression in primary GC tissues and cell lines. Dual-luciferase reporter assay further verified TRIM24 is a direct target of miR-511. Functional assays showed miR-511 overexpression inhibited cell growth, colony formation ability and cell cycle progression. Conversely, inhibition of endogenous miR-511 promoted these phenotypes in GC cells. Moreover, reintroduction of TRIM24 rescued miR-511-induced inhibitory effects on GC cells. Furthermore, miR-511 elicits tumor-suppressive effects through inactivating PI3K/AKT and Wnt/β-catenin pathways by suppressing TRIM24. Conclusions Our results provide the new evidence supporting the tumor-suppressive role of miR-511 in GC by suppressing TRIM24, suggesting that this novel miR-511/TRIM24 axis is critical in the control of gastric cancer tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0489-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ziling Fang
- Department of Oncology, the First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Ling Zhang
- Department of Oncology, the First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Quan Liao
- Department of Oncology, the First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Yi Wang
- Department of Oncology, the First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Feng Yu
- Department of Oncology, the First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Miao Feng
- Department of Oncology, the First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Xiaojun Xiang
- Department of Oncology, the First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China.
| | - Jianping Xiong
- Department of Oncology, the First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China.
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Deng J, Lei W, Xiang X, Zhang L, Lei J, Gong Y, Song M, Wang Y, Fang Z, Yu F, Feng M, Sun Z, Chen J, Zhan Z, Xiong J. Cullin 4A (CUL4A), a direct target of miR-9 and miR-137, promotes gastric cancer proliferation and invasion by regulating the Hippo signaling pathway. Oncotarget 2017; 7:10037-50. [PMID: 26840256 PMCID: PMC4891102 DOI: 10.18632/oncotarget.7048] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Accepted: 12/07/2015] [Indexed: 02/07/2023] Open
Abstract
Although Cullin 4A (CUL4A) is mutated or amplified in several human cancer types, its role in gastric cancer (GC) and the mechanisms underlying its regulation remain largely uncharacterized. In the present study, we report that the expression of CUL4A significantly correlated with the clinical stage of the tumor and lymph node metastasis, and survival rates were lower in GC patients with higher levels of CUL4A than in patients with lower CUL4A levels. The upregulation of CUL4A promoted GC cell proliferation and epithelial-mesenchymal transition (EMT) by downregulating LATS1-Hippo-YAP signaling. Knocking down CUL4A had the opposite effect in vitro and in vivo. Interestingly, CUL4A expression was inhibited by the microRNAs (miRNAs), miR-9 and miR-137, which directly targeted the 3′-UTR of CUL4A. Overexpression of miR-9 and miR-137 downregulated the CUL4A-LATS1-Hippo signaling pathway and suppressed GC cell proliferation and invasion in vitro. Taken together, our findings demonstrate that perturbations to miR-9/137-CUL4A-Hippo signaling contribute to gastric tumorigenesis, and suggest potential therapeutic targets for the future treatment of GC.
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Affiliation(s)
- Jun Deng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Wan Lei
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Xiaojun Xiang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Ling Zhang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Jun Lei
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Yu Gong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Meijiao Song
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Yi Wang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Ziling Fang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Feng Yu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Miao Feng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Ze Sun
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Jun Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Zhengyu Zhan
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
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