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Zhang J, Yin R, Xue Y, Qin R, Wang X, Wu S, Zhu J, Li YS, Zhang C, Wei Y. Advances in the study of epithelial mesenchymal transition in cancer progression: Role of miRNAs. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 196:69-90. [PMID: 40185337 DOI: 10.1016/j.pbiomolbio.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 04/02/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
Epithelial-mesenchymal transition (EMT) has been extensively studied for its roles in tumor metastasis, the generation and maintenance of cancer stem cells and treatment resistance. Epithelial mesenchymal plasticity allows cells to switch between various states within the epithelial-mesenchymal spectrum, resulting in a mixed epithelial/mesenchymal phenotypic profile. This plasticity underlies the acquisition of multiple malignant features during cancer progression and poses challenges for EMT in tumors. MicroRNAs (miRNAs) in the microenvironment affect numerous signaling processes through diverse mechanisms, influencing physiological activities. This paper reviews recent advances in EMT, the role of different hybrid states in tumor progression, and the important role of miRNAs in EMT. Furthermore, it explores the relationship between miRNA-based EMT therapies and their implications for clinical practice, discussing how ongoing developments may enhance therapeutic outcomes.
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Affiliation(s)
- Jia Zhang
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China.
| | - Yongwang Xue
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Rong Qin
- Department of Medical Oncology, Jiangsu University Affiliated People's Hospital, Zhenjiang Clinical Medical College of Nanjing Medical University, Zhenjiang, China
| | - Xuequan Wang
- Department of Radiation Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shuming Wu
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Jun Zhu
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Yan-Shuang Li
- Department of Breast Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Cai Zhang
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China.
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Barjasteh AH, Jaseb Mazhar AleKassar R, Al-Asady AM, Latifi H, Avan A, Khazaei M, Ryzhikov M, Hassanian SM. Therapeutic Potentials of MiRNA for Colorectal Cancer Liver Metastasis Treatment: A Narrative Review. IRANIAN JOURNAL OF MEDICAL SCIENCES 2025; 50:202-219. [PMID: 40255223 PMCID: PMC12008659 DOI: 10.30476/ijms.2024.102910.3622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/01/2024] [Accepted: 11/26/2024] [Indexed: 04/22/2025]
Abstract
Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide and is the fourth leading cause of cancer-related deaths. Metastasis poses a significant obstacle in CRC treatment, as distant metastasis, particularly to the liver, remains the primary cause of mortality. Colorectal liver metastasis (CRLM) occurs frequently due to the liver's direct vascular connection to the colorectal region via the portal vein. Standard treatment approaches for CRLM are limited; only a few patients qualify for surgical intervention, resulting in a persistently low survival rate. Additionally, resistance to chemotherapy is common, emphasizing the need for more effective targeted therapies. Emerging evidence highlights the pivotal role of microRNAs (miRNAs) in modulating critical pathways associated with CRLM, including tumor invasion, epithelial-mesenchymal transition, and angiogenesis. MiRNAs exhibit dual functions as tumor suppressors and oncogenes by targeting multiple genes, thus playing a complex role in both the initiation and progression of metastasis. The regulatory mechanisms of miRNAs could help to identify novel biomarkers for early diagnosis and prognosis of CRLM, as well as promising therapeutic targets to overcome chemoresistance. Despite numerous studies on miRNA involvement in CRC metastasis, dedicated reviews focusing on miRNAs and CRLM remain scarce. This review aims to approach targeted therapies by examining the current understanding of miRNA involvement in CRLM and exploring their potential as diagnostic, prognostic, and therapeutic agents. Through an integrative approach, we aim to provide insights that could transform CRLM management and improve patient outcomes.
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Affiliation(s)
- Amir Hossein Barjasteh
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rawa Jaseb Mazhar AleKassar
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdulridha Mohammed Al-Asady
- Department of Medical Sciences, Faculty of Nursing, Warith Al-Anbiyaa University, Iraq
- Department of Medical Sciences, Faculty of Dentistry, University of Kerbala, Iraq
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Latifi
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Araujo RLC, Fonseca LG, Silva RO, Linhares MM, Uson Junior PLS. Molecular profiling and patient selection for the multimodal approaches for patients with resectable colorectal liver metastases. Hepatobiliary Surg Nutr 2024; 13:273-292. [PMID: 38617479 PMCID: PMC11007353 DOI: 10.21037/hbsn-22-616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/31/2023] [Indexed: 04/16/2024]
Abstract
Colorectal cancer represents the third most common cancer and about 20% are diagnosed with synchronous metastatic disease. From a historical point of view, surgery remains the mainstream treatment for resectable colorectal liver metastases (CRLM). Furthermore, disease outcomes are improving due significant advances in systemic treatments and diagnostic methods. However, the optimal timing for neoadjuvant chemotherapy or upfront surgery for CRLM has not yet been established and remains an open question. Thus, patient selection combining image workouts, time of recurrence, positive lymph nodes, and molecular biomarkers can improve the decision-making process. Nevertheless, molecular profiling is rising as a promising field to be incorporated in the multimodal approach and guide patient selection and sequencing of treatment. Tumor biomakers, genetic profiling, and circulating tumor DNA have been used to offer as much personalized treatment as possible, based on the precision oncology concept of tailored care rather than a guideline-based therapy. This review article discusses the role of molecular pathology and biomarkers as prognostic and predictor factors in the diagnosis and treatment of resectable CRLM.
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Affiliation(s)
- Raphael L. C. Araujo
- Department of Surgery, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Hospital e Maternidade Brasil—Rede D’Or São Luiz, Santo André, SP, Brazil
- Department of Oncology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Leonardo G. Fonseca
- Hospital e Maternidade Brasil—Rede D’Or São Luiz, Santo André, SP, Brazil
- Department of Oncology, Instituto do Cancer do Estado de São Paulo, University of Sao Paulo, São Paulo, SP, Brazil
| | - Raphael Oliveira Silva
- Department of Surgery, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Department of Oncology, Hospital Ministro Costa Cavalcanti, Foz do Iguaçu, PR, Brazil
| | | | - Pedro L. S. Uson Junior
- Department of Oncology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Center for Personalized Medicine, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
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4
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Fang A, Yuan Y, Sui B, Wang Z, Zhang Y, Zhou M, Chen H, Fu ZF, Zhao L. Inhibition of miR-200b-3p confers broad-spectrum resistance to viral infection by targeting TBK1. mBio 2023; 14:e0086723. [PMID: 37222520 PMCID: PMC10470528 DOI: 10.1128/mbio.00867-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 04/11/2023] [Indexed: 05/25/2023] Open
Abstract
The host innate immune system's defense against viral infections depends heavily on type I interferon (IFN-I) production. Research into the mechanisms of virus-host interactions is essential for developing novel antiviral therapies. In this study, we compared the effect of the five members of the microRNA-200 (miR-200) family on IFN-I production during viral infection and found that miR-200b-3p displayed the most pronounced regulatory effect. During viral infection, we discovered that the transcriptional level of microRNA-200b-3p (miR-200b-3p) increased with the infection of influenza virus (IAV) and vesicular stomatitis virus (VSV), and miR-200b-3p production was modulated by the activation of the ERK and p38 pathways. We identified cAMP response element binding protein (CREB) as a novel transcription factor that binds to the miR-200b-3p promoter. MiR-200b-3p reduces NF-κB and IRF3-mediated IFN-I production by targeting the 3' untranslated region (3' UTR) of TBK1 mRNA. Applying miR-200b-3p inhibitor enhances IFN-I production in IAV and VSV-infected mouse models, thus inhibiting viral replication and improving mouse survival ratio. Importantly, in addition to IAV and VSV, miR-200b-3p inhibitors exhibited potent antiviral effects against multiple pathogenic viruses threatening human health worldwide. Overall, our study suggests that miR-200b-3p might be a potential therapeutic target for broad-spectrum antiviral therapy. IMPORTANCE The innate immune response mediated by type I interferon (IFN-I) is essential for controlling viral replication. MicroRNAs (miRNAs) have been found to regulate the IFN signaling pathway. In this study, we describe a novel function of miRNA-200b-3p in negatively regulating IFN-I production during viral infection. miRNA-200b-3p was upregulated by the MAPK pathway activated by IAV and VSV infection. The binding of miRNA-200b-3p to the 3' UTR of TBK1 mRNA reduced IFN-I activation mediated by IRF3 and NF-κB. Application of miR-200b-3p inhibitors exhibited potent antiviral effects against multiple RNA and DNA viruses. These results provide fresh insight into understanding the impact of miRNAs on host-virus interactions and reveal a potential therapeutic target for common antiviral intervention.
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Affiliation(s)
- An Fang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yueming Yuan
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Baokuen Sui
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Zhihui Wang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yuan Zhang
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Ming Zhou
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Huanchun Chen
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei Hongshan Laboratory, Wuhan, China
| | - Zhen F. Fu
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Ling Zhao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Hubei Hongshan Laboratory, Wuhan, China
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Pavlič A, Urh K, Boštjančič E, Zidar N. Analyzing the invasive front of colorectal cancer - By punching tissue block or laser capture microdissection? Pathol Res Pract 2023; 248:154727. [PMID: 37517168 DOI: 10.1016/j.prp.2023.154727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/01/2023]
Abstract
The aim of this study was to determine the advantages and limitations of two commonly used sampling techniques, i.e., punching tissue block (PTB) and laser capture microdissection (LCM) when investigating tumor cell-derived gene expression patterns at the invasive front of colorectal cancer (CRC). We obtained samples from 20 surgically removed CRCs at locations crucial for tumor progression, i.e., the central part, the expansive front and the infiltrative front exhibiting tumor budding (TB), using both sampling techniques. At each location, we separately analyzed the expressions of miR-200 family (miR-141, miR-200a, miR-200b, miR-200c and miR-429), known as reliable markers of epithelial-mesenchymal transition (EMT). We found significant downregulation of all members of miR-200 family at the infiltrative front in comparison to the central part regardless of the used sampling technique. However, when comparing miR-200 expression between the expansive and the infiltrative front, we found significant downregulation of all tested miR-200 at the infiltrative front only in samples obtained by LCM. Our results suggest that, PTB is an adequate technique for studying the differences in tumor gene expression between the central part and the invasive front of CRC, but is insufficient to analyze and compare morphologically distinct patterns along the invasive front including TB. For this purpose, the use of LCM is essential.
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Affiliation(s)
- Ana Pavlič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
| | - Kristian Urh
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia.
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Pavlič A, Boštjančič E, Kavalar R, Ilijevec B, Bonin S, Zanconati F, Zidar N. Tumour budding and poorly differentiated clusters in colon cancer - different manifestations of partial epithelial-mesenchymal transition. J Pathol 2022; 258:278-288. [PMID: 36062412 PMCID: PMC9825925 DOI: 10.1002/path.5998] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/24/2022] [Accepted: 08/04/2022] [Indexed: 01/11/2023]
Abstract
Morphological features including infiltrative growth, tumour budding (TB), and poorly differentiated clusters (PDCs) have a firmly established negative predictive value in colorectal cancer (CRC). Despite extensive research, the mechanisms underlying different tumour growth patterns remain poorly understood. The aim of this study was to investigate the involvement of epithelial-mesenchymal transition (EMT) in TB and PDCs in CRC. Using laser-capture microdissection, we obtained distinct parts of the primary CRC including TB, PDCs, expansive tumour front, and the central part of the tumour, and analysed the expression of EMT-related markers, i.e. the miR-200 family, ZEB1/2, RND3, and CDH1. In TB, the miR-200 family and CDH1 were significantly downregulated, while ZEB2 was significantly upregulated. In PDCs, miR-141, miR-200c, and CDH1 were significantly downregulated. No significant differences were observed in the expression of any EMT-related markers between the expansive tumour front and the central part of the tumour. Our results suggest that both TB and PDCs are related to partial EMT. Discrete differences in morphology and expression of EMT-related markers between TB and PDCs indicate that they represent different manifestations of partial EMT. TB seems to be closer to complete EMT than PDCs. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Ana Pavlič
- Institute of Pathology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
| | - Rajko Kavalar
- Department of PathologyUniversity Medical Centre MariborMariborSlovenia
| | - Bojan Ilijevec
- Department of Abdominal and General SurgeryUniversity Medical Centre MariborMariborSlovenia
| | - Serena Bonin
- Department of Medical SciencesUniversity of TriesteTriesteItaly
| | | | - Nina Zidar
- Institute of Pathology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
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7
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Ranković B, Boštjančič E, Zidar N, Žlajpah M, Jeruc J. miR-200b, ZEB2 and PTPN13 Are Downregulated in Colorectal Carcinoma with Serosal Invasion. Biomedicines 2022; 10:2149. [PMID: 36140249 PMCID: PMC9496117 DOI: 10.3390/biomedicines10092149] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/23/2022] [Accepted: 08/27/2022] [Indexed: 11/16/2022] Open
Abstract
Serosal invasion is an independent negative prognostic factor in certain cancers, including CRC. However, the mechanisms behind serosal invasion are poorly understood. We therefore assumed that epithelial-mesenchymal transition (EMT) might be involved. Our study included 34 patients with CRC, 3 stage pT2, 14 stage pT3 and 17 showing serosal invasion (stage pT4a according to TNM staging system). RNA isolated from formalin-fixed paraffin-embedded tissue samples was analysed for expression of the miR-200 family and their target genes CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2 using real-time PCR. We found upregulation of miR-200b and ONECUT2 in CRC pT3 and pT4a compared to normal mucosa, and downregulation of CDKN1B in CRC pT3. Moreover, we observed, downregulation of miR-200b, PTPN13 and ZEB2 in CRC with serosal invasion (pT4a) compared to pT3. Our results suggest the involvement of partial EMT in serosal invasion of CRC. In addition, PTPN13 seems to be one of the important regulators involved in serosal invasion, and ONECUT2 in tumour growth.
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Affiliation(s)
| | | | | | | | - Jera Jeruc
- Faculty of Medicine, Institute of Pathology, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
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Hisamori S, Mukohyama J, Koul S, Hayashi T, Rothenberg ME, Maeda M, Isobe T, Valencia Salazar LE, Qian X, Johnston DM, Qian D, Lao K, Asai N, Kakeji Y, Gennarino VA, Sahoo D, Dalerba P, Shimono Y. Upregulation of BMI1-suppressor miRNAs (miR-200c, miR-203) during terminal differentiation of colon epithelial cells. J Gastroenterol 2022; 57:407-422. [PMID: 35244768 PMCID: PMC10091510 DOI: 10.1007/s00535-022-01865-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 02/10/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) are key regulators of stem cell functions, including self-renewal and differentiation. In this study, we aimed to identify miRNAs that are upregulated during terminal differentiation in the human colon epithelium, and elucidate their role in the mechanistic control of stem cell properties. METHODS "Bottom-of-the-crypt" (EPCAM+/CD44+/CD66alow) and "top-of-the-crypt" (EPCAM+/CD44neg/CD66ahigh) epithelial cells from 8 primary colon specimens (6 human, 2 murine) were purified by flow cytometry and analyzed for differential expression of 335 miRNAs. The miRNAs displaying the highest upregulation in "top-of-the-crypt" (terminally differentiated) epithelial cells were tested for positive correlation and association with survival outcomes in a colon cancer RNA-seq database (n = 439 patients). The two miRNAs with the strongest "top-of-the-crypt" expression profile were evaluated for capacity to downregulate self-renewal effectors and inhibit in vitro proliferation of colon cancer cells, in vitro organoid formation by normal colon epithelial cells and in vivo tumorigenicity by patient-derived xenografts (PDX). RESULTS Six miRNAs (miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-345) were upregulated in "top-of-the-crypt" cells and positively correlated in expression among colon carcinomas. Overexpression of the three miRNAs with the highest inter-correlation coefficients (miR-200a, miR-200b, miR-200c) associated with improved survival. The top two over-expressed miRNAs (miR-200c, miR-203) cooperated synergistically in suppressing expression of BMI1, a key regulator of self-renewal in stem cell populations, and in inhibiting proliferation, organoid-formation and tumorigenicity of colon epithelial cells. CONCLUSION In the colon epithelium, terminal differentiation associates with the coordinated upregulation of miR-200c and miR-203, which cooperate to suppress BMI1 and disable the expansion capacity of epithelial cells.
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Affiliation(s)
- Shigeo Hisamori
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA.,Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Junko Mukohyama
- Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.,Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY, 10032, USA.,Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY, 10032, USA.,Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY, 10032, USA.,Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, USA.,Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, 6500017, Japan.,Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, International University of Health and Welfare (IUHW), Tokyo, 1088329, Japan
| | - Sanjay Koul
- Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.,Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY, 10032, USA.,Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY, 10032, USA.,Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY, 10032, USA.,Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, USA.,Department of Biological Sciences and Geology, Queensboro Community College (QCC), City University of New York (CUNY), New York, NY, 11364, USA
| | - Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Michael Evan Rothenberg
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Masao Maeda
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan.,Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Taichi Isobe
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Luis Enrique Valencia Salazar
- Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.,Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY, 10032, USA.,Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY, 10032, USA.,Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY, 10032, USA.,Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, USA
| | - Xin Qian
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Darius Michael Johnston
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA.,Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, 94305, USA
| | - Dalong Qian
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Kaiqin Lao
- Genetic Sciences Division (GSD), Thermo Fisher Scientific, South San Francisco, CA, 94080, USA
| | - Naoya Asai
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, 6500017, Japan
| | - Vincenzo Alessandro Gennarino
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, 10032, USA.,Department of Neurology, Columbia University, New York, NY, 10032, USA.,Department of Pediatrics, Columbia University, New York, NY, 10032, USA.,Initiative for Columbia Ataxia and Tremor (ICAT), Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Debashis Sahoo
- Department of Computer Science and Engineering and Department of Pediatrics, University of California San Diego (UCSD), San Diego, CA, 92123, USA
| | - Piero Dalerba
- Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA. .,Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY, 10032, USA. .,Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY, 10032, USA. .,Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY, 10032, USA. .,Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, USA.
| | - Yohei Shimono
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA. .,Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan.
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9
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Pavlič A, Hauptman N, Boštjančič E, Zidar N. Long Non-Coding RNAs as Potential Regulators of EMT-Related Transcription Factors in Colorectal Cancer—A Systematic Review and Bioinformatics Analysis. Cancers (Basel) 2022; 14:cancers14092280. [PMID: 35565409 PMCID: PMC9105237 DOI: 10.3390/cancers14092280] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Emerging evidence highlights long non-coding RNAs as important regulators of epithelial–mesenchymal transition. Numerous studies have attempted to define their possible diagnostic, prognostic and therapeutic values in various human cancers. The aim of this review is to summarize long non-coding RNAs involved in the regulation of epithelial–mesenchymal transition in colorectal carcinoma. Additional candidate long non-coding RNAs are identified through a bioinformatics analysis. Abstract Epithelial–mesenchymal transition (EMT) plays a pivotal role in carcinogenesis, influencing cancer progression, metastases, stemness, immune evasion, metabolic reprogramming and therapeutic resistance. EMT in most carcinomas, including colorectal carcinoma (CRC), is only partial, and can be evidenced by identification of the underlying molecular drivers and their regulatory molecules. During EMT, cellular reprogramming is orchestrated by core EMT transcription factors (EMT-TFs), namely ZEB1/2, TWIST1/2, SNAI1 (SNAIL) and SNAI2 (SLUG). While microRNAs have been clearly defined as regulators of EMT, the role of long non-coding RNAs (lncRNAs) in EMT is poorly defined and controversial. Determining the role of lncRNAs in EMT remains a challenge, because they are involved in a number of cellular pathways and are operating through various mechanisms. Adding to the complexity, some lncRNAs have controversial functions across different tumor types, acting as EMT promotors in some tumors and as EMT suppressors in others. The aim of this review is to summarize the role of lncRNAs involved in the regulation of EMT-TFs in human CRC. Additional candidate lncRNAs were identified through a bioinformatics analysis.
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Transcriptional and post-transcriptional control of epithelial-mesenchymal plasticity: why so many regulators? Cell Mol Life Sci 2022; 79:182. [PMID: 35278142 PMCID: PMC8918127 DOI: 10.1007/s00018-022-04199-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 01/18/2022] [Accepted: 02/07/2022] [Indexed: 12/12/2022]
Abstract
The dynamic transition between epithelial-like and mesenchymal-like cell states has been a focus for extensive investigation for decades, reflective of the importance of Epithelial-Mesenchymal Transition (EMT) through development, in the adult, and the contributing role EMT has to pathologies including metastasis and fibrosis. Not surprisingly, regulation of the complex genetic networks that underlie EMT have been attributed to multiple transcription factors and microRNAs. What is surprising, however, are the sheer number of different regulators (hundreds of transcription factors and microRNAs) for which critical roles have been described. This review seeks not to collate these studies, but to provide a perspective on the fundamental question of whether it is really feasible that so many regulators play important roles and if so, what does this tell us about EMT and more generally, the genetic machinery that controls complex biological processes.
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11
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Zhou H, Liu Z, Wang Y, Wen X, Amador EH, Yuan L, Ran X, Xiong L, Ran Y, Chen W, Wen Y. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther 2022; 7:70. [PMID: 35246503 PMCID: PMC8897452 DOI: 10.1038/s41392-022-00922-2] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.
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Affiliation(s)
- Hui Zhou
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Zhongtao Liu
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Yongxiang Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiaoyong Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Eric H Amador
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA
| | - Liqin Yuan
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xin Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| | - Yuping Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Chen
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA.
- Medical Technology Research Centre, Chelmsford Campus, Anglia Ruskin University, Chelmsford, CM1 1SQ, UK.
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
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12
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HOTAIR Induces the Downregulation of miR-200 Family Members in Gastric Cancer Cell Lines. IRANIAN BIOMEDICAL JOURNAL 2022; 26:77-84. [PMID: 34923813 PMCID: PMC8784900 DOI: 10.52547/ibj.26.1.77] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Background Gastric cancer (GC) is the fourth most common human malignancy and the second reason for cancer morbidity worldwide. Long noncoding RNA (LncRNA) HOX transcript antisense RNA (HOTAIR) has recently emerged as a promoter of metastasis in various cancer types, including GC, through the epithelial‑mesenchymal transition (EMT) process. However, the exact mechanism of HOTAIR in promoting EMT is unknown. Aberrant expression of the miR-200 family has been linked to the occurrence and development of various types of malignant tumors. This study investigates the correlation between the HOTAIR and miR-200 family gene expression patterns in GC cell lines. We investigated the miR-200 and HOTAIR due to their common molecular features in the EMT process. Methods AGS and MKN45 cell lines were transfected with si-HOTAIR, along with a negative control. The effect of HOTAIR knockdown was also analyzed on cell viability and also on the expression of miR-200 family members, including miR-200a, -200b, and -200c, in cell lines using qRT-PCR. Statistical analysis was performed to find the potential correlation between the expression level of HOTAIR and miRs. Results Our results showed significant increased miR-200 family expression level in transfected AGS and MKN45 GC cells (fold changes > 2; p < 0.001). Moreover, a negative correlation was observed between HOTAIR and miR-200 expression levels in GC cell lines (p < 0.05). Conclusion Our findings showed a significant association between miR-200 family and HOTAIR expression levels in GC cell lines. Taken together, the HOTAIR-miR-200 axis seems to play a vital role in human GC, suggesting a potential therapeutic target in future GC treatment.
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Cavallari I, Ciccarese F, Sharova E, Urso L, Raimondi V, Silic-Benussi M, D’Agostino DM, Ciminale V. The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers. Cancers (Basel) 2021; 13:5874. [PMID: 34884985 PMCID: PMC8656820 DOI: 10.3390/cancers13235874] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.
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Affiliation(s)
- Ilaria Cavallari
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Francesco Ciccarese
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Evgeniya Sharova
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Loredana Urso
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
| | - Vittoria Raimondi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Micol Silic-Benussi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Donna M. D’Agostino
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Biomedical Sciences, University of Padua, 35131 Padova, Italy
| | - Vincenzo Ciminale
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
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Cheng X, Wei H, Zhang S, Zhang F. Predictive and Prognostic Value of an MicroRNA Signature for Gastric Carcinoma Undergoing Adjuvant Chemotherapy. DNA Cell Biol 2021; 40:1428-1444. [PMID: 34767733 DOI: 10.1089/dna.2021.0377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Gastric carcinoma (GC) is one of the most common cause of tumor-related death. Chemotherapy resistance usually occurs, leading to cancer relapse and poor survival of GC patients. To investigate the role of miRNAs in chemotherapy resistance for GC patients, we conducted an integrated analysis of miRNA expression and survival information using data obtained from The Cancer Genome Atlas project. Genome-wide screening of chemotherapy response-specific miRNAs was performed using Cox proportional hazards regression analyses for patients who received chemotherapy or those who had never received chemotherapy, respectively. A four-miRNA expression signature (involving two protective miRNAs, miR-200b and miR-103a, and two risk ones miR-199 and miR-152) was predicted as a specific indicator for GC chemoresistance (p = 0.00053; hazard ratio = 8.63), outperforming those clinicopathological factors. Functional experiments confirmed the roles of these signature miRNAs in regulation of chemotherapy response. Functional enrichment of these signature miRNAs and risk score revealed positive association with epithelial-mesenchymal transition (EMT), and negative association with cell cycle checkpoint and DNA damage response. Furthermore, the immune infiltration-miRNA functional network analysis revealed transformation from activated effector cells to resting immunosuppressive cells are preferred in GCs with adverse chemotherapy response. In summary, our work identifies a four-miRNA expression signature as a promising chemoresistance biomarker in GC, which provides novel insights into developing new strategies to overcome GC chemoresistance.
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Affiliation(s)
- Xiaowei Cheng
- Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Wuxi City, People's Republic of China
| | - Hongkuang Wei
- The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning City, People's Republic of China
| | - Sheng Zhang
- Wuxi Eighth People's Hospital, Wuxi City, People's Republic of China
| | - Fuzheng Zhang
- Department of Radiation Oncology, Affiliated Hospital of Jiangnan University, Wuxi City, People's Republic of China
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Sempere LF, Azmi AS, Moore A. microRNA-based diagnostic and therapeutic applications in cancer medicine. WILEY INTERDISCIPLINARY REVIEWS. RNA 2021; 12:e1662. [PMID: 33998154 PMCID: PMC8519065 DOI: 10.1002/wrna.1662] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 01/18/2023]
Abstract
It has been almost two decades since the first link between microRNAs and cancer was established. In the ensuing years, this abundant class of short noncoding regulatory RNAs has been studied in virtually all cancer types. This tremendously large body of research has generated innovative technological advances for detection of microRNAs in tissue and bodily fluids, identified the diagnostic, prognostic, and/or predictive value of individual microRNAs or microRNA signatures as potential biomarkers for patient management, shed light on regulatory mechanisms of RNA-RNA interactions that modulate gene expression, uncovered cell-autonomous and cell-to-cell communication roles of specific microRNAs, and developed a battery of viral and nonviral delivery approaches for therapeutic intervention. Despite these intense and prolific research efforts in preclinical and clinical settings, there are a limited number of microRNA-based applications that have been incorporated into clinical practice. We review recent literature and ongoing clinical trials that highlight most promising approaches and standing challenges to translate these findings into viable microRNA-based clinical tools for cancer medicine. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Lorenzo F. Sempere
- Department of Radiology, Precision Health ProgramMichigan State UniversityEast LansingMichiganUSA
| | - Asfar S. Azmi
- Department of OncologyWayne State University School of MedicineDetroitMichiganUSA
- Karmanos Cancer InstituteDetroitMichiganUSA
| | - Anna Moore
- Departments of Radiology and Physiology, Precision Health ProgramMichigan State UniversityEast LansingMichiganUSA
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The emerging role of miR-200 family in metastasis: focus on EMT, CSCs, angiogenesis, and anoikis. Mol Biol Rep 2021; 48:6935-6947. [PMID: 34510322 DOI: 10.1007/s11033-021-06666-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Cancer is the second major threat to human society and one of the main challenges facing healthcare systems. One of the main problems of cancer care is the metastases of cancer cells that cause 90% of deaths due to cancer. Multiple molecular mechanisms are involved in cancer cell metastasis. Therefore, a better understanding of these molecular mechanisms is necessary for designing restrictive strategies against cancer cell metastasis. Accumulating data suggests that MicroRNAs (miRNAs) are involved in metastasis and invasion of human tumors through regulating multiple genes expression levels that are involved in molecular mechanisms of metastasis. The goal of this review is to present the molecular pathways by which the miR 200 family manifests its effects on EMT, cancer stem cells, angiogenesis, anoikis, and the effects of tumor cell metastases. METHODS A detailed literature search was conducted to find information about the role of the miR-200 family in the processes involved in metastasis in various databases. RESULTS Numerous lines of evidence revealed an association between the mir-200 family and metastasis of human tumors by impressing processes such as cancer stem cells, EMT, angiogenesis, and anoikis. CONCLUSIONS Understanding the molecular mechanisms associated with metastasis in which the miR-200 family is involved can be effective in treating metastatic cancers.
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Tito C, De Falco E, Rosa P, Iaiza A, Fazi F, Petrozza V, Calogero A. Circulating microRNAs from the Molecular Mechanisms to Clinical Biomarkers: A Focus on the Clear Cell Renal Cell Carcinoma. Genes (Basel) 2021; 12:1154. [PMID: 34440329 PMCID: PMC8391131 DOI: 10.3390/genes12081154] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
microRNAs (miRNAs) are emerging as relevant molecules in cancer development and progression. MiRNAs add a post-transcriptional level of control to the regulation of gene expression. The deregulation of miRNA expression results in changing the molecular circuitry in which miRNAs are involved, leading to alterations of cell fate determination. In this review, we describe the miRNAs that are emerging as innovative molecular biomarkers from liquid biopsies, not only for diagnosis, but also for post-surgery management in cancer. We focus our attention on renal cell carcinoma, in particular highlighting the crucial role of circulating miRNAs in clear cell renal cell carcinoma (ccRCC) management. In addition, the functional deregulation of miRNA expression in ccRCC is also discussed, to underline the contribution of miRNAs to ccRCC development and progression, which may be relevant for the identification and design of innovative clinical strategies against this tumor.
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Affiliation(s)
- Claudia Tito
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy; (C.T.); (A.I.); (F.F.)
| | - Elena De Falco
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (E.D.F.); (P.R.); (V.P.)
- Mediterranea Cardiocentro, 80122 Naples, Italy
| | - Paolo Rosa
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (E.D.F.); (P.R.); (V.P.)
| | - Alessia Iaiza
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy; (C.T.); (A.I.); (F.F.)
| | - Francesco Fazi
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy; (C.T.); (A.I.); (F.F.)
| | - Vincenzo Petrozza
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (E.D.F.); (P.R.); (V.P.)
| | - Antonella Calogero
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (E.D.F.); (P.R.); (V.P.)
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Marinović S, Škrtić A, Catela Ivković T, Poljak M, Kapitanović S. Regulation of KRAS protein expression by miR-544a and KRAS-LCS6 polymorphism in wild-type KRAS sporadic colon adenocarcinoma. Hum Cell 2021; 34:1455-1465. [PMID: 34235620 DOI: 10.1007/s13577-021-00576-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/29/2021] [Indexed: 12/24/2022]
Abstract
Colorectal carcinoma (CRC) results from the accumulation of genetic mutations and alterations in signaling pathways. KRAS is mutated in 40% of CRC cases and is involved in increased tumor cells proliferation and survival. Although KRAS mutations are a dominant event in CRC tumorigenesis, increased wild-type KRAS expression has a similar effect on accelerated tumor growth. In this study, we investigated the KRAS status in correlation with clinicopathological features in sporadic CRC and more importantly the role of let-7a-5p and miR-544a-3p in the regulation of wild-type KRAS protein expression in the tumor center (T1) and invasive tumor front (T2). Analysis showed that 39.1% of tumor samples had KRAS mutations. In wild-type KRAS tumors, 62.0% were positive for KRAS protein expression and there was a higher percentage of KRAS-positive tumor cells and a higher intensity of immunohistochemical reaction in T2 than in T1 samples. This could not be attributed to differences in KRAS mRNA levels, suggesting regulation via miR-544a-3p expression which was significantly decreased in T2 samples. Furthermore, we demonstrated that tumor samples carrying the KRAS-LCS6 variant allele had significantly higher protein expression of the wild-type KRAS. Our results suggest the role of the KRAS-LCS6 polymorphism and miR-544a-3p expression in the regulation of wild-type KRAS protein expression in sporadic CRC.
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Affiliation(s)
- Sonja Marinović
- Division of Molecular Medicine, Laboratory for Personalized Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Anita Škrtić
- Department of Pathology, Clinical Hospital Merkur, Zagreb, Croatia
| | - Tina Catela Ivković
- Division of Molecular Medicine, Laboratory for Personalized Medicine, Ruđer Bošković Institute, Zagreb, Croatia.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Mirko Poljak
- Department of Surgery, Clinical Hospital Merkur, Zagreb, Croatia
| | - Sanja Kapitanović
- Division of Molecular Medicine, Laboratory for Personalized Medicine, Ruđer Bošković Institute, Zagreb, Croatia.
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Pavlič A, Urh K, Štajer K, Boštjančič E, Zidar N. Epithelial-Mesenchymal Transition in Colorectal Carcinoma: Comparison Between Primary Tumor, Lymph Node and Liver Metastases. Front Oncol 2021; 11:662806. [PMID: 34046357 PMCID: PMC8144630 DOI: 10.3389/fonc.2021.662806] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/12/2021] [Indexed: 01/06/2023] Open
Abstract
There is emerging evidence suggesting that epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) play an important role in colorectal carcinoma (CRC), but their exact role remains controversial. Our aim was to analyze the miR-200 family as EMT markers and their target genes expression at invasive tumor front and in nodal and liver metastases. Sixty-three formalin-fixed paraffin-embedded tissue samples from 19 patients with CRC were included. Using a micropuncture technique, tissue was obtained from central part and invasive front of the primary tumor, and nodal and liver metastases. Expression of the miR-200 family and their target genes CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2 was analyzed using real-time PCR. We found miR-200 family down-regulation at invasive front compared to central part, and up-regulation of miRNA-200a/b/c and miR-429 in metastases compared to invasive front. At invasive front, TGFB2 was the only gene with inverse expression to the miR-200 family, whereas in metastases inverse expression was found for ONECUT2 and SOX2. CDKN1B, PTPN13 and ZEB2 were down-regulated at invasive front and up-regulated in metastases. Our results suggest the involvement of partial EMT at invasive tumor front, and partial MET in metastases in CRC, based on miR-200 family and its target genes expression.
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Affiliation(s)
- Ana Pavlič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Kristian Urh
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Katarina Štajer
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Wen B, Zhu R, Jin H, Zhao K. Differential expression and role of miR-200 family in multiple tumors. Anal Biochem 2021; 626:114243. [PMID: 33964251 DOI: 10.1016/j.ab.2021.114243] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/23/2021] [Accepted: 05/01/2021] [Indexed: 01/02/2023]
Abstract
microRNA (miRNA) can maintain the homeostasis of the human by participating in the regulation of cell proliferation, apoptosis, differentiation, and metabolism. During the entire stage of tumorigenesis, miRNA can maintain the heterogeneity of cancer stem cells by regulating the formation and metastasis of the tumor, which leads to chemotherapy resistance. miR-200 family consists of five members, which can regulate the proliferation, invasion, and migration of cancer cells by inhibiting the transcription of downstream genes (including zinc finger E-box binding homeobox 1 and 2, E-cadherin, N-cadherin, transforming growth factor-β, and cancer stem cell related-proteins). Meanwhile, Long non-coding RNA can bind to miR-200s to regulate the proliferation and apoptosis of cancer cells. Besides, the expression of the miR-200 family can affect the mechanism of chemotherapy resistance.
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Affiliation(s)
- Bin Wen
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Rong Zhu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Hai Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Kui Zhao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China.
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21
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O'Brien SJ, Fiechter C, Burton J, Hallion J, Paas M, Patel A, Patel A, Rochet A, Scheurlen K, Gardner S, Eichenberger M, Sarojini H, Srivastava S, Rai S, Kalbfleisch T, Polk HC, Galandiuk S. Long non-coding RNA ZFAS1 is a major regulator of epithelial-mesenchymal transition through miR-200/ZEB1/E-cadherin, vimentin signaling in colon adenocarcinoma. Cell Death Discov 2021; 7:61. [PMID: 33771981 PMCID: PMC7998025 DOI: 10.1038/s41420-021-00427-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/12/2020] [Accepted: 02/03/2021] [Indexed: 12/13/2022] Open
Abstract
Colon adenocarcinoma is a common cause of cancer-related deaths worldwide. Epithelial-mesenchymal transition is a major regulator of cancer metastasis, and increased understanding of this process is essential to improve patient outcomes. Long non-coding RNA (lncRNA) are important regulators of carcinogenesis. To identify lncRNAs associated with colon carcinogenesis, we performed an exploratory differential gene expression analysis comparing paired colon adenocarcinoma and normal colon epithelium using an RNA-sequencing data set. This analysis identified lncRNA ZFAS1 as significantly increased in colon cancer compared to normal colon epithelium. This finding was validated in an institutional cohort using laser capture microdissection. ZFAS1 was also found to be principally located in the cellular cytoplasm. ZFAS1 knockdown was associated with decreased cellular proliferation, migration, and invasion in two colon cancer cell lines (HT29 and SW480). MicroRNA-200b and microRNA-200c (miR-200b and miR-200c) are experimentally validated targets of ZFAS1, and this interaction was confirmed using reciprocal gene knockdown. ZFAS1 knockdown regulated ZEB1 gene expression and downstream targets E-cadherin and vimentin. Knockdown of miR-200b or miR-200c reversed the effect of ZFAS1 knockdown in the ZEB1/E-cadherin, vimentin signaling cascade, and the effects of cellular migration and invasion, but not cellular proliferation. ZFAS1 knockdown was also associated with decreased tumor growth in an in vivo mouse model. These results demonstrate the critical importance of ZFAS1 as a regulator of the miR-200/ZEB1/E-cadherin, vimentin signaling cascade.
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Affiliation(s)
- Stephen J O'Brien
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Casey Fiechter
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - James Burton
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Jacob Hallion
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Mason Paas
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Ankur Patel
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Ajay Patel
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Andre Rochet
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Katharina Scheurlen
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Sarah Gardner
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Maurice Eichenberger
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Harshini Sarojini
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Sudhir Srivastava
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, USA
- Centre for Agricultural Bioinformatics, ICAR-Indian Agricultural Statistics Research Institute, New Delhi, India
| | - Shesh Rai
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, USA
| | - Theodore Kalbfleisch
- Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, KY, USA
| | - Hiram C Polk
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
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22
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Zhang N, Hu X, Du Y, Du J. The role of miRNAs in colorectal cancer progression and chemoradiotherapy. Biomed Pharmacother 2021; 134:111099. [PMID: 33338745 DOI: 10.1016/j.biopha.2020.111099] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/17/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
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23
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Zang Y, Dong Q, Lu Y, Dong K, Wang R, Liang Z. Lumican inhibits immune escape and carcinogenic pathways in colorectal adenocarcinoma. Aging (Albany NY) 2021; 13:4388-4408. [PMID: 33493133 PMCID: PMC7906189 DOI: 10.18632/aging.202401] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/23/2020] [Indexed: 12/18/2022]
Abstract
Lumican (LUM), a small leucine-rich proteoglycan, is a component of the extracellular matrix. Abnormal LUM expression is potentially associated with cancer progression. In the present study, we confirmed high LUM mRNA expression in colorectal adenocarcinoma (COAD) through the UALCAN database. The Kaplan-Meier method, univariate, and multivariate COX analysis showed that high LUM expression is an independent determinant of poor prognosis in COAD. A COX regression model was constructed based on clinical information and LUM expression. The receiver operating characteristic (ROC) curve indicated that this model was highly accurate in monitoring COAD prognosis. The co-expression network of LUM was determined by LinkedOmics, which showed that LUM expression was closely related to immune escape and the miR200 family. Furthermore, we studied the co-expression network of LUM and found that LUM could promote tumor metastasis and invasion. The Tumor Immune Estimation Resource website showed that LUM was closely related to immune infiltration and correlated with regulatory T cells, tumour-associated macrophages, and dendritic cells. We found that LUM cultivated cancer progression by targeting the miR200 family to promote epithelial-to-mesenchymal transition. These findings suggest that LUM is a potential target for inhibiting immune escape and carcinogenic pathways.
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Affiliation(s)
- Yiqing Zang
- Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Qiuping Dong
- Department of Cancer Cell Biology, Tianjin's Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
| | - Yi Lu
- Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Kaiti Dong
- Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Rong Wang
- Department of Laboratory Medicine, Tianjin Medical University, Tianjin 300060, China
| | - Zheng Liang
- Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China
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24
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Mao Y, Chen W, Wu H, Liu C, Zhang J, Chen S. Mechanisms and Functions of MiR-200 Family in Hepatocellular Carcinoma. Onco Targets Ther 2021; 13:13479-13490. [PMID: 33447052 PMCID: PMC7801920 DOI: 10.2147/ott.s288791] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/18/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common clinically malignant tumors of the digestive system. It ranks the sixth most common malignant tumor in the world and ranks fourth among cancer-related death worldwide. At present, early diagnosis and prognosis monitoring of hepatocellular carcinoma mainly use alpha-fetoprotein combined with ultrasonography, which leads to clinical frequently missed diagnosis or even misdiagnosis. Therefore, seeking specific diagnostic and monitoring molecules of hepatocellular carcinoma are still hot topics in contemporary medical practice. MicroRNA is an endogenous non-coding small RNA that regulates the expression of the target molecule and participates in various biological processes in vivo. The miR-200 family, the most common celebrity family of microRNAs, is commonly lower expression in a variety of cancers and is closely associated with tumorigenesis and outcome, especially hepatocellular carcinoma. This review mainly discusses the expression changes, specific molecular mechanisms, biological functions and clinical values of miR-200 family in hepatocellular carcinoma. Moreover, we highlighted utilization of miR-200 family as molecular biomarkers for early diagnosis, prognostic monitoring and appropriate therapy in hepatocellular carcinoma.
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Affiliation(s)
- Yinqi Mao
- School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Wei Chen
- School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Han Wu
- School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Chenbin Liu
- School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Jingjun Zhang
- Department of Rehabilitation, Huashan Hospital Affiliated to Fudan University, Shanghai, People's Republic of China
| | - Shuying Chen
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
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25
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Chen S, Zhang J, Chen Q, Cheng J, Chen X, Mao Y, Chen W, Liu C, Wu H, Lv Y, Lin Y. MicroRNA-200a and microRNA-141 have a synergetic effect on the suppression of epithelial-mesenchymal transition in liver cancer by targeting STAT4. Oncol Lett 2020; 21:137. [PMID: 33552256 PMCID: PMC7798046 DOI: 10.3892/ol.2020.12398] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs or miRs) are non-coding small RNAs that target specific messenger RNAs to inhibit protein translation. miR-200a and miR-141 function as tumor suppressors by targeting STAT4. These two miRNAs belong to the same family, and their expression is often decreased in various cancer types, but are located on different chromosomes of the human genome. The present study showed that the expression levels of miR-141 and miR-200a in serum and cells of liver cancer are significantly downregulated. The expression levels of miR-141 and miR-200a are closely associated with clinicopathological features of liver cancer, especially metastasis and invasion. It is first reported that STAT4 is the new common target gene of miR-141 and miR-200a. In the present study, miR-141 and miR-200a were confirmed to inhibit the expression of E-cadherin and vimentin synergistically during epithelial-mesenchymal transition to regulate the proliferation, migration and invasion of liver cancer cells by targeting STAT4. Simultaneous overexpression of miR-200a and miR-141 resulted in stronger effects compared with each miRNA alone. In addition, overexpression of STAT4 significantly reversed the tumor suppressive roles of miR-200a and miR-141 in liver cancer cells. These findings enrich the tumor suppressor mechanisms of the miR-200 family, and may also provide new experimental and theoretical basis for the use of miRNAs for early diagnosis, prognosis and thorough treatment of liver cancer.
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Affiliation(s)
- Shuying Chen
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jingjun Zhang
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Qiudan Chen
- Department of Central Laboratory, Clinical Laboratory, Jingan District Central Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Juan Cheng
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Xiaotong Chen
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Yinqi Mao
- School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China
| | - Wei Chen
- School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China
| | - Chenbin Liu
- School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China
| | - Han Wu
- School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China
| | - Yuan Lv
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Yong Lin
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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26
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MiR-429 Involves in the Pathogenesis of Colorectal Cancer via Directly Targeting LATS2. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:5316276. [PMID: 33414893 PMCID: PMC7769676 DOI: 10.1155/2020/5316276] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 09/18/2020] [Accepted: 12/10/2020] [Indexed: 11/17/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death around the world whose recurrence and metastasis rate is high. Due to the underlying unclear pathogenesis, it is hard so far to predict the tumorigenesis and prevent its recurrence. YAP/TAZ has been reported to be activated and functioned as a potential oncogene in multiple cancer types and proved to be essential for the carcinogenesis of most solid tumors. In the present study, we found that YAP/TAZ was markedly upregulated in CRC tissues comparing with the adjacent noncancerous tissues due to the downregulation of LATS2, the main upstream regulator. We further identified miR-429 as a direct regulator of LATS2-YAP/TAZ activation, suggesting that the miR-429-LATS2-YAP/TAZ might be novel effective diagnostic axis and therapeutic targets for CRC.
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27
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Ibrahim H, Lim YC. KRAS-associated microRNAs in colorectal cancer. Oncol Rev 2020; 14:454. [PMID: 32685110 PMCID: PMC7365993 DOI: 10.4081/oncol.2020.454] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/20/2020] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancerrelated death worldwide. Despite progress in treatment of cancers, CRC with KRAS mutations are resistant towards anti-EGFR treatment. MicroRNAs have been discovered in an exponential manner within the last few years and have been known to exert either an onco-miRNA or tumor suppressive effect. Here, the various roles of microRNAs involved in the initiation and progression of KRAS-regulated CRC are summarized. A thorough understanding of the roles and functions of the plethora of microRNAs associated with KRAS in CRC will grant insights into the provision of other potential therapeutic targets as well as treatment. MicroRNAs may also serve as potential molecular classifier or early detection biomarkers for future treatment and diagnosis of CRC.
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Affiliation(s)
| | - Ya Chee Lim
- PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Brunei Darussalam
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28
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Ladak SS, Roebuck E, Powell J, Fisher AJ, Ward C, Ali S. The Role of miR-200b-3p in Modulating TGF-β1-induced Injury in Human Bronchial Epithelial Cells. Transplantation 2020; 103:2275-2286. [PMID: 31283671 DOI: 10.1097/tp.0000000000002845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Dysregulation of microRNAs (miRNAs) has been implicated in airway diseases where transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT) may contribute to pathophysiology. Our study investigated the role of miRNA-200b in TGF-β1-induced EMT in human bronchial epithelial cells. METHODS NanoString nCounter miRNA assay was used to profile miRNA in control versus TGF-β1 (1, 4, and 24 h) stimulated BEAS-2B cells. Immortalized primary bronchial epithelial cell line (BEAS-2B cells), human primary bronchial epithelial cells (PBECs), and PBECs derived post-lung transplant were transfected with miR-200b-3p mimics and EMT marker expression was examined at RNA and protein level. miRNA target studies were performed and validated using computational tools and luciferase assay. In situ hybridization was done on normal lung tissue to localize miR-200b-3p in airway epithelium. RESULTS miR-200b-3p was downregulated post-TGF-β1 treatment compared with control in BEAS-2B. miR-200b-3p mimic transfection before TGF-β1 stimulation maintained epithelial marker expression and downregulated mesenchymal cell markers at RNA and protein level in BEAS-2B cells and PBECs. Furthermore, miR-200b-3p mimics reversed established TGF-β1-induced EMT in BEAS-2B cells. miR-200b-3p targets, ZNF532, and ZEB2 were validated as direct targets using luciferase assay. miR-200b-3p mimics suppress TGF-β1-induced EMT via inhibition of ZNF532 and ZEB2. In situ hybridization showed that miR-200b-3p is expressed in the normal lung epithelium. Additionally, miR-200b-3p mimics inhibit EMT in the presence of TGF-β1 in PBECs derived from lung allograft. CONCLUSIONS We provide proof of concept that miR-200b-3p protects airway epithelial cells from EMT. Manipulating miR-200b-3p expression may represent a novel therapeutic modulator in airway pathophysiology.
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Affiliation(s)
- Shameem S Ladak
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Eliott Roebuck
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jason Powell
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.,Department of Otolaryngology, Head and Neck Surgery, Freeman Hospital, Newcastle upon Tyne, United Kingdom
| | - Andrew J Fisher
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.,Institute of Transplantation, Newcastle Upon Tyne Hospitals, Newcastle upon Tyne, United Kingdom
| | - Chris Ward
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Simi Ali
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
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29
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Li L, Gou J, Yi T, Li Z. MicroRNA-30a-3p regulates epithelial-mesenchymal transition to affect embryo implantation by targeting Snai2†. Biol Reprod 2020; 100:1171-1179. [PMID: 30753312 DOI: 10.1093/biolre/ioz022] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 11/11/2018] [Accepted: 02/08/2019] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE To study the potential role of miR-30a-3p in embryo implantation and explore underlying mechanisms. METHODS We first established normal pregnancy, pseudopregnancy, delayed implantation, and artificial decidualization mouse models. Next, we detected miR-30a-3p expression profiles of these models with real-time reverse transcription PCR(qRT-PCR), then predicted potential target genes through a dual-luciferase assay. Immunofluorescence-fluorescence in situ hybridization co-located miR-30a-3p and target genes. We then examined the effect of miR-30a-3p on embryo implantation in vivo and in vitro. Wound healing and transwell assays were employed to explore possible miR-30a-3p effects on epithelial-mesenchymal transition (EMT), before molecules related to the latter process were examined with qRT-PCR. RESULTS MiR-30a-3p expression decreased significantly on embryo implantation day, compared with the peri-implantation period (P < 0.05). Identified target gene Snai2 expression increased significantly during implantation (P < 0.05). In vivo and in vitro analysis showed that up-regulation of miR-30a-3p by agomir and mimics resulted in decreased implantation sites and embryo implantation rate. Transfection of miR-30a-3p mimics to HEC-1-b cells decreased expression of Snai2 and mesenchymal markers (Vimentin and N-cadherin). Furthermore, wound healing area decreased, as did migration and invasion capacity. CONCLUSION MiR-30a-3p is down-regulated in the embryo implantation period and might have some effect on embryo implantation by acting as a suppressor of EMT through targeting Snai2.
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Affiliation(s)
- Lin Li
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Jinhai Gou
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Tao Yi
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, P. R. China
| | - Zhengyu Li
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, P. R. China
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30
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Li X, Geng J, Ren Z, Xiong C, Li Y, Liu H. WAVE3 upregulation in esophageal squamous cell carcinoma and its effect on the migration of human esophageal cancer cell lines in vitro. Mol Med Rep 2020; 22:465-473. [PMID: 32377706 PMCID: PMC7248532 DOI: 10.3892/mmr.2020.11126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 03/31/2020] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to investigate the role of Wiskott-Aldrich syndrome verprolin-homologous protein 3 (WAVE3) in the progression of esophageal squamous cell carcinoma (ESCC), and to explore its effect on the migration of esophageal cancer cell lines in vitro. The expression level of WAVE3 in ESCC tissues was determined via immunohistochemistry, and the relative levels of WAVE3 mRNA and micro (mi)RNA200b were assessed in the serum of patients with ESCC using reverse transcription-quantitative PCR (RT-qPCR). Following cell transfection, the levels of miRNA200b and WAVE3 protein were determined via RT-qPCR and western blot analysis, and cell migration was examined using a Transwell assay. Subsequently, the clinical parameters were used to analyze whether the expression of WAVE3 in tissues and serum was associated with the occurrence and development of ESCC. The results demonstrated that the expression of WAVE3 was increased in ESCC tissues compared with normal tissues. The results also revealed increased expression levels of WAVE3 and decreased expression levels of miRNA200b in the serum of patients with ESCC, compared with healthy volunteers. High expression of WAVE3 was significantly associated with tumor TNM stage, invasion depth and lymphatic invasion of ESCC. In cells transfected with miRNA200b mimic, the miRNA200b was overexpressed, WAVE3 protein was downregulated and cell migration ability was decreased. The results of the present study suggest that WAVE3 may serve as an oncogene in ESCC, and its inhibition via miRNA200b decreased tumor cell migration. Therefore, WAVE3 may serve as a novel biological marker and therapeutic target for ESCC.
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Affiliation(s)
- Xuebing Li
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jie Geng
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhenzhen Ren
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Chao Xiong
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yuqing Li
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hongchun Liu
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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31
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Xia L, Han Q, Chi C, Zhu Y, Pan J, Dong B, Huang Y, Xia W, Xue W, Sha J. Transcriptional regulation of PRKAR2B by miR-200b-3p/200c-3p and XBP1 in human prostate cancer. Biomed Pharmacother 2020; 124:109863. [PMID: 31986411 DOI: 10.1016/j.biopha.2020.109863] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 12/30/2019] [Accepted: 12/30/2019] [Indexed: 02/02/2023] Open
Abstract
The cyclic adenosine monophosphate (cAMP)-activated protein kinase A (PKA) pathway is profoundly implicated in Prostate cancer (PCa) progression. Previously, we showed that PRKAR2B, the type II-beta regulatory subunit of PKA, is highly expressed in castration-resistant prostate cancer (CRPC) and can induce epithelial-mesenchymal transition by activating Wnt/β-catenin signaling in PCa cells. However, the molecular mechanism of dysregulated PRKAR2B expression pattern is still largely unknown. In this study, we found that the mutation, copy number alteration, and methylation status of PRKAR2B gene have no correlation with its expression level in PCa. Then, we identified two microRNAs (miR-200b-3p and miR-200c-3p) to be critical regulators of PRKAR2B expression in PCa. Notably, miR-200b-3p and miR-200c-3p expression were significantly downregulated in metastatic CRPC and negatively correlated with the expression level of PRKAR2B in PCa tissues. Moreover, we characterized X-Box Binding Protein 1 (XBP1) as a key transcription factor responsible for PRKAR2B expression in PCa. Importantly, miR-200b-3p/200c-3p or XBP1 knockdown inhibited PCa cell proliferation and promoted cell apoptosis and these inhibitory roles could be largely restored by PRKAR2B, suggesting that PRKAR2B is a functional mediator of miR-200b-3p, miR-200c-3p, and XBP1 in PCa. Collectively, our study firstly identified miR-200b-3p/200c-3p and XBP1 as the critical upstream regulators of PRKAR2B in PCa and provided novel insights to PRKAR2B-driven PCa progression.
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Affiliation(s)
- Lei Xia
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Qing Han
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, PR China
| | - Chenfei Chi
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Yinjie Zhu
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Jiahua Pan
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Baijun Dong
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Yiran Huang
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Weiliang Xia
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, PR China
| | - Wei Xue
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
| | - Jianjun Sha
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
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Epithelial-Mesenchymal Transition-Related MicroRNAs and Their Target Genes in Colorectal Cancerogenesis. J Clin Med 2019; 8:jcm8101603. [PMID: 31623346 PMCID: PMC6832722 DOI: 10.3390/jcm8101603] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs of the miR-200 family have been shown experimentally to regulate epithelial-mesenchymal transition (EMT). Although EMT is the postulated mechanism of development and progression of colorectal cancer (CRC), there are still limited and controversial data on expression of miR-200 family and their target genes during CRC cancerogenesis. Our study included formalin-fixed paraffin-embedded biopsy samples of 40 patients (10 adenomas and 30 cases of CRC with corresponding normal mucosa). Expression of miR-141, miR-200a/b/c and miR-429 and their target genes (CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2) was analysed using quantitative real-time PCR. Expression of E-cadherin was analysed using immunohistochemistry. All miRNAs were down-regulated and their target genes showed the opposite expression in CRC compared to adenoma. Down-regulation of the miR-200 family at the invasive front in comparison to the central part of tumour was observed as well as a correlation of expression of miR-200b, CDKN1B, ONECUT2 and ZEB2 expression to nodal metastases. Expression of the miR-200 family and SOX2 also correlated with E-cadherin staining. These results suggest that the miR-200 family and their target genes contribute to progression of adenoma to CRC, invasive properties and development of metastases. Our results strongly support the postulated hypotheses of partial EMT and intra-tumour heterogeneity during CRC cancerogenesis.
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Carter JV, O'Brien SJ, Burton JF, Oxford BG, Stephen V, Hallion J, Bishop C, Galbraith NJ, Eichenberger MR, Sarojini H, Hattab E, Galandiuk S. The microRNA-200 family acts as an oncogene in colorectal cancer by inhibiting the tumor suppressor RASSF2. Oncol Lett 2019; 18:3994-4007. [PMID: 31565080 PMCID: PMC6759516 DOI: 10.3892/ol.2019.10753] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 04/03/2019] [Indexed: 12/17/2022] Open
Abstract
This study aimed to determine whether manipulation of the microRNA-200 (miR-200) family could influence colon adenocarcinoma cell behavior. The miR-200 family has a significant role in tumor suppression and functions as an oncogene. In vitro studies on gain and loss of function with small interfering RNA demonstrated that the miR-200 family could regulate RASSF2 expression. Knockdown of the miR-200 family in the HT-29 colon cancer cell line increased KRAS expression but decreased signaling in the MAPK/ERK signaling pathway through reduced ERK phosphorylation. Increased expression of the miR-200 family in the CCD-841 colon epithelium cell line increased KRAS expression and led to increased signaling in the MAPK/ERK signaling pathway but increased ERK phosphorylation. Functionally, knockdown of the miR-200 family led to decreased cell proliferation in the HT-29 cells; therefore, increased miR-200 family expression could increase cell proliferation in the CCD-841 cell line. The present study included a large paired miR array dataset (n=632), in which the miR-200 family was significantly found to be increased in colon cancer when compared with normal adjacent colon epithelium. In a miR-seq dataset (n=199), the study found that miR-200 family expression was increased in localized colon cancer compared with metastatic disease. Decreased expression was associated with poorer overall survival. The miR-200 family directly targeted RASSF2 and was inversely correlated with RASSF2 expression (n=199, all P<0.001). Despite the well-defined role of the miR-200 family in tumor suppression, the present findings demonstrated a novel function of the miR-200 family in tumor proliferation.
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Affiliation(s)
- Jane V Carter
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA.,Department of Surgery, North Cumbria University Hospitals NHS Trust, Carlisle, Cumbria CA2 7HY, UK
| | - Stephen J O'Brien
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - James F Burton
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Brent G Oxford
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA.,School of Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Vince Stephen
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA.,School of Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Jake Hallion
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Campbell Bishop
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Norman J Galbraith
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA.,Department of Surgery, University Hospital Wishaw, Wishaw, North Lanarkshire ML2 0DP, UK
| | - Maurice R Eichenberger
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Harshini Sarojini
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Eyas Hattab
- Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Zong M, Liu Y, Zhang K, J Y, Chen L. The effects of miR-429 on cell migration and invasion by targeting Slug in esophageal squamous cell carcinoma. Pathol Res Pract 2019; 215:152526. [PMID: 31324391 DOI: 10.1016/j.prp.2019.152526] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/27/2019] [Accepted: 07/05/2019] [Indexed: 02/07/2023]
Abstract
Increasing evidence indicates that microRNAs may play important roles in tumor development and may take part in different processes in different cancers. miR-429 is known as a cancer suppressor or oncogene that is dysregulated in different malignancies, including esophageal squamous cell carcinoma (ESCC). However, the effect of miR-429 in ESCC has not been fully explored. The purpose of this study was to investigate the functions of miR-429 in ESCC. qRT-PCR assays were performed to detect miR-429 expression in ESCC tissues and cell lines. To assess the effects of miR-429 on ESCC cells, wound healing and transwell assays were used. Luciferase reporter and western blot assays were employed to determine whether Slug is a major target of miR-429.Our results showed that the expression levels of miR-429 in ESCC tissues and cells were lower than in normal esophageal epithelial tissues and cells. Furthermore, overexpression of endogenous miR-429 inhibited the migration and invasion of ESCC cell lines. In addition, Luciferase reporter and western blot assays provided evidence that miR-429 can bind to the 3' untranslated regions of Slug to regulate its expression and that of downstream epithelial-to-mesenchymal transition (EMT) markers. We found that Slug serves as a major target of miR-429. miR-429 plays a vital role in ESCC progression and represents a new therapeutic target for ESCC.
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Affiliation(s)
- Mingzhu Zong
- Jinling Hosp Dept of Medical Oncology, Nanjing Med Univ, Nanjing, 210002, PR China; The Affiliated Huaian No.1 People, s Hospital of Nanjing Medical University, PR China
| | - Yan Liu
- Jinling Hosp Dept of Medical Oncology, Nanjing Med Univ, Nanjing, 210002, PR China
| | - Kai Zhang
- Jinling Hosp Dept of Medical Oncology, Nanjing Univ, Sch Med, Nanjing, 210002, PR China
| | - Yi J
- Jinling Hosp Dept of Medical Oncology, Nanjing Univ, Sch Med, Nanjing, 210002, PR China
| | - Longbang Chen
- Jinling Hosp Dept of Medical Oncology, Nanjing Med Univ, Nanjing, 210002, PR China; Jinling Hosp Dept of Medical Oncology, Nanjing Univ, Sch Med, Nanjing, 210002, PR China.
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Chen BJ, Tang YJ, Tang YL, Liang XH. What makes cells move: Requirements and obstacles for leader cells in collective invasion. Exp Cell Res 2019; 382:111481. [PMID: 31247191 DOI: 10.1016/j.yexcr.2019.06.026] [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: 01/24/2019] [Revised: 06/15/2019] [Accepted: 06/23/2019] [Indexed: 02/05/2023]
Abstract
Most recently, mounting evidence has shown that cancer cells can invade as a cohesive and multicellular group with coordinated movement, which is called collective invasion. In this cohesive cancer cell group, cancer cells at the front of collective invasion are defined as leader cell that are responsible for many aspects of collective invasion, including sensing the microenvironment, determining the invasion direction, modifying the path of invasion and transmitting information to other cells. To fulfill their dispensable roles, leader cells are required to embark on some specific phenotypes with unusual expression of some proteins and it's very important to investigate into these proteins as they may serve as potential therapeutic targets. Here, in this review we will summarize current knowledge on four emerging proteins highly expressed in leader cells including K14, ΔNp63α, Dll4 and cysteine protease cathepsin B (CTSB), with a focus on their important roles in collective invasion and special mechanisms by which they promote collective invasion.
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Affiliation(s)
- Bing-Jun Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, China.
| | - Ya-Jie Tang
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China.
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Oral Pathology, West China Hospital of Stomatology, Sichuan University.China.
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, China.
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Aiello NM, Kang Y. Context-dependent EMT programs in cancer metastasis. J Exp Med 2019; 216:1016-1026. [PMID: 30975895 PMCID: PMC6504222 DOI: 10.1084/jem.20181827] [Citation(s) in RCA: 414] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 03/22/2019] [Accepted: 03/22/2019] [Indexed: 12/12/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a developmental process whereby stationary, adherent cells acquire the ability to migrate. EMT is critical for dramatic cellular movements during embryogenesis; however, tumor cells can reactivate EMT programs, which increases their aggressiveness. In addition to motility, EMT is associated with enhanced stem cell properties and drug resistance; thus it can drive metastasis, tumor recurrence, and therapy resistance in the context of cancer. However, the precise requirements for EMT in metastasis have not been fully delineated, with different tumor types relying on discrete EMT effectors. Most tumor cells do not undergo a full EMT, but rather adopt some qualities of mesenchymal cells and maintain some epithelial characteristics. Emerging evidence suggests that partial EMT can drive distinct migratory properties and enhance the epithelial-mesenchymal plasticity of cancer cells as well as cell fate plasticity. This review discusses the diverse regulatory mechanisms and functional consequences of EMT, with an emphasis on the importance of partial EMT.
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Affiliation(s)
- Nicole M Aiello
- Department of Molecular Biology, Princeton University, Princeton, NJ
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ
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Zhang LQ, Lu N. Role of miR-200c in early diagnosis of gastric cancer: Current status and prospects. Shijie Huaren Xiaohua Zazhi 2019; 27:382-388. [DOI: 10.11569/wcjd.v27.i6.382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of the digestive tract, and its morbidity and mortality still rank the second among all cancers. The proportion of patients with advanced GC is higher, and their therapeutic effect is extremely poor. In recent years, numerous studies have shown that the content of miR-200c in GC patients is significantly increased, and the level of miR-200c is closely related to epithelial-mesenchymal transition and lymph node metastasis. Therefore, in-depth disclosure of the role of miR-200c in the diagnosis of GC will not only contribute to the early diagnosis of GC, but also help develop new effective treatment strategies and judge the prognosis of patients with GC. This article reviews the role of miR-200c in the early diagnosis of GC and discusses its application prospects.
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Affiliation(s)
- Ling-Qian Zhang
- Department of Oncology, Xinjiang Military Command General Hospital of PLA, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
| | - Ning Lu
- Department of Oncology, Xinjiang Military Command General Hospital of PLA, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
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The Immunohistochemical Pattern of Epithelial-Mesenchymal Transition Markers In Endometrial Carcinoma. Appl Immunohistochem Mol Morphol 2019; 28:339-346. [PMID: 30829665 DOI: 10.1097/pai.0000000000000754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The majority of endometrial carcinoma are diagnosed at an early stage and exhibit a favorable prognosis. However, 10% to 15% of ECs recur and the majority are type II tumors which are high-grade carcinomas. The epithelial-mesenchymal transition (EMT) has been considered as a fundamental step for the development of the invasive phenotype of cancer cells. During EMT, many of epithelial surface markers, primarily E-cadherin disappear, and mesenchymal markers including N-cadherin gain. This feature resides predominantly at the invasive front (IF) of the tumor. Therefore, we examined the immunohistochemical expression of E-cadherin and N-cadherin at the IF, in central areas of the tumor and lymphovascular space, in type I and type II endometrial carcinoma. The association of each protein with the clinicopathologic features was also evaluated. Our results confirmed a stronger E-cadherin immunostaining in type I tumors indicating that the loss of E-cadherin may be responsible for a more aggressive behavior of type II ECs. In both types, E-cadherin was strongly expressed in central areas and the reactivity decreased toward the IF. On contrary, N-cadherin was overexpressed at the IF confirming an inverse relationship between these markers. In addition, a decrease in E-cadherin expression was observed in cells within the lymphovascular space. Downregulation of E-cadherin was associated only with high-grade tumors while no correlations between both markers and other clinicopathologic features were found. Our results confirm that EMT occurs at the IF that represents a critical interface between the tumor and the host.
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MiR-218-5p targets LHFPL3 to regulate proliferation, migration, and epithelial-mesenchymal transitions of human glioma cells. Biosci Rep 2019; 39:BSR20180879. [PMID: 30314994 PMCID: PMC6395304 DOI: 10.1042/bsr20180879] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 07/27/2018] [Accepted: 08/20/2018] [Indexed: 01/01/2023] Open
Abstract
Glioblastoma (GBM) is a main subtype of high-grade gliomas with features in progressive brain tumor. Lipoma HMGIC fusion partner-like 3 (LHFPL3) is reported to be highly expressed in malignant glioma, but the relationship and mechanism between LHFPL3 and tumor is inexplicit. The present study aimed to screen the miRNAs targeting LHFPL3 and verify the pathogenesis and development of gliomas. Bioinformatics software predicted that miR-218-5p and miR-138-5p can specifically bind to LHFPL3 mRNA. And the expression of miR-218-5p and miR-138-5p was down-regulated in glioma cell lines and glioma tissues from the patients compared with the normal cells. While dual luciferase activity experiment confirmed, only miR-218-5p can directly bind to LHFPL3. After miR-218-5p transfection of U251 and U87 cells, cytological examinations found a reduction in cell activity, proliferation and invasive ability. Further study showed that miR-218-5p transfection could inhibit epithelial–mesenchymal transitions (EMT). Therefore, miR-218-5p targeting LHFPL3 mRNA plays significant roles in preventing the invasiveness of glioma cells. The present study also revealed a novel mechanism for miRNA–LHFPL3 interaction in glioma cells, which may be potential targets for developing therapies in treating glioma.
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Abbaszadegan MR, Moghbeli M. Genetic and molecular origins of colorectal Cancer among the Iranians: an update. Diagn Pathol 2018; 13:97. [PMID: 30579343 PMCID: PMC6303916 DOI: 10.1186/s13000-018-0774-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one the leading causes of cancer related deaths among Iranians. Despite the various progresses in new therapeutic methods, it has still a low rate of survival. This high ratio of mortality is mainly related to the late diagnosis, in which the patients refer for treatment in advanced stages of tumor. MAIN BODY: colorectal cancer progression is largely associated with molecular and genetic bases. Although Iran has a high ratio of CRC mortality, there is not an efficient genetic panel for detection and prognosis. Therefore, it is critical to introduce new diagnostic markers with ability to detect in early stages. CONCLUSION Present review summarizes all of the genetic and epigenetic factors which are reported in CRC until now among the Iranian patients to pave the way of incorporation of new ethnic specific markers into the clinical practice and development of new targeted therapeutic methods.
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Affiliation(s)
| | - Meysam Moghbeli
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Comprehensive and in-depth analysis of microRNA and mRNA expression profile in salivary adenoid cystic carcinoma. Gene 2018; 678:349-360. [PMID: 30098429 DOI: 10.1016/j.gene.2018.08.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 07/19/2018] [Accepted: 08/06/2018] [Indexed: 12/24/2022]
Abstract
OBJECTIVES To conduct an integrated analysis of microRNA and mRNA expression profile and further discover vital molecules to uncover novel pathogenic mechanisms in salivary adenoid cystic carcinoma (SACC). MATERIALS AND METHODS MicroRNA and mRNA expression profiles were obtained from six paired primary SACC tumors and corresponding adjacent normal glands using high-throughput next-generation sequencing technology followed by an overall integrated bioinformatics analysis and subsequently molecular biology techniques validation. RESULTS Compared with adjacent noncancerous normal gland, 2107 significant differentially expressed mRNA were determined in SACC. Gene ontology and KEGG pathway analysis suggested that the differentially expressed genes were relevant to many significant biological implications. Venn diagram analysis of differentially expressed genes in different group identified 29 differentially expressed overlapping mRNA. 40 differentially expressed microRNAs were also identified in SACC. Furthermore, integrated analysis of microRNA and mRNA expression profiles recognized a core microRNA-mRNA regulatory network and unmasked many novel genes including SCUBE3, CA6, hsa-miR-885-5p and other molecules which may play an essential role in the carcinogenesis of SACC. Also, Q-PCR and immunohistochemistry results reveal the high expression and distribution of SCUBE3 in SACC and dual luciferase reporter assay also preliminarily validated that SCUBE3 was a target of hsa-miR-885-5p. CONCLUSION Contemporary microRNA/mRNA analysis have uncovered many mRNAs and microRNAs worthy further exploration in SACC. These are bound to help us shed light on the overall genetic background of SACC and further elucidate the potential molecular mechanism of SACC.
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Guo D, Jiang H, Chen Y, Yang J, Fu Z, Li J, Han X, Wu X, Xia Y, Wang X, Chen L, Tang Q, Wu W. Elevated microRNA-141-3p in placenta of non-diabetic macrosomia regulate trophoblast proliferation. EBioMedicine 2018; 38:154-161. [PMID: 30420300 PMCID: PMC6306401 DOI: 10.1016/j.ebiom.2018.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/21/2018] [Accepted: 11/01/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Several studies have reported microRNAs (miRNAs) could regulate the placental development, though the role and mechanism of miRNAs in the development of non-diabetic macrosomia (NDFMS) remains unclear. METHODS To identify the aberrantly expressed key miRNAs in placenta of NDFMS, we employed a strategy consisting of initial screening with miRNA microarray and further validation with quantitative RT-PCR assay (qRT-PCR). In vitro cellular model and a mouse pregnancy model were used to delineate the functional effects of key miRNA on proliferation, invasion, and migration. FINDINGS miR-141-3p was identified as the key miRNA with expression level significantly higher in placentas of NDFMS compared with those from normal controls. Overexpressed miR-141-3p in HTR-8/SVneo cells contributed to increased cell proliferation, invasion, and migration. miR-141-3p inhibition in HTR-8/SVneo cells resulted in decreased cell proliferation and invasion. Significantly increased infant birth weight was observed in late pregnancy of C57BL/6J mice treated with miR-141-3p agomir. However, no significant difference was found in early pregnancy of C57BL/6J mice treated with miR-141-3p agomir. INTERPRETATION miR-141-3p could stimulate placental cell proliferation to participate in the occurrence and development of NDFMS.
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Affiliation(s)
- Dan Guo
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China; Department of Preventive Health Branch, The Affiliated Jiangning Hospital With Nanjing Medical University, Nanjing, China
| | - Hua Jiang
- Department of Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Yiqiu Chen
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jing Yang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ziqiang Fu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jing Li
- Department of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiumei Han
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xian Wu
- Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, USA
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xinru Wang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Liping Chen
- Department of Gynecology and Obstetrics, Second Affiliated Hospital of Nantong University, Nantong, China.
| | - Qiuqin Tang
- Department of Obstetrics, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.
| | - Wei Wu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
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Kong X, Gong S, Yan T, Yang Y. MicroRNA-200b expression level is negatively associated with pathological grading in human gliomas. Cancer Manag Res 2018; 10:2825-2834. [PMID: 30197535 PMCID: PMC6112773 DOI: 10.2147/cmar.s171137] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Aim To elucidate the clinical implication of microRNA (miRNA)-200b in the pathological grading of gliomas. Methods We searched the Chinese National Knowledge Infrastructure, Web of Knowledge, Embase, and PubMed databases. Related articles were assessed, and ORs with 95% CIs were calculated to examine the relationship between miRNA-200b expression levels and the World Health Organization (WHO) glioma grade, patients’ sex and age, tumor size, and extent of surgical resection. Heterogeneity, publication bias, and stability of the pooled results of the included studies were also analyzed. MiR-200b expression in 87 human glioma tissues (50 high grade and 37 low grade) and matched 41 non-neoplastic brain tissues was measured by real-time quantitative RT-PCR assay. Results Five eligible studies involving 630 patients were included in the present meta-analysis. The miRNA-200b expression in glioma tissues was negatively associated with the WHO glioma grade (OR, 0.070; 95% CI, 0.007–0.678; P=0.022). No significant correlations were found between miRNA-200b and sex (P=0.858), age (P=0.776), tumor size (P=0.134), or extent of resection (P=0.778). In our own test, compared with non-neoplastic brain tissues, the expression level of miR-200b was significantly decreased in glioma tissues (tumor vs normal: 4.29±1.90 vs 10.45±2.34, P<0.001). In addition, we found that the glioma tissues from high-grade tumors (grade III and IV) had much lower miR-200b expression than glioma tissues from low grade tumors (grade I and II). Conclusion Our results suggest that the miRNA-200 expression level may be negatively associated with the WHO glioma grade (malignancy). MiRNA-200 might serve as a prognostic and diagnostic biomarker or a helpful therapeutic target.
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Affiliation(s)
- Xiangyi Kong
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, People's Republic of China, .,Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Shun Gong
- Department of Neurosurgery, The General Hospital of Shenyang Military, Army Institute of Neurology, Shenyang 110016, People's Republic of China.,Department of Neurosurgery, Shanghai Institute of Neurosurgery, PLA Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, People's Republic of China.,Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tao Yan
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Yi Yang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, People's Republic of China,
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Wang Y, Wu Z, Hu L. The regulatory effects of metformin on the [SNAIL/miR-34]:[ZEB/miR-200] system in the epithelial-mesenchymal transition(EMT) for colorectal cancer(CRC). Eur J Pharmacol 2018; 834:45-53. [PMID: 30017802 DOI: 10.1016/j.ejphar.2018.07.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/22/2018] [Accepted: 07/09/2018] [Indexed: 01/26/2023]
Abstract
The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, metastasis and drug resistance. The transcription factor(TF) and microRNA (miR) chimeric [SNAIL/miR-34]:[ZEB/miR-200] unit is the core regulatory system for the EMT process. Here, we proposed to assess the anti-EMT abilities and explore the inherent pharmacological mechanisms of the classic hypoglycaemic agent metformin for colorectal cancer(CRC). For the EMT model, the TGF-β-induced CRC cell lines SW480 and HCT116 were treated with metformin. The viability, migration and invasion abilities of the cells were evaluated with the Cell Counting Kit-8, wound-healing and trans-well assay. The alterations of the [SNAIL/miR-34]:[ZEB/miR-200] system and the EMT markers E-cadherin and vimentin were detected by western blot, qPCR and immunofluorescent staining. Metformin exhibited inhibitory effects on the proliferation, migration and invasion of the CRC SW480 cells. The up-regulation of E-cadherin and the down-regulation of vimentin for both SW480 and HCT116 cells revealed the anti-EMT abilities of metformin. For the [SNAIL/miR-34]:[ZEB/miR-200] system, metformin increased miR-200a, miR-200c and miR-429 levels and decreased miR-34a, SNAIL1 and ZEB1 levels in the TGF-β-induced EMT. From immunofluorescence, we observed increased E-cadherin and ZEB1 co-expression in metformin-treated cells. Metformin may perform bidirectional regulations of the [SNAIL/miR-34]:[ZEB/miR-200] system in the EMT process for colorectal cancer. Such regulation is expressed as the inhibition of EMT in general as well as an increased higher proportion of E/M hybrid cells in the total population.
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Affiliation(s)
- Yaodu Wang
- Cancer Center, Shandong University Qilu Hospital, West Wenhua Road 107, Jinan 250012, Shandong Province, PR China
| | - Zhiyang Wu
- Intensive Care Unit, Shandong University Qilu Hospital(Qingdao), Hefei Road 758, Qingdao 266035, Shandong Province, PR China
| | - Likuan Hu
- Cancer Center, Shandong University Qilu Hospital, West Wenhua Road 107, Jinan 250012, Shandong Province, PR China.
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Eslamizadeh S, Heidari M, Agah S, Faghihloo E, Ghazi H, Mirzaei A, Akbari A. The Role of MicroRNA Signature as Diagnostic Biomarkers in Different Clinical Stages of Colorectal Cancer. CELL JOURNAL 2018; 20:220-230. [PMID: 29633600 PMCID: PMC5893294 DOI: 10.22074/cellj.2018.5366] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 08/27/2017] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer-related death worldwide. The early diagnosis of colorectal tumors is one of the most important challenges in cancer management. MicroRNAs (miRNAs) have provided new insight into CRC development and have been suggested as reliable and stable biomarkers for diagnosis and prognosis. This study's objective was to analyze the differential expression of miRNAs at differentstages of CRC searching for possible correlation with clinicopathological features to examine their potential value as diagnostic biomarkers. MATERIALS AND METHODS In this case-control study, plasma and matched tissue samples were collected from 74 CRC patients at stage II-IV as well as blood samples from 32 healthy controls. After exhaustive study of the current literature, eight miRNAs including miR-200c, 20a, 21, 31,135b, 133b,145 and let-7g were selected. The expression level of the miRNAs was assayed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Statistical analysis, including t test , Mann-Whitney U, Kruskall-Wallis tests and receiver operating characteristic (ROC) curve was applied, where needed. RESULTS Significantly elevated levels of miR-21, miR-31, miR-20a, miR-135b, and decreased levels of miR- 200c, miR-145 and let-7 g were detected in both plasma and matched tissue samples compared to the healthy group (P<0.05). However, no significant differences were observed in the expression level of plasma and tissue miR-133b (P>0.05). ROC for tissue miRNAs showed an area under the ROC curve (AUC) of 0.98 and P<0.001 for miR-21, 0.91 and P<0.001 for miR-135b, 0.91 and P<0.001 for miR-31, and 0.92 and P<0.001 for miR-20a. CONCLUSIONS Our results indicate that the expression levels of microRNAs are systematically altered in CRC tissue and plasma. In conclusion, detection of miR-21, miR-135b, miR-31 and miR-20a levels in the tissue might be helpful to illuminate the molecular mechanisms underlying CRC carcinogenesis and serve as tumor-associated biomarkers for diagnosis.
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Affiliation(s)
- Sara Eslamizadeh
- Department of Molecular Genetics, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran.,Department of Molecular Genetics, Science and Research Branch, Islamic Azad University, Fars, Iran
| | - Mansour Heidari
- Department of Molecular Biology and Genetics, Bushehr Branch, Islamic Azad University, Bushehr, Iran
| | - Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Ghazi
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Mirzaei
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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46
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Jiang Q, Zhou Y, Yang H, Li L, Deng X, Cheng C, Xie Y, Luo X, Fang W, Liu Z. A directly negative interaction of miR-203 and ZEB2 modulates tumor stemness and chemotherapy resistance in nasopharyngeal carcinoma. Oncotarget 2018; 7:67288-67301. [PMID: 27589832 PMCID: PMC5341875 DOI: 10.18632/oncotarget.11691] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 07/18/2016] [Indexed: 12/27/2022] Open
Abstract
miR-203 is a tumor suppressor that is disregulated in numerous malignancies including nasopharyngeal carcinoma (NPC). However, the role of miR-203 in suppressing tumor stemness, chemotherapy resistance as well as its molecular mechanisms are unclear. In this study, we observed that miR-203 suppressed cell migration, invasion, tumor stemness, and chemotherapy resistance to cisplatin (DDP) in vitro and in vivo. miR-203 exerted these effects by targeting ZEB2 and downstream epithelial-mesenchymal transition (EMT) and tumor stemness signals. Interestingly we observed that miR-203 expression was directly suppressed by ZEB2 via targeting its promoter, which significantly reduced cell migration, invasion, tumor stemness, and chemotherapy resistance in NPC cells. Finally, we found that miR-203 was negatively correlated with ZEB2 expression in NPC tissues and tumor spheres. Our data demonstrate a directly negative feedback loop between miR-203 and ZEB2 participating in tumor stemness and chemotherapy resistance, highlighting the therapeutic potential of targeting this signal for NPC chemotherapy.
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Affiliation(s)
- Qingping Jiang
- Department of Pathology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Ying Zhou
- Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China
| | - Huiling Yang
- Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Sino-American Cancer Research Institute, Guangdong Medical College, Dongguan 523808, China
| | - Libo Li
- Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China
| | - Xiaojie Deng
- Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Chao Cheng
- Cancer Research Institute, Southern Medical University, Guangzhou 510515, China
| | - Yingying Xie
- Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China
| | - Xiaojun Luo
- Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China
| | - Weiyi Fang
- Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China
| | - Zhen Liu
- Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.,Department of Pathology, Medical University of Guangzhou, Guangzhou 510182, China
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O'Brien SJ, Carter JV, Burton JF, Oxford BG, Schmidt MN, Hallion JC, Galandiuk S. The role of the miR-200 family in epithelial-mesenchymal transition in colorectal cancer: a systematic review. Int J Cancer 2018; 142:2501-2511. [DOI: 10.1002/ijc.31282] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 01/16/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Stephen J. O'Brien
- Price Institute of Surgical Research, The Hiram C. Polk Jr., M.D. Department of Surgery, University of Louisville; Louisville KY
| | - Jane V. Carter
- Price Institute of Surgical Research, The Hiram C. Polk Jr., M.D. Department of Surgery, University of Louisville; Louisville KY
- Department of Surgery; North Cumbria University Hospitals NHS Trust; Whitehaven Cumbria United Kingdom
| | - James F. Burton
- Price Institute of Surgical Research, The Hiram C. Polk Jr., M.D. Department of Surgery, University of Louisville; Louisville KY
| | - Brent G. Oxford
- Price Institute of Surgical Research, The Hiram C. Polk Jr., M.D. Department of Surgery, University of Louisville; Louisville KY
| | - Miranda N. Schmidt
- Price Institute of Surgical Research, The Hiram C. Polk Jr., M.D. Department of Surgery, University of Louisville; Louisville KY
| | - Jacob C. Hallion
- Price Institute of Surgical Research, The Hiram C. Polk Jr., M.D. Department of Surgery, University of Louisville; Louisville KY
| | - Susan Galandiuk
- Price Institute of Surgical Research, The Hiram C. Polk Jr., M.D. Department of Surgery, University of Louisville; Louisville KY
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Yang L, Luo P, Song Q, Fei X. DNMT1/miR-200a/GOLM1 signaling pathway regulates lung adenocarcinoma cells proliferation. Biomed Pharmacother 2018; 99:839-847. [PMID: 29710483 DOI: 10.1016/j.biopha.2018.01.161] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 01/22/2018] [Accepted: 01/29/2018] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Lung adenocarcinoma (LAD) comprises about 80% of all diagnosed lung cancers. However, the underlying regulatory mechanism of LAD cell proliferation is largely unclear. The emergence of microRNAs and molecular-targeted therapies adds a new dimension in our efforts to combat this deadly disease. METHOD In this work, the A549 and H1650 human lung cancer cell lines were used in this study. The proliferation was evaluated by the MTT and BrdU assay. The expression level of related proteins was detected by western blot. RESULT We reported GOLM1 was highly expressed in LAD cells and associated with low survival ratio and higher grade malignancy. Knockdown of GOLM1 repressed the LAD cell proliferation. Overexpression of GOLM1 promoted the cell proliferation. Further we found that the level of microRNA-200a (miR-200a) expression was low in LAD cells. miR-200a repress GOLM1 expression by directly targeting its 3? UTR. Overexpression of miR-200a repressed the cell proliferation and blocked the increase of LAD cell proliferation caused by GOLM1 overexpression. Further, we found that miR-200 was downregulated by DNMT1.Overexpression of DNMT1 blocked the function of miR-200a on repressing proliferation. We then found that knockdown of DNMT1 repressed LAD cell proliferation, which could be rescued by GOLM1 overexpression. CONCLUSION This work revealed the critical function of GOLM1/miR-200a/DNMT1 signaling pathway on regulating LAD cell proliferation, and might lay the foundation for further clinical treatment of LAD.
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Affiliation(s)
- Longqiu Yang
- Department of Anesthesiology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, 435000, China
| | - Pengcheng Luo
- Department of Urology Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, 435000, China
| | - Qiong Song
- Department of Anesthesiology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 195 Tongbai Road, Zhengzhou, Henan, 450007, China.
| | - Xuejie Fei
- Department of Intensive Care Unit, Shuguang Hospital Affiliated With Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China.
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Sulforaphane inhibits human bladder cancer cell invasion by reversing epithelial-to-mesenchymal transition via directly targeting microRNA-200c/ZEB1 axis. J Funct Foods 2018. [DOI: 10.1016/j.jff.2017.12.034] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
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50
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Yu L, Wu D, Gao H, Balic JJ, Tsykin A, Han TS, Liu YD, Kennedy CL, Li JK, Mao JQ, Tan P, Oshima M, Goodall GJ, Jenkins BJ. Clinical Utility of a STAT3-Regulated miRNA-200 Family Signature with Prognostic Potential in Early Gastric Cancer. Clin Cancer Res 2018; 24:1459-1472. [PMID: 29330205 DOI: 10.1158/1078-0432.ccr-17-2485] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 11/29/2017] [Accepted: 01/03/2018] [Indexed: 11/16/2022]
Abstract
Purpose: The majority of gastric cancer patients are diagnosed with late-stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early-stage gastric cancer (EGC) because the molecular events promoting gastric cancer initiation remain ill-defined.Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple data sets and independent gastric cancer patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130F/F-based mouse strains and human gastric cancer cells genetically engineered for suppressed activation of the oncogenic latent transcription factor STAT3. Human gastric cancer cells with modulated expression of the miR-200 family member miR-429 were also assessed for their proliferative response.Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130F/F mice and EGC (i.e., stage IA) in patient cohorts. Overexpression of miR-429 also elicited contrasting pro- and antiproliferative responses in human gastric cancer cells depending on their cellular histologic subtype. We also identified a miR-200 family-regulated 15-gene signature that integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology, and stage, and provides superior predictive power for overall survival compared with each EGC indicator alone.Conclusions: Collectively, our discovery of a STAT3-regulated, miR-200 family-associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment. Clin Cancer Res; 24(6); 1459-72. ©2018 AACR.
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Affiliation(s)
- Liang Yu
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Di Wu
- Department of Periodontology, School of Dentistry, Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Hugh Gao
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Jesse J Balic
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Anna Tsykin
- Discipline of Medicine, University of Adelaide, Adelaide, South Australia.,School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia.,Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia
| | - Tae-Su Han
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - You Dong Liu
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.,Department of General Surgery, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Catherine L Kennedy
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Ji Kun Li
- Department of General Surgery, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Qi Mao
- Department of General Surgery, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Patrick Tan
- Genome Institute of Singapore, Singapore.,Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Gregory J Goodall
- Discipline of Medicine, University of Adelaide, Adelaide, South Australia.,School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia.,Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. .,Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
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