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Jamialahmadi H, Asadnia A, Khalili-Tanha G, Mohit R, Azari H, Khazaei M, Maftooh M, Nassiri M, Hassanian SM, Ghayour-Mobarhan M, Ferns GA, Nazari E, Avan A. Identification of miR-20a as a Diagnostic and Prognostic Biomarker in Colorectal Cancer: MicroRNA Sequencing and Machine Learning Analysis. Microrna 2025; 14:73-91. [PMID: 39318221 DOI: 10.2174/0122115366320538240912080053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/19/2024] [Accepted: 07/23/2024] [Indexed: 09/26/2024]
Abstract
INTRODUCTION The differential expression of miRNAs, a key regulator in many cell signaling pathways, has been studied in various malignancies and may have an important role in cancer progression, including colorectal cancer (CRC). METHODS The present study used machine learning and gene interaction study tools to explore the prognostic and diagnostic value of miRNAs in CRC. Integrative analysis of 353 CRC samples and normal tissue data was obtained from the TCGA database and further analyzed by R packages to define the deferentially expressed miRNAs (DEMs). Furthermore, machine learning and Kaplan Meier survival analysis helped better specify the significant prognostic value of miRNAs. A combination of online databases was then used to evaluate the interactions between target genes, their molecular pathways, and the correlation between the DEMs. RESULTS The results indicated that miR-19b and miR-20a have a significant prognostic role and are associated with CRC progression. The ROC curve analysis discovered that miR-20a alone and combined with other miRNAs, including hsa-mir-21 and hsa-mir-542, are diagnostic biomarkers in CRC. In addition, 12 genes, including NTRK2, CDC42, EGFR, AGO2, PRKCA, HSP90AA1, TLR4, IGF1, ESR1, SMAD2, SMAD4, and NEDD4L, were found to be the highest score targets for these miRNAs. Pathway analysis identified the two correlated tyrosine kinase and MAPK signaling pathways with the key interaction genes, i.e., EGFR, CDC42, and HSP90AA1. CONCLUSION To better define the role of these miRNAs, the ceRNA network, including lncRNAs, was also prepared. In conclusion, the combination of R data analysis and machine learning provides a robust approach to resolving complicated interactions between miRNAs and their targets.
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Affiliation(s)
- Hamid Jamialahmadi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Asadnia
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ghazaleh Khalili-Tanha
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Mohit
- Department of Anesthesia, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Hanieh Azari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mina Maftooh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammadreza Nassiri
- Recombinant Proteins Research Group, The Research Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Elham Nazari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Health Information Technology and Management, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 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, Australia
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Mohajeri Khorasani A, Mohammadi S, Raghibi A, Haj Mohammad Hassani B, Bazghandi B, Mousavi P. miR-17-92a-1 cluster host gene: a key regulator in colorectal cancer development and progression. Clin Exp Med 2024; 24:85. [PMID: 38662056 PMCID: PMC11045601 DOI: 10.1007/s10238-024-01331-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/14/2024] [Indexed: 04/26/2024]
Abstract
Colorectal cancer (CRC), recognized among the five most prevalent malignancies and most deadly cancers, manifests multifactorial influences stemming from environmental exposures, dietary patterns, age, and genetic predisposition. Although substantial progress has been made in comprehending the etiology of CRC, the precise genetic components driving its pathogenesis remain incompletely elucidated. Within the expansive repertoire of non-coding RNAs, particular focus has centered on the miR-17-92a-1 cluster host gene (MIR17HG) and its associated miRNAs, which actively participate in diverse cellular processes and frequently exhibit heightened expression in various solid tumors, notably CRC. Therefore, the primary objective of this research is to undertake an extensive inquiry into the regulatory mechanisms, structural features, functional attributes, and potential diagnostic and therapeutic implications associated with this cluster in CRC. Furthermore, the intricate interplay between this cluster and the development and progression of CRC will be explored. Our findings underscore the upregulation of the miR-17-92a-1 cluster host gene (MIR17HG) and its associated miRNAs in CRC compared to normal tissues, thus implying their profound involvement in the progression of CRC. Collectively, these molecules are implicated in critical oncogenic processes, encompassing metastatic activity, regulation of apoptotic pathways, cellular proliferation, and drug resistance. Consequently, these findings shed illuminating insights into the potential of MIR17HG and its associated miRNAs as promising targets for therapeutic interventions in the management of CRC.
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Affiliation(s)
- Amirhossein Mohajeri Khorasani
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Samane Mohammadi
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Alireza Raghibi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behzad Haj Mohammad Hassani
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Behina Bazghandi
- Protein Research Center, Shahid Beheshti University, Tehran, Iran
| | - Pegah Mousavi
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
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Al-Nakhle HH. Unraveling the Multifaceted Role of the miR-17-92 Cluster in Colorectal Cancer: From Mechanisms to Biomarker Potential. Curr Issues Mol Biol 2024; 46:1832-1850. [PMID: 38534736 DOI: 10.3390/cimb46030120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease driven by intricate mechanisms, making it challenging to understand and manage. The miR-17-92 cluster has gained significant attention in CRC research due to its diverse functions and crucial role in various aspects of the disease. This cluster, consisting of multiple individual miRNAs, influences critical processes like tumor initiation, angiogenesis, metastasis, and the epithelial-mesenchymal transition (EMT). Beyond its roles in tumorigenesis and progression, miR-17-92's dysregulation in CRC has substantial implications for diagnosis, prognosis, and treatment, including chemotherapy responsiveness. It also shows promise as a diagnostic and prognostic biomarker, offering insights into treatment responses and disease progression. This review provides a comprehensive overview of recent advancements and the context-dependent role of the miR-17-92 cluster in colorectal cancer, drawing from the latest high-quality published data. It summarizes the established mechanisms governing miR-17-92 expression and the molecular pathways under its influence. Furthermore, it examines instances where it functions as an oncogene or a tumor suppressor, elucidating how cellular contexts dictate its biological effects. Ultimately, miR-17-92 holds promise as a biomarker for prognosis and therapy response, as well as a potential target for cancer prevention and therapeutic interventions. In essence, this review underscores the multifaceted nature of miR-17-92 in CRC research, offering promising avenues for enhancing the management of CRC patients.
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Affiliation(s)
- Hakeemah H Al-Nakhle
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Monawarah 42353, Saudi Arabia
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Exosomes in metastasis of colorectal cancers: Friends or foes? World J Gastrointest Oncol 2023; 15:731-756. [PMID: 37275444 PMCID: PMC10237026 DOI: 10.4251/wjgo.v15.i5.731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/07/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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SENCAR L, YILMAZ DM, GÖKTÜRK D, ÖZANDAÇ POLAT S, COŞKUN G, ŞAKER D, SAPMAZ T, KARA S, ÇELENK A, POLAT S. Glioblastoma hücre hattında (U87) siklopamin ve temozolomid kombine tedavisinin miR-20a ekspresyonu üzerine etkileri. CUKUROVA MEDICAL JOURNAL 2021. [DOI: 10.17826/cumj.996520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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Nie R, Li Z, You ZH, Bao W, Li J. Efficient framework for predicting MiRNA-disease associations based on improved hybrid collaborative filtering. BMC Med Inform Decis Mak 2021; 21:254. [PMID: 34461870 PMCID: PMC8406577 DOI: 10.1186/s12911-021-01616-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 08/23/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Accumulating studies indicates that microRNAs (miRNAs) play vital roles in the process of development and progression of many human complex diseases. However, traditional biochemical experimental methods for identifying disease-related miRNAs cost large amount of time, manpower, material and financial resources. METHODS In this study, we developed a framework named hybrid collaborative filtering for miRNA-disease association prediction (HCFMDA) by integrating heterogeneous data, e.g., miRNA functional similarity, disease semantic similarity, known miRNA-disease association networks, and Gaussian kernel similarity of miRNAs and diseases. To capture the intrinsic interaction patterns embedded in the sparse association matrix, we prioritized the predictive score by fusing three types of information: similar disease associations, similar miRNA associations, and similar disease-miRNA associations. Meanwhile, singular value decomposition was adopted to reduce the impact of noise and accelerate predictive speed. RESULTS We then validated HCFMDA with leave-one-out cross-validation (LOOCV) and two types of case studies. In the LOOCV, we achieved 0.8379 of AUC (area under the curve). To evaluate the performance of HCFMDA on real diseases, we further implemented the first type of case validation over three important human diseases: Colon Neoplasms, Esophageal Neoplasms and Prostate Neoplasms. As a result, 44, 46 and 44 out of the top 50 predicted disease-related miRNAs were confirmed by experimental evidence. Moreover, the second type of case validation on Breast Neoplasms indicates that HCFMDA could also be applied to predict potential miRNAs towards those diseases without any known associated miRNA. CONCLUSIONS The satisfactory prediction performance demonstrates that our model could serve as a reliable tool to guide the following research for identifying candidate miRNAs associated with human diseases.
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Affiliation(s)
- Ru Nie
- Engineering Research Center of Mine Digitalization of Ministry of Education, China University of Mining and Technology, Xuzhou, 221116, China
- School of Computer Science and Technology, China University of Mining and Technology, Xuzhou, 221116, China
| | - Zhengwei Li
- Engineering Research Center of Mine Digitalization of Ministry of Education, China University of Mining and Technology, Xuzhou, 221116, China.
- School of Computer Science and Technology, China University of Mining and Technology, Xuzhou, 221116, China.
- Institute of Machine Learning and Systems Biology, College of Electronics and Information Engineering, Tongji University, Shanghai, 201804, China.
- KUNPAND Communications (Kunshan) Co., Ltd., Suzhou, 215300, China.
| | - Zhu-Hong You
- School of Computer Science, Northwestern Polytechnical University, Xi'an, 710072, China.
| | - Wenzheng Bao
- School of Information Engineering, Xuzhou University of Technology, Xuzhou, 221018, China
| | - Jiashu Li
- Engineering Research Center of Mine Digitalization of Ministry of Education, China University of Mining and Technology, Xuzhou, 221116, China
- School of Computer Science and Technology, China University of Mining and Technology, Xuzhou, 221116, China
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Pidíková P, Herichová I. miRNA Clusters with Up-Regulated Expression in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13122979. [PMID: 34198662 PMCID: PMC8232258 DOI: 10.3390/cancers13122979] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary As miRNAs show the capacity to be used as CRC biomarkers, we analysed experimentally validated data about frequently up-regulated miRNA clusters in CRC tissue. We identified 15 clusters that showed increased expression in CRC: miR-106a/363, miR-106b/93/25, miR-17/92a-1, miR-181a-1/181b-1, miR-181a-2/181b-2, miR-181c/181d, miR-183/96/182, miR-191/425, miR-200c/141, miR-203a/203b, miR-222/221, mir-23a/27a/24-2, mir-29b-1/29a, mir-301b/130b and mir-452/224. Cluster positions in the genome are intronic or intergenic. Most clusters are regulated by several transcription factors, and by long non-coding RNAs. In some cases, co-expression of miRNA with other cluster members or host gene has been proven. miRNA expression patterns in cancer tissue, blood and faeces were compared. The members of the selected clusters target 181 genes. Their functions and corresponding pathways were revealed with the use of Panther analysis. Clusters miR-17/92a-1, miR-106a/363, miR-106b/93/25 and miR-183/96/182 showed the strongest association with metastasis occurrence and poor patient survival, implicating them as the most promising targets of translational research. Abstract Colorectal cancer (CRC) is one of the most common malignancies in Europe and North America. Early diagnosis is a key feature of efficient CRC treatment. As miRNAs can be used as CRC biomarkers, the aim of the present study was to analyse experimentally validated data on frequently up-regulated miRNA clusters in CRC tissue and investigate their members with respect to clinicopathological characteristics of patients. Based on available data, 15 up-regulated clusters, miR-106a/363, miR-106b/93/25, miR-17/92a-1, miR-181a-1/181b-1, miR-181a-2/181b-2, miR-181c/181d, miR-183/96/182, miR-191/425, miR-200c/141, miR-203a/203b, miR-222/221, mir-23a/27a/24-2, mir-29b-1/29a, mir-301b/130b and mir-452/224, were selected. The positions of such clusters in the genome can be intronic or intergenic. Most clusters are regulated by several transcription factors, and miRNAs are also sponged by specific long non-coding RNAs. In some cases, co-expression of miRNA with other cluster members or host gene has been proven. miRNA expression patterns in cancer tissue, blood and faeces were compared. Based on experimental evidence, 181 target genes of selected clusters were identified. Panther analysis was used to reveal the functions of the target genes and their corresponding pathways. Clusters miR-17/92a-1, miR-106a/363, miR-106b/93/25 and miR-183/96/182 showed the strongest association with metastasis occurrence and poor patient survival, implicating them as the most promising targets of translational research.
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Dos Santos IL, Penna KGBD, Dos Santos Carneiro MA, Libera LSD, Ramos JEP, Saddi VA. Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review. Mol Biol Rep 2021; 48:1853-1867. [PMID: 33598796 DOI: 10.1007/s11033-020-06075-1] [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: 06/12/2020] [Accepted: 12/10/2020] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
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Affiliation(s)
- Igor Lopes Dos Santos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil.
| | - Karlla Greick Batista Dias Penna
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | | | | | - Jéssica Enocencio Porto Ramos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | - Vera Aparecida Saddi
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
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Eslamizadeh S, Zare AA, Talebi A, Tabaeian SP, Eshkiki ZS, Heydari-Zarnagh H, Akbari A. Differential Expression of miR-20a and miR-145 in Colorectal Tumors as Potential Location-specific miRNAs. Microrna 2020; 10:66-73. [PMID: 33349227 DOI: 10.2174/2211536609666201221123604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/16/2020] [Accepted: 11/27/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs), as tissue specific regulators of gene transcription, may be served as biomarkers for Colorectal Cancer (CRC). OBJECTIVE This study aimed to investigate the potential role of the cancer-related hsa-miRNAs as biomarkers in Colon Cancer (CC) and Rectal Cancer (RC). METHODS A total of 148 CRC samples (74 rectum and 74 colon) and 74 adjacent normal tissues were collected to examine the differential expression of selected ten hsa-miRNAs using quantitative Reverse Transcriptase PCR (qRT-PCR). RESULTS The significantly elevated levels of miR-21, miR-133b, miR-18a, miR-20a, and miR-135b, and decreased levels of miR-34a, miR-200c, miR-145, and let-7g were detected in colorectal tumors compared to the healthy tissues (P<0.05). Hsa-miR-20a was significantly overexpressed in rectum compared to colon (p =0.028) from a cut-off value of 3.15 with a sensitivity of 66% and a specificity of 60% and an AUC value of 0.962. Also, hsa-miR-145 was significantly overexpressed in colon compared to the rectum (p =0.02) from a cut-off value of 3.9 with a sensitivity of 55% and a specificity of 61% and an AUC value of 0.91. CONCLUSION In conclusion, hsa-miR-20a and hsa-miR-145, as potential tissue-specific biomarkers for distinguishing RC and CC, improve realizing the molecular differences between these local tumors.
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Affiliation(s)
- Sara Eslamizadeh
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Zare
- Young Researchers and Elites club, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Atefeh Talebi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Zahra Shokati Eshkiki
- Alimentary Tract Research Center, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hafez Heydari-Zarnagh
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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Maminezhad H, Ghanadian S, Pakravan K, Razmara E, Rouhollah F, Mossahebi-Mohammadi M, Babashah S. A panel of six-circulating miRNA signature in serum and its potential diagnostic value in colorectal cancer. Life Sci 2020; 258:118226. [PMID: 32771555 DOI: 10.1016/j.lfs.2020.118226] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/02/2020] [Accepted: 08/04/2020] [Indexed: 12/24/2022]
Abstract
AIM Colorectal carcinoma (CRC) is one of the most prevalent cancers throughout the world. Circulating serum-derived microRNAs (miRNAs, miRs) can be used as non-invasive biomarkers for CRC diagnosis. This study aimed to identify a panel of six serum exosomal miRNAs as novel diagnostic biomarkers for CRC. MAIN METHODS Exosomes were isolated and characterized from the conditioned media of the human colon adenocarcinoma cells (HCT-116 and Caco2). Sera were isolated from peripheral blood of 45 CRC and also 45 healthy individuals. The expression levels and diagnostic value of candidate circulating miRNAs (miR-19a, miR-20a, miR-150, miR-143, miR-145, and let-7a) were measured through quantitative real-time PCR. Receiver operating characteristic (ROC) curves were applied to evaluate the diagnostic accuracy of selected miRNAs. The association of candidate miRNAs and clinicopathological characteristics e.g. tumor node metastasis (TNM) staging and lymph node metastasis (LNM) were further evaluated. KEY FINDINGS Circulating serum miR-19a, miR-20a, miR-150, and let-7a were significantly up-regulated in CRC patients, while miR-143 and miR-145 showed a significant down-regulation. The higher levels of miR-143 and miR-145 in patients with TNM stage I-II were detected, whereas miR-19a, miR-20a, miR-150, and let-7a were highly expressed in TNM stage III. The expression levels of miR-19a, miR-20a, and miR-150 were positively correlated with LNM status, while the expression levels of miR-143 and miR-145 were lower in patients with LNM. Area under the ROC curves of miR-19a, miR-20a, miR-150, miR-143, miR-145, and let-7a were 0.87, 0.83, 0.75, 0.76, 0.78 and 0.71, respectively. SIGNIFICANCE We established a panel of six-circulating miRNA signature (i.e. miR-19a, miR-20a, miR-143, miR-145, miR-150, and let-7a) in serum as a non-invasive biomarker for CRC diagnosis. These findings confirm that serum-derived miRNAs have a strong potential to be a diagnostic biomarker for patients with CRC.
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Affiliation(s)
- Hamidreza Maminezhad
- Department of Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sharareh Ghanadian
- Department of Microbiology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences of Islamic Azad University, Tehran, Iran
| | - Katayoon Pakravan
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ehsan Razmara
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Rouhollah
- Department of Cellular and Molecular Sciences, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Majid Mossahebi-Mohammadi
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China.
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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11
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Li YY, Xu QW, Xu PY, Li WM. MSC-derived exosomal miR-34a/c-5p and miR-29b-3p improve intestinal barrier function by targeting the Snail/Claudins signaling pathway. Life Sci 2020; 257:118017. [PMID: 32603821 DOI: 10.1016/j.lfs.2020.118017] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023]
Abstract
AIMS Mesenchymal stem cell (MSC)-derived exosomes (MSCs-exos) regulate biological functions in different diseases, such as liver fibrosis, diabetes, and ischaemic heart injury. However, the function of MSC-derived exosomes on the intestinal barrier and the underlying mechanisms are poorly characterized. MAIN METHODS The expression of miR-34a/c-5p, miR-29b-3p and Claudin-3 in human normal intestinal tissues and damaged intestinal tissues was evaluated by RT-qPCR. The effect of MSC-secreted exosomes on Claudins in Caco-2 cells was measured by using confocal microscopy, RT-qPCR and Western blot. Dual luciferase reporter assays and RNA immunoprecipitation (RIP) assays were performed to study the interaction between miR-34a/c-5p, miR-29b-3p and Snail. I/R-induced intestinal damage in rats was used to determine the in vivo effect of MSC-exos on intestinal barrier function. KEY FINDINGS In this study, we found that miR-34a/c-5p, miR-29b-3p and Claudin-3 were downregulated in damaged human intestinal tissues. MSC-exos increased the expression of Claudin-3, Claudin-2 and ZO-1 in Caco-2 cells. Further studies demonstrated that MSC-exos promoted Claudin-3, Claudin-2 and ZO-1 expression in Caco-2 cells by Snail, which was targeted by miR-34a/c-5p and miR-29b-3p. In vivo experiments showed that MSC-derived exosomes could improve I/R-induced intestinal damage through the Snail/Claudins signaling pathway. SIGNIFICANCE The findings here suggest a novel molecular basis for the therapy of intestinal barrier dysfunction.
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Affiliation(s)
- Yi-Yun Li
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, PR China
| | - Qing-Wen Xu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, PR China
| | - Peng-Yuan Xu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, PR China
| | - Wei-Ming Li
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, PR China.
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12
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Evran S, Baran O, Kayhan A, Katar S, Akkaya E, Cevik S, Kaya M, Sonmez D, Serin H, Kaynar MY. The Expression of MIR17HG Protein as a Potential Therapeutic Target in Meningioma. World Neurosurg 2020; 137:e554-e563. [PMID: 32068173 DOI: 10.1016/j.wneu.2020.02.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND MIR17 host gene (MIR17HG) is a potential therapeutic target for some cancer types. The aim of this study was to assess MIR17HG protein levels in patients with meningioma who had not been reported previously in the literature and comparing with normal meninges tissues. METHODS MIR17HG protein levels were measured in 46 samples including 25 meningioma tissues procured during surgery and 21 normal meninges tissues obtained within 4 hours of death during autopsy procedures. Each sample was stored at -80°C until the evaluation of MIR17HG protein using a sandwich enzyme-linked immunoassay principle. Results were compared between the groups. RESULTS MIR17HG protein levels were significantly higher in meningioma tissues compared with controls and difference was statistically significant (P = 0.012). Both World Health Organization grade I and grade II meningiomas had higher MIR17HG protein levels compared with controls and differences were statistically significant (P = 0.026 for grade I and P = 0.042 for grade II). Receiver operating characteristic curve analysis was performed to determine the cutoff of MIR17HG protein value in differentiating meningioma and control groups. At the cutoff value for MIR17HG protein of >0.0998 ng/mL, the sensitivity was 73.91%, 71.43%, and 77.78% and area under the curve was 0.756, 0.753, and 0.761 for meningioma group, grade I, and grade II subgroups, respectively, and specificity was 69.23% for each group. CONCLUSIONS MIR17HG protein expression was found to have a higher level in meningiomas than in normal meninges tissues in our study. Considering the recurrence and irresectability for some meningiomas, which require further treatment, MIR17HG may be a new target for treatment in meningiomas and our study will shed light on further studies.
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Affiliation(s)
- Sevket Evran
- Neurosurgery Clinic, Haseki Research and Training Hospital, Istanbul, Turkey.
| | - Oguz Baran
- Neurosurgery Clinic, Haseki Research and Training Hospital, Istanbul, Turkey
| | - Ahmet Kayhan
- Neurosurgery Clinic, Haseki Research and Training Hospital, Istanbul, Turkey
| | - Salim Katar
- Neurosurgery Clinic, Diyarbakir State Hospital, Diyarbakir, Turkey
| | - Enes Akkaya
- Neurosurgery Clinic, Sisli Hamidiye Etfal Research and Training Hospital, Istanbul, Turkey
| | - Serdar Cevik
- Neurosurgery Clinic, Memorial Hospital, Istanbul, Turkey
| | - Mustafa Kaya
- Neurosurgery Clinic, Eregli State Hospital, Zonguldak, Turkey
| | - Derya Sonmez
- Clinical Biochemistry Laboratory, Istanbul Research and Training Hospital, Istanbul, Turkey
| | - Huriye Serin
- Clinical Biochemistry Laboratory, Istanbul Research and Training Hospital, Istanbul, Turkey
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13
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Xiao Z, Chen S, Feng S, Li Y, Zou J, Ling H, Zeng Y, Zeng X. Function and mechanisms of microRNA-20a in colorectal cancer. Exp Ther Med 2020; 19:1605-1616. [PMID: 32104211 PMCID: PMC7027132 DOI: 10.3892/etm.2020.8432] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 10/29/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-associated mortality worldwide. CRC currently has no specific biomarkers to promote its diagnosis and treatment and the underlying mechanisms regulating its pathogenesis have not yet been determined. MicroRNAs (miRs) are small, non-coding RNAs that exhibit regulatory functions and have been demonstrated to serve a crucial role in the post-transcriptional regulatory processes of gene expression that is associated with cell physiology and disease progression. Recently, abnormal miR-20a expression has been identified in a number of cancers types and this has become a novel focus within cancer research. High levels of miR-20a expression have been identified in CRC tissues, serum and plasma. In a recent study, miR-20a was indicated to be present in feces and to exhibit a high sensitivity to CRC. Therefore, miR-20a may be used as a marker for CRC and an indicator that can prevent the invasive examination of patients with this disease. Changes in the expression of miR-20a during chemotherapy can be used as a biomarker for monitoring resistance to treatment. In conclusion, miR-20a exhibits the potential for clinical application as a novel diagnostic biomarker and therapeutic target for use in patients with CRC. The present study focused on the role and mechanisms of miR-20a in CRC.
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Affiliation(s)
- Zheng Xiao
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Shi Chen
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Shujun Feng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yukun Li
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Juan Zou
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hui Ling
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ying Zeng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,School of Nursing, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xi Zeng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
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14
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Awad AR, Youness RA, Ibrahim M, Motaal AA, El-Askary HI, Assal RA, Gad MZ. An acetylated derivative of vitexin halts MDA-MB-231 cellular progression and improves its immunogenic profile through tuning miR- 20a-MICA/B axis. Nat Prod Res 2019; 35:3126-3130. [PMID: 31691589 DOI: 10.1080/14786419.2019.1686372] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The activating immune ligands, MICA/B, act as a "kill me" signal through the NKG2D receptor expressed on natural killer (NK) cells. Recently, the oncogenic miR-20a was found to mediate immune escape through repressing MICA/B levels in breast cancer (BC) cells. However, targeting miR-20a-MICA/B using natural compounds has rarely been investigated. Our group has successfully isolated 3'-O-acetylvitexin that showed cytotoxic effects against colon cancer cells but has never been evaluated in BC. Our aim is to investigate the effects of 3'-O-acetylvitexin on BC cell lines and to further elucidate its molecular mechanism of action.The results showed that 3'-O-acetylvitex depicted a more pronounced dose-dependent repression of TNBC cellular viability, colonogenicity and migration capacity than Vitexin. 3'-O-acetylvitexin treatment resulted in a marked dose-dependent repression of miR-20a with a concomitant dose-dependent increase in MICA/B expression. In conclusion, 3'-O-acetylvitexin might act as a promising therapeutic agent for TNBC patients.
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Affiliation(s)
- Aya R Awad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Rana A Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - M Ibrahim
- Pharmacognosy Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Amira Abdel Motaal
- Pharmacognosy Department, College of Pharmacy, King Khalid University, Abha, Saudi Arabia.,Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Hesham I El-Askary
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Reem A Assal
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Mohamed Z Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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15
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Emami SS, Akbari A, Zare AA, Agah S, Masoodi M, Talebi A, Minaeian S, Fattahi A, Moghadamnia F. MicroRNA Expression Levels and Histopathological Features of Colorectal Cancer. J Gastrointest Cancer 2019; 50:276-284. [PMID: 29404790 DOI: 10.1007/s12029-018-0055-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Non-coding RNAs have opened a new window in cancer biology. MicroRNAs (miRNAs), as a family of non-coding RNAs, play an important role in the gene regulation. The aberrant expression of these small molecules has been documented to involve in colorectal cancer (CRC) pathogenesis. This study aimed to examine the expression of miRNAs in CRC and to correlate their expression levels with histological markers (Ki-67 and CD34). MATERIALS AND METHODS Tumor tissues and matched normal adjacent tissues were collected from 36 patients with newly diagnosed CRC. Immunohistochemical (IHC) staining of tumor tissues was performed for Ki-67 (proliferation) and CD34 (angiogenesis) markers, and the immunoexpression staining scores were obtained. A polyadenylation SYBER Green quantitative real-time PCR technique was used to quantify the expression of a panel of five CRC-related miRNAs (hsa-miR-21, 31, 20a, 133b, and 145). Histopathological (H) scores and miRNA expression levels were correlated with clinicopathological features including the degree of differentiation, staging, and lymphovascular invasion. RESULTS Our results showed the significant difference between the two groups for the expression level of hsa-miR-21, hsa-miR-31, hsa-miR-145, and miR-20a (P < 0.001), but not for hsa-miR-133b (P = 0.57). Further analysis revealed an inverse significant correlation between hsa-miR-145 and Ki-67 (r = - 0.942, P < 0.001). While a positive correlation was observed between hsa-miR-21 and Ki-67 (r = 0.920, P < 0.001), and hsa-miR-21 and CD34 (r = 0.981, P < 0.001). Also, a positive correlation between hsa-miR-31 and Ki-67 (r = 0.913, P < 0.001), hsa-miR-31 and CD34 (r = 0.798, P < 0.05), hsa-miR-20a and Ki-67 (r = 0.871, P < 0.001), and hsa-miR-20a and CD34 (r = 0.890, P < 0.001) was found. CONCLUSION Dysregulation of miRNAs and correlation with molecular histopathology indicate a biological role for miRNAs in various cellular processes including cell proliferation and angiogenesis in CRC development. On the other hand, the pattern of miRNA expression and its correlation with histological markers are potentially valuable to apply as diagnostic biomarkers for CRC.
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Affiliation(s)
- Sahar Sarmasti Emami
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Ali-Akbar Zare
- Young Researchers and Elites Club, Science and Research Branch, Islamic Azad University, Tehran, Iran. .,Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohsen Masoodi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Atefeh Talebi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Minaeian
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Azam Fattahi
- Research Center of Pediatric Infectious Diseases, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Farahnaz Moghadamnia
- Department of Genetics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
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16
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Chen P, Bai Y, Li Y, Yuan Y, Cheng Y, Pang J, Zhu H, Chen C. Association between polymorphisms of MIR17HG and risk of colorectal cancer in the Chinese Han population. Mol Genet Genomic Med 2019; 7:e667. [PMID: 30941921 PMCID: PMC6565593 DOI: 10.1002/mgg3.667] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 02/13/2019] [Accepted: 03/08/2019] [Indexed: 02/06/2023] Open
Abstract
Background Colorectal cancer is the third most common cancer worldwide. Recently, an increasing number of evidences suggest that genetic susceptibility plays an important role in the occurrence of colorectal cancer. This study aimed to better understand the influence of MIR17HG polymorphisms on colorectal cancer susceptibility in the Chinese Han population. Methods We recruited 514 patients with colorectal cancer and 510 healthy controls to investigate the association between polymorphisms of MIR17HG and risk of colorectal cancer in the Chinese Han population. Genotyping was performed with the Agena MassARRAY platform. We used the χ2 test to compare the distributions of single nucleotide polymorphisms (SNPs) allele and genotypes frequencies between cases and controls. Odds ratios and 95% confidence intervals were calculated by logistic regression analysis to evaluate the association under genetic models. Linkage disequilibrium between the five SNPs was assessed using the Haploview software. Results Overall analysis found that rs7336610 and rs1428 and haplotype CTAGA were significantly associated with increased risk of colorectal cancer. However, we found rs7318578 was associated with a decreased risk of colorectal cancer in the dominant model. Stratification analysis showed that rs7336610, rs7318578, and rs1428 were also associated with rectal cancer risk. Gender stratification analysis found that rs7336610, rs7318578, rs17735387, and rs1428 were significantly associated with colorectal cancer risk in males. Conclusion In conclusion, this study indicated that the polymorphisms of MIR17HG were associated with colorectal cancer risk. Therefore, our findings may provide new insights into the development of colorectal cancer. Further association and functional studies are of great importance to confirm these results and to define the potential biological mechanism of colorectal cancer.
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Affiliation(s)
- Peng Chen
- The National Engineering Research Centre for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, P.R. China.,Institution of Basic Medical Science, Xi'an Medical University, Xi'an, P.R. China
| | - Yuwei Bai
- The National Engineering Research Centre for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, P.R. China
| | - Yaru Li
- The National Engineering Research Centre for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, P.R. China
| | - Yuemin Yuan
- The National Engineering Research Centre for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, P.R. China
| | - Yimin Cheng
- The National Engineering Research Centre for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, P.R. China
| | | | - Hongli Zhu
- The National Engineering Research Centre for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, P.R. China
| | - Chao Chen
- The National Engineering Research Centre for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, P.R. China
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17
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Moreno EC, Pascual A, Prieto-Cuadra D, Laza VF, Molina-Cerrillo J, Ramos-Muñoz ME, Rodríguez-Serrano EM, Soto JL, Carrato A, García-Bermejo ML, Guillén-Ponce C. Novel Molecular Characterization of Colorectal Primary Tumors Based on miRNAs. Cancers (Basel) 2019; 11:cancers11030346. [PMID: 30862091 PMCID: PMC6468580 DOI: 10.3390/cancers11030346] [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: 01/21/2019] [Revised: 03/05/2019] [Accepted: 03/06/2019] [Indexed: 12/13/2022] Open
Abstract
microRNAs (miRNA) expression in colorectal (CR) primary tumours can facilitate a more precise molecular characterization. We identified and validated a miRNA profile associated with clinical and histopathological features that might be useful for patient stratification. In situ hybridization array using paraffin-embedded biopsies of CR primary tumours were used to screen 1436 miRNAs. 17 miRNAs were selected for validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) (n = 192) and were further correlated with clinical and histopathological data. We demonstrated that miRNAs associated to Colorectal Cancer (CRC) diagnosis age (over 50s and 60s) included miR-1-3p, miR-23b-3p, miR-27b-3p, miR-143-3p, miR-145-5p and miR-193b-5p. miR-23b-3p and miR-24-3p discriminated between Lynch Syndrome and sporadic CRC. miR-10a-5p, miR-20a-5p, miR-642b and Let-7a-5p were associated to stroma abundance. miR-642b and Let-7a-5p were associated with to peritumoral inflammation abundance. miR-1-3p, miR-143-3p and miR-145-5p correlated with mucinous component. miR-326 correlated with tumour location (right or left sided). miR-1-3p associated with tumour grade. miR-20a-5p, miR-193b-5p, miR-320a, miR-326 and miR-642b-3p associated to tumour stage and progression. Remarkably, we also demonstrated that miR-1-3p and miR-326 expression significantly associated with patient overall survival (OS). Hierarchical clustering and bioinformatics analysis indicated that selected miRNAs could re-classify the patients and work cooperatively, modulating common target genes involved in colorectal cancer key signalling pathways. In conclusion, molecular characterization of CR primary tumours based on miRNAs could lead to more accurate patient reclassification and may be useful for efficient patient management.
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Affiliation(s)
- Elisa Conde Moreno
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | - Alejandro Pascual
- Pathology Department, Ramon y Cajal Research Institute, University Hospital, 28034 Madrid, Spain.
| | - Daniel Prieto-Cuadra
- SynlabPathology, Pathology Department, Virgen de la Victoria, University Hospital, 29010 Málaga, Spain.
| | - Val F Laza
- Microbiology Department and Bioinformatics Core Facility, IRYCIS, 28034 Madrid, Spain.
| | - Javier Molina-Cerrillo
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, 28034 Madrid, Spain.
| | - Miren Edurne Ramos-Muñoz
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | | | - José Luis Soto
- Hereditary Cancer Program Valencian Region, Molecular Genetics Laboratory, Elche University Hospital, Elche, 03202 Alicante, Spain.
| | - Alfredo Carrato
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, Alcala University, 28034 Ciberonc, Spain.
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | - Carmen Guillén-Ponce
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, 28034 Madrid, Spain.
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18
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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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19
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The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases. Int J Mol Sci 2018; 19:ijms19123711. [PMID: 30469518 PMCID: PMC6321452 DOI: 10.3390/ijms19123711] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 11/19/2018] [Accepted: 11/20/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial⁻mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.
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20
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Ricciardiello F, Capasso R, Kawasaki H, Abate T, Oliva F, Lombardi A, Misso G, Ingrosso D, Leone CA, Iengo M, Caraglia M. A miRNA signature suggestive of nodal metastases from laryngeal carcinoma. ACTA OTORHINOLARYNGOLOGICA ITALICA 2018; 37:467-474. [PMID: 29327732 PMCID: PMC5782423 DOI: 10.14639/0392-100x-851] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 03/11/2017] [Indexed: 12/16/2022]
Abstract
The discovery that miRNAs are frequently deregulated in tumours offers the opportunity to identify them as prognostic and diagnostic markers. The aim of this multicentric study is to identify a miRNA expression profile specific for laryngeal cancer. The secondary endpoint was to identify specific deregulated miRNAs with potential as prognostic biomarkers for tumour spread and nodal involvement, and specifically to search for a miRNA pattern pathognomonic for N+ laryngeal cancer and for N- tissues. We identified 20 miRNAs specific for laryngeal cancer and a tissue-specific miRNA signature that is predictive of lymph node metastases in laryngeal carcinoma characterised by 11 miRNAs, seven of which are overexpressed (upregulated) and four downregulated. These results allow the identification of a group of potential specific tumour biomarkers for laryngeal carcinoma that can be used to improve its diagnosis, particularly in early stages, as well as its prognosis.
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Affiliation(s)
- F Ricciardiello
- Ear Nose and Throat Unit, Cardarelli Hospital, Naples, Italy
| | - R Capasso
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - H Kawasaki
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.,Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., Akitakata, Hiroshima, Japan
| | - T Abate
- Ear Nose and Throat Unit, University of Naples Federico II, Naples, Italy
| | - F Oliva
- Ear Nose and Throat Unit, Cardarelli Hospital, Naples, Italy
| | - A Lombardi
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - G Misso
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - D Ingrosso
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - C A Leone
- Ear Nose and Throat Unit and Neck Surgery, Monaldi Hospital, Naples, Italy
| | - M Iengo
- Ear Nose and Throat Unit, Cardarelli Hospital, Naples, Italy
| | - M Caraglia
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
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21
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Gao S, Zhao ZY, Wu R, Zhang Y, Zhang ZY. Prognostic value of microRNAs in colorectal cancer: a meta-analysis. Cancer Manag Res 2018; 10:907-929. [PMID: 29750053 PMCID: PMC5935085 DOI: 10.2147/cmar.s157493] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Numerous studies have shown that miRNA levels are closely related to the survival time of patients with colon, rectal, or colorectal cancer (CRC). However, the outcomes of different investigations have been inconsistent. Accordingly, a meta-analysis was conducted to study associations among the three types of cancers. Materials and methods Studies published in English that estimated the expression levels of miRNAs with survival curves in CRC were identified until May 20, 2017 by online searches in PubMed, Embase, Web of Science, and the Cochrane Library by two independent authors. Pooled HRs with 95% CIs were used to estimate the correlation between miRNA expression and overall survival. Results A total of 63 relevant articles regarding 13 different miRNAs, with 10,254 patients were ultimately included. CRC patients with high expression of blood miR141 (HR 2.52, 95% CI 1.68-3.77), tissue miR21 (HR 1.31, 95% CI 1.12-1.53), miR181a (HR 1.52, 95% CI 1.26-1.83), or miR224 (HR 2.12, 95% CI 1.04-4.34), or low expression of tissue miR126 (HR 1.55, 95% CI 1.24-1.93) had significantly poor overall survival (P<0.05). Conclusion In general, blood miR141 and tissue miR21, miR181a, miR224, and miR126 had significant prognostic value. Among these, blood miR141 and tissue miR224 were strong biomarkers of prognosis for CRC.
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Affiliation(s)
- Song Gao
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Zhi-Ying Zhao
- School of Computer Science and Engineering, Northeastern University, Shenyang
| | - Rong Wu
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Yue Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhen-Yong Zhang
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
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22
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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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23
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Sayagués JM, Corchete LA, Gutiérrez ML, Sarasquete ME, Del Mar Abad M, Bengoechea O, Fermiñán E, Anduaga MF, Del Carmen S, Iglesias M, Esteban C, Angoso M, Alcazar JA, García J, Orfao A, Muñoz-Bellvis L. Genomic characterization of liver metastases from colorectal cancer patients. Oncotarget 2018; 7:72908-72922. [PMID: 27662660 PMCID: PMC5341953 DOI: 10.18632/oncotarget.12140] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 09/13/2016] [Indexed: 01/09/2023] Open
Abstract
Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.
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Affiliation(s)
- José María Sayagués
- Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain
| | - Luís Antonio Corchete
- Cáncer Research Center and Service of Hematology, University Hospital of Salamanca, Salamanca, Spain
| | - María Laura Gutiérrez
- Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain
| | - Maria Eugenia Sarasquete
- Cáncer Research Center and Service of Hematology, University Hospital of Salamanca, Salamanca, Spain
| | - María Del Mar Abad
- Department of Pathology, University Hospital of Salamanca, Salamanca, Spain
| | - Oscar Bengoechea
- Department of Pathology, University Hospital of Salamanca, Salamanca, Spain
| | - Encarna Fermiñán
- Genomics Unit, Cancer Research Center, IBMCC-CSIC/USAL, Salamanca, Spain
| | - María Fernanda Anduaga
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Sofia Del Carmen
- Department of Pathology, University Hospital of Salamanca, Salamanca, Spain
| | - Manuel Iglesias
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Carmen Esteban
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - María Angoso
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Jose Antonio Alcazar
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Jacinto García
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
| | - Alberto Orfao
- Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain
| | - Luís Muñoz-Bellvis
- Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain
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24
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Ioannou M, Kouvaras E, Papamichali R, Samara M, Chiotoglou I, Koukoulis G. Smad4 and epithelial-mesenchymal transition proteins in colorectal carcinoma: an immunohistochemical study. J Mol Histol 2018; 49:235-244. [PMID: 29468299 DOI: 10.1007/s10735-018-9763-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/19/2018] [Indexed: 12/24/2022]
Abstract
Epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. During EMT, tumor cells acquire the capacity to migrate and invade the stroma. Activation of the transforming growth factor-b (TGF-b) signaling pathway is of major importance for the initiation of EMT. Smad4, an essential protein of this pathway, is known to complex with multiple transcription factors (e.g. Snail-1, Slug, Twist-1), in various types of cancer, promoting the repression or activation of target genes. The role of Smad4 in colorectal cancer (CRC) is not straightforward so far. In the present study forty eight resected CRC tumor specimens were immunohistochemically examined in order to assess the expression of Smad4 and its association with E-cadherin, Snail-1, Slug, Twist-1 protein expression and with various pathological parameters. Smad4 was found to be positively correlated with Snail-1, Slug and Twist-1 expression (p < 0.001). On the other hand it was negatively correlated with the expression of E-cadherin (p < 0.001). Furthermore, lymphatic invasion could be clearly associated with Smad4 expression, a finding complying with the metastatic ability of EMT cells. In conclusion, Smad4 could be considered as a central component of EMT transition in human colorectal cancer that combines with transcriptional factors to reduce E-cadherin and alter the expression of the epithelial phenotype.
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Affiliation(s)
- M Ioannou
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece.
- Department of Pathology, School of Medicine, University of Thessaly, Biopolis, Larissa, 41110, Greece.
| | - E Kouvaras
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
| | - R Papamichali
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
| | - M Samara
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
| | - I Chiotoglou
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
| | - G Koukoulis
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
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25
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Agrawal S, Tapmeier T, Rahmioglu N, Kirtley S, Zondervan K, Becker C. The miRNA Mirage: How Close Are We to Finding a Non-Invasive Diagnostic Biomarker in Endometriosis? A Systematic Review. Int J Mol Sci 2018; 19:ijms19020599. [PMID: 29463003 PMCID: PMC5855821 DOI: 10.3390/ijms19020599] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 02/08/2018] [Accepted: 02/09/2018] [Indexed: 12/27/2022] Open
Abstract
Background: Endometriosis is a common disorder of the reproductive age group, characterised by the presence of ectopic endometrial tissue. The disease not only causes enormous suffering to the affected women, but also brings a tremendous medical and economic burden to bear on society. There is a long lag phase between the onset and diagnosis of the disease, mainly due to its non-specific symptoms and the lack of a non-invasive test. Endometriosis can only be diagnosed invasively by laparoscopy. A specific, non-invasive test to diagnose endometriosis is an unmet clinical need. The recent discovery of microRNAs (miRNAs) as modulators of gene expression, and their stability and specificity, make them an attractive candidate biomarker. Various studies on miRNAs in endometriosis have identified their cardinal role in the pathogenesis of the disease, and have proposed them as potential biomarkers in endometriosis. Rationale/Objectives: The aims of this review were to study the role of circulatory miRNAs in endometriosis, and bring to light whether circulatory miRNAs could be potential non-invasive biomarkers to diagnose the disease. Search methods: Three databases, PubMed, EMBASE, and BIOSIS were searched, using a combination of Mesh or Emtree headings and free-text terms, to identify literature relating to circulating miRNAs in endometriosis published from 1996 to 31 December 2017. Only peer-reviewed, full-text original research articles in English were included in the current review. The studies meeting the inclusion criteria were critically assessed and checked using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. The dysregulated miRNAs were assessed regarding the concordance between the various studies and their role in the disease. Outcomes: Nine studies were critically analysed, and 42 different miRNAs were found to be dysregulated in them, with only one common miRNA (miR-20a) differentially expressed in more than one study. miR-17-5p/20a, miR-200, miR-199a, miR-143, and miR-145 were explored for their pivotal role in the aetiopathogenesis of endometriosis. Wider implications: It is emerging that miRNAs play a central role in the pathogenesis of endometriosis and have the potential of being promising biomarkers. Circulating miRNAs as a non-invasive diagnostic tool may shorten the delay in the diagnosis of the disease, thus alleviating the suffering of women and reducing the burden on health care systems. However, despite numerous studies on circulating miRNAs in endometriosis, no single miRNA or any panel of them seems to meet the criteria of a diagnostic biomarker. The disagreement between the various studies upholds the demand of larger, well-controlled systematic validation studies with uniformity in the research approaches and involving diverse populations.
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Affiliation(s)
- Swati Agrawal
- Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford OX1 2JD, UK;.
| | - Thomas Tapmeier
- Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford OX1 2JD, UK;.
| | - Nilufer Rahmioglu
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.
| | - Shona Kirtley
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX1 2JD, UK.
| | - Krina Zondervan
- Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford OX1 2JD, UK;.
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.
| | - Christian Becker
- Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford OX1 2JD, UK;.
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26
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Signs SA, Fisher RC, Tran U, Chakrabarti S, Sarvestani SK, Xiang S, Liska D, Roche V, Lai W, Gittleman HR, Wessely O, Huang EH. Stromal miR-20a controls paracrine CXCL8 secretion in colitis and colon cancer. Oncotarget 2018; 9:13048-13059. [PMID: 29560130 PMCID: PMC5849194 DOI: 10.18632/oncotarget.24495] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 02/10/2018] [Indexed: 01/24/2023] Open
Abstract
Inflammatory bowel disease (IBD) affects one million people in the US. Ulcerative colitis (UC) is a subtype of IBD that can lead to colitis-associated cancer (CAC). In UC, the rate of CAC is 3-5-fold greater than the rate of sporadic colorectal cancer (CRC). The pathogenesis of UC and CAC are due to aberrant interactions between host immune system and microenvironment, but precise mechanisms are still unknown. In colitis and CAC, microenvironmental fibroblasts exhibit an activated, inflammatory phenotype that contributes to tumorigenesis accompanied by excessive secretion of the chemokine CXCL8. However, mechanisms regulating CXCL8 secretion are unclear. Since it is known that miRNAs regulate chemokines such as CXCL8, we queried a microRNA library for mimics affecting CXCL8 secretion. Among the identified microRNAs, miR-20a/b was further investigated as its stromal expression levels inversely correlated with the amounts of CXCL8 secreted and predicted fibroblast tumor-promoting activity. Indeed, miR-20a directly bound to the 3′UTR of CXCL8 mRNA and regulated its expression by translational repression. In vivo co-inoculation studies with CRC stem cells demonstrated that fibroblasts characterized by high miR-20a expression had reduced tumor-promoting activities. These studies reveal that in stromal fibroblasts, miR-20a modulates CXCL8 function, therefore influencing tumor latency.
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Affiliation(s)
- Steven A Signs
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Robert C Fisher
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Uyen Tran
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Susmita Chakrabarti
- Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Samaneh K Sarvestani
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Shao Xiang
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - David Liska
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Veronique Roche
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Wei Lai
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Haley R Gittleman
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio USA
| | - Oliver Wessely
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Emina H Huang
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA
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27
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Rammer M, Webersinke G, Haitchi-Petnehazy S, Maier E, Hackl H, Charoentong P, Malli T, Steinmair M, Petzer AL, Rumpold H. MicroRNAs and their role for T stage determination and lymph node metastasis in early colon carcinoma. Clin Exp Metastasis 2017; 34:431-440. [PMID: 29134398 DOI: 10.1007/s10585-017-9863-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/12/2017] [Indexed: 12/14/2022]
Abstract
Worldwide, colon cancer is among the most common cancer entities. Understanding the molecular background is the key to enable accurate stage determination, which is crucial to assess optimal therapy options. The search for preoperative biomarkers is ongoing. In recent years, several studies have proposed a diagnostic and prognostic role for miRNAs in cancer. Aim of this study was to evaluate miRNA expression patterns correlating with tumor stage, especially lymph node metastasis, in primary colon carcinoma tissue. Screening was accomplished using GeneChip® miRNA v3.0 arrays (Thermo Fisher Scientific, Waltham, MA, USA) and validated via TaqMan® qPCR assays (Thermo Fisher Scientific, Waltham, MA, USA) to investigate miRNA expressions in 168 FFPE and 83 fresh frozen colon carcinoma samples. Regarding lymph node status, analyses displayed no significantly differential miRNA expression. Interestingly, divergent expression of miR-18a-5p, miR-20a-5p, miR-21-5p, miR-152-3p and miR-1973 was detected in stage pT1. Although miRNAs might not represent reliable biomarkers regarding lymph node metastasis status, they could support risk assessment in stage T1 tumors.
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Affiliation(s)
- Melanie Rammer
- Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I: Medical Oncology, Hematology and Gastroenterology, Ordensklinikum Linz, Barmherzige Schwestern, Linz, Austria
| | - Gerald Webersinke
- Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I: Medical Oncology, Hematology and Gastroenterology, Ordensklinikum Linz, Barmherzige Schwestern, Linz, Austria
| | | | - Eva Maier
- Department of Pathology, Ordensklinikum Linz, Barmherzige Schwestern, Linz, Austria
| | - Hubert Hackl
- Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Pornpimol Charoentong
- Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Theodora Malli
- Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I: Medical Oncology, Hematology and Gastroenterology, Ordensklinikum Linz, Barmherzige Schwestern, Linz, Austria
| | - Maria Steinmair
- Department of Pathology, Ordensklinikum Linz, Barmherzige Schwestern, Linz, Austria
| | - Andreas L Petzer
- Department of Internal Medicine I: Medical Oncology, Hematology and Gastroenterology, Ordensklinikum Linz, Barmherzige Schwestern, Linz, Austria
| | - Holger Rumpold
- Department of Internal Medicine I: Medical Oncology, Hematology and Gastroenterology, Ordensklinikum Linz, Barmherzige Schwestern, Linz, Austria.
- Internal Medicine II: Medical Oncology, Hematology, Gastroenterology and Rheumatology, Academic Teaching Hospital Feldkirch, Carinagasse 47, 6807, Feldkirch, Austria.
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28
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Zhou Y, He D, Zeng J, Bao S, Lai J, Weng Y, Chen S. The Effects of Antisense miRNA-20a Alone or in Combination with Imatinib on K562 Cell Proliferation. Front Pharmacol 2017; 8:127. [PMID: 28367122 PMCID: PMC5355440 DOI: 10.3389/fphar.2017.00127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 02/28/2017] [Indexed: 12/26/2022] Open
Abstract
Objective: The effects of microRNA-20a (miR-20a) antisense oligonucleotides (ASODNs) on the proliferation and apoptosis of K562 cells were investigated, and the effects of these ASODNs in combination with imatinib on K562 cells were preliminarily observed. Methods: miR-20a ASODNs and scrambled oligonucleotides (SODNs) were chemically synthesized, and the later was used as the control. miR-20a ASODNs were transfected into K562 cells using Lipofectamine 2000 transfection reagent, and the expression of miR-20a was detected using real-time quantitative RT-PCR (qRT-PCR). The CCK8 assay was performed to detect the inhibition of the cell growth rate. The cells were stained by Hoechst 33258 to detect apoptotic cell morphology. Annexin V/PI double staining was used to detect the cell apoptosis rate using flow cytometry. The protein expression levels of E2F1, P21, and Bim in the K562 cell line were detected using western blotting. Results: The qRT-PCR results showed that the expression level of miR-20a in K562 cells transfected with miR-20a ASODNs was lower than those in the normal control, SODN and blank transfection groups (p < 0.05). miR-20a ASODNs significantly inhibited the growth of K562 cells as compared to the controls (p < 0.05). The Hoechst staining results showed morphological changes, suggesting apoptosis. The cell apoptosis rates in the ASODN group was (13.9 ± 1.5)%, which was significantly higher than that in the normal control group (1.84 ± 0.21)%, blank transfection group (3.21 ± 0.32)%, and SODN group (3.72 ± 0.44)% (p < 0.05). The protein expression of E2F1 and P21 in K562 cells transfected with miR-20a ASODNs were higher, while the level of Bim protein was significantly lower than that in the control groups. When miR-20a ASODNs were combined with imatinib, the growth of K562 cells was significantly inhibited as compared to the ASODN treatment alone, imatinib alone, and SODN+imatinib groups (p < 0.05). Conclusions: miR-20a ASODNs could induce apoptosis and inhibit the proliferation of K562 cells. In addition, imatinib combined with miR-20a ASODNs can increase the inhibitory effect on K562 cell proliferation.
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Affiliation(s)
- Ying Zhou
- Departmemt of Hematology, The First Affiliated Hospital, Jinan University Guangzhou, China
| | - Dongmei He
- School of Medicine, Institute of Hematology, Jinan University Guangzhou, China
| | - Jinrong Zeng
- Departmemt of Hematology, The First Affiliated Hospital, Jinan University Guangzhou, China
| | - Shijie Bao
- Departmemt of Hematology, The First Affiliated Hospital, Jinan University Guangzhou, China
| | - Jing Lai
- Departmemt of Hematology, The First Affiliated Hospital, Jinan University Guangzhou, China
| | - Yujun Weng
- Department of Internal Medicine, Guangzhou Nansha Central Hospital Guangzhou, China
| | - Shengting Chen
- Departmemt of Hematology, The First Affiliated Hospital, Jinan University Guangzhou, China
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29
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Abstract
MicroRNAs (miRNAs) are a class of endogenous, evolutionarily conserved small non-coding RNAs, which play a vital role in tumour formation, development, metastasis and recurrence by inducing DNA methylation, changing tumor microenvironment and regulating signal pathways such as Wnt/β-catenin, phosphoinositide3-kinase (PI3K), K-RAS, epithelial mesenchymal transitions (EMT) and so on. Recent studies have found that the expression of many miRNAs is dyregulated in colorectal cancer, and they participate in and control the formation and development of colorectal cancer. Thus, understanding the roles and mechanisms of action of miRNAs in colorectal cancer can provide a new avenue for its early diagnosis, clinical staging, treatment and prognosis evaluation.
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Zhou J, Jiang J, Wang S, Xia X. Oncogenic role of microRNA‑20a in human uveal melanoma. Mol Med Rep 2016; 14:1560-6. [PMID: 27356499 PMCID: PMC4940053 DOI: 10.3892/mmr.2016.5433] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 04/25/2016] [Indexed: 02/07/2023] Open
Abstract
As a member of the microRNA (miR)-17-92 cluster, miR‑20a has been indicated to be involved in the regulation of the proliferation and invasion of various cancer cells. Previous studies have observed elevated plasma levels of miR‑20a in patients with uveal melanoma (UM), compared with normal controls. In the present study, the potential function of miR‑20a in UM was investigated. Reverse transcription‑quantitative polymerase chain reaction analysis was performed to detect the expression levels of miR‑20a in UM cells and tissues. The functions of miR‑20a on cell proliferation, migration and invasion were determined in vitro using 3‑(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays, respectively. The expression levels of miR‑20a were significantly increased in the UM cells and tissues (P<0.05). Subsequently, miR‑20a mimics were transfected into UM cells, which led to increases in cell growth, migration and invasion activities. By contrast, miR‑20a inhibition markedly suppressed the viability and motility of UM cells in vitro. These data provided convincing evidence that miR‑20a may function as an oncogenic miRNA, and may be involved in promoting cell growth and motility in the molecular etiology of UM, suggesting its potential as a candidate therapeutic target for the treatment of patients with UM.
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Affiliation(s)
- Jinzi Zhou
- Department of Ophthalmology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Jian Jiang
- Department of Ophthalmology, Xiangya Hospital Central South University, Changsha, Hunan 410008, P.R. China
| | - Shuhong Wang
- Department of Ophthalmology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Xiaobo Xia
- Department of Ophthalmology, Xiangya Hospital Central South University, Changsha, Hunan 410008, P.R. China
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Molinari C, Salvi S, Foca F, Teodorani N, Saragoni L, Puccetti M, Passardi A, Tamberi S, Avanzolini A, Lucci E, Calistri D. miR-17-92a-1 cluster host gene (MIR17HG) evaluation and response to neoadjuvant chemoradiotherapy in rectal cancer. Onco Targets Ther 2016; 9:2735-42. [PMID: 27226732 PMCID: PMC4866748 DOI: 10.2147/ott.s105760] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is the gold standard for the treatment of patients with locally advanced rectal cancer (LARC). However, response is variable, and no predictive markers have been validated. The amplification of 13q31-34 seemed to distinguish between nonresponders and responders to NCRT. The miR-17-92a-1 cluster host gene (MIR17HG), which is involved in the development, progression, and aggressiveness of colorectal cancer, and the ABCC4 gene, an ATP-binding cassette transporter, are located at this region. Moreover, the transcription factor c-Myc is closely related to MIR17HG. The aim of this study was to examine the role of MIR17HG, ABCC4, and CMYC gene copy numbers (CNs) in determining response to NCRT. We analyzed DNA CN of pretherapy biopsies from 108 LARC patients and the expression of microRNA (miR)-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1 in 34 biopsies. MIR17HG, CMYC, and ABCC4 gene CNs were frequently altered in pretreatment tumors, amplification being the most frequent alteration. With regard to response to therapy, 41% of responders showed MIR17HG deletion, while MIR17HG amplification was observed in 41% of nonresponders. With regard to pathological T stage (ypT), a higher percentage of ypT3-4 than ypT0-2 tumors showed MIR17HG amplification. Finally, a higher, albeit nonsignificant, variability in the expression of MIR17HG cluster members was detected in nonresponders compared to responders. No association was observed between clinical pathological parameters and ABCC4 or CMYC CN. Our data did not highlight a significant association between MIR17HG, CMYC, and ABCC4 gene CNs and response to NCRT in LARC. However, MIR17HG gene amplification would seem to be related to a lack of response. Evaluation of the expression of MIR17HG cluster members is warranted in a larger case series, together with functional studies, to evaluate the potential of this gene as a new predictive marker.
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Affiliation(s)
- Chiara Molinari
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Samanta Salvi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Flavia Foca
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Nazario Teodorani
- Radiotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Luca Saragoni
- Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy
| | | | | | - Stefano Tamberi
- Department of Medical Oncology, Infermi Hospital, Faenza, Italy
| | - Andrea Avanzolini
- Department of General Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy
| | - Enrico Lucci
- Department of General Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy
| | - Daniele Calistri
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Yau TO, Wu CW, Tang CM, Chen Y, Fang J, Dong Y, Liang Q, Man Ng SS, Chan FKL, Sung JJY, Yu J. MicroRNA-20a in human faeces as a non-invasive biomarker for colorectal cancer. Oncotarget 2016; 7:1559-1568. [PMID: 26621842 PMCID: PMC4811480 DOI: 10.18632/oncotarget.6403] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Accepted: 11/15/2015] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Detection of microRNA (miRNA) aberrations in human faeces is a new approach for colorectal cancer (CRC) screening. The aim of this study was to characterise miR-20a in faeces as a non-invasive biomarker for diagnosis of CRC. RESULTS miR-20a expression was significantly higher in the 40 CRC tumours compared to their respective adjacent normal tissues (P = 0.0065). Levels of miR-20a were also significantly higher in faecal samples from CRC patients (P < 0.0001). The area under receiver operating characteristic (AUROC) curve for miR-20a was 0.73, with a sensitivity of 55% and specificity of 82% for CRC patients compared with controls. No significant difference in the level of miR-20a was found between patients with proximal, distal, and rectal cancer. The use of antibiotics did not influence faecal miR-20a levels. PATIENTS AND METHODS miR-20a was selected from an expression microarray containing 667 miRNAs. Further verification of miR-20a was performed in 40 pairs of primary CRC tissues, as well as 595 faecal samples (198 CRCs, 199 adenomas, and 198 healthy controls) using TaqMan probe based quantitative Real-Time PCR (qRT-PCR). CONCLUSIONS Faecal-based miR-20a can be utilised as a potential non-invasive biomarker for CRC screening.
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Affiliation(s)
- Tung On Yau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Chung Wah Wu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Ceen-Ming Tang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
- Oxford University Clinical Academic Graduate School, John Radcliffe Hospital, Oxford, UK
| | - Yingxuan Chen
- Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Jingyuan Fang
- Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yujuan Dong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Qiaoyi Liang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Simon Siu Man Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Francis Ka Leung Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Joseph Jao Yiu Sung
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
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Kaller M, Hermeking H. Interplay Between Transcription Factors and MicroRNAs Regulating Epithelial-Mesenchymal Transitions in Colorectal Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 937:71-92. [DOI: 10.1007/978-3-319-42059-2_4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Yang S, Cho YJ, Jin L, Yuan G, Datta A, Buckhaults P, Datta PK. An epigenetic auto-feedback loop regulates TGF-β type II receptor expression and function in NSCLC. Oncotarget 2015; 6:33237-33252. [PMID: 26356817 PMCID: PMC4741762 DOI: 10.18632/oncotarget.4893] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 07/31/2015] [Indexed: 01/22/2023] Open
Abstract
The downregulation of transforming growth factor-β (TGF-β) type II receptor (TβRII) expression and function plays a pivotal role in the loss of the TGF-β-induced tumor suppressor function that contributes to lung cancer progression. The aberrant expression of miRNAs has been shown to be involved in the regulation of oncogenes and tumor suppressor genes. Our current study involving miRNA microarray, northern blot and QRT-PCR analysis shows an inverse correlation between miR-20a and TβRII expression in non-small cell lung cancer (NSCLC) tissues and cell lines. Stable expression of miR-20a downregulates TβRII in lung epithelial cells which results in an inhibition of TGF-β signaling and attenuation of TGF-β-induced cell growth suppression and apoptosis. Stable knock down of miR-20a increases TβRII expression and inhibits tumorigenicity of lung cancer cells in vivo. Oncogene c-Myc promotes miR-20a expression by activating its promoter leading to downregulation of TβRII expression and TGF-ß signaling. MiR-145, which is upregulated by TGF-β, inhibits miR-20a expression by targeting c-Myc and upregulates TβRII expression. These correlations among miRNAs and cellular proteins are supported by TCGA public database using NSCLC specimens. These results suggest a novel mechanism for the loss of TβRII expression and TGF-β-induced tumor suppressor functions in lung cancer through a complex auto-feedback loop TGF-β/miR-145/c-Myc/miR-20a/TβRII.
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MESH Headings
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Epigenesis, Genetic
- Feedback, Physiological/physiology
- Gene Expression Regulation, Neoplastic
- Genes, myc/physiology
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- MicroRNAs/physiology
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/physiology
- Receptor, Transforming Growth Factor-beta Type II
- Receptors, Transforming Growth Factor beta/genetics
- Receptors, Transforming Growth Factor beta/physiology
- Tumor Cells, Cultured
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Affiliation(s)
- Shanzhong Yang
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
- Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
| | - Yong-Jig Cho
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Lin Jin
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
- Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
| | - Guandou Yuan
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Arunima Datta
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Phillip Buckhaults
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Pran K. Datta
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
- Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
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Sica GS, Fiorani C, Stolfi C, Monteleone G, Candi E, Amelio I, Catani V, Sibio S, Divizia A, Tema G, Iaculli E, Gaspari AL. Peritoneal expression of Matrilysin helps identify early post-operative recurrence of colorectal cancer. Oncotarget 2015; 6:13402-13415. [PMID: 25596746 PMCID: PMC4537023 DOI: 10.18632/oncotarget.2830] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 11/27/2014] [Indexed: 12/20/2022] Open
Abstract
Recurrence of colorectal cancer (CRC) following a potentially curative resection is a challenging clinical problem. Matrix metalloproteinase-7 (MMP-7) is over-expressed by CRC cells and supposed to play a major role in CRC cell diffusion and metastasis. MMP-7 RNA expression was assessed by real-time PCR using specific primers in peritoneal washing fluid obtained during surgical procedure. After surgery, patients underwent a regular follow up for assessing recurrence. transcripts for MMP-7 were detected in 31/57 samples (54%). Patients were followed-up (range 20-48 months) for recurrence prevention. Recurrence was diagnosed in 6 out of 55 patients (11%) and two patients eventually died because of this. Notably, all the six patients who had relapsed were positive for MMP-7. Sensitivity and specificity of the test were 100% and 49% respectively. Data from patients have also been corroborated by computational approaches. Public available coloncarcinoma datasets have been employed to confirm MMP7 clinical impact on the disease. Interestingly, MMP-7 expression appeared correlated to Tgfb-1, and correlation of the two factors represented a poor prognostic factor. This study proposes positivity of MMP-7 in peritoneal cavity as a novel biomarker for predicting disease recurrence in patients with CRC.
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Affiliation(s)
- Giuseppe S. Sica
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
- European Society Degenerative Disease (ESDD). www.esdd.it
| | - Cristina Fiorani
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Carmine Stolfi
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Giovanni Monteleone
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Ivano Amelio
- Medical Research Council, Toxicology Unit, Leicester, UK
| | - Valeria Catani
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Simone Sibio
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Andrea Divizia
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Giorgia Tema
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Edoardo Iaculli
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Achille L. Gaspari
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
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36
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RETRACTED ARTICLE: Identification of core miRNA based on small RNA-seq and RNA-seq for colorectal cancer by bioinformatics. Tumour Biol 2014; 36:2249-55. [DOI: 10.1007/s13277-014-2832-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 11/07/2014] [Indexed: 12/18/2022] Open
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37
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Liu J, Du X, Zhou J, Pan Z, Liu H, Li Q. MicroRNA-26b functions as a proapoptotic factor in porcine follicular Granulosa cells by targeting Sma-and Mad-related protein 4. Biol Reprod 2014; 91:146. [PMID: 25395673 DOI: 10.1095/biolreprod.114.122788] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Sma- and Mad-related protein 4 (SMAD4) is the central mediator of the transforming growth factor beta signaling pathway and is closely related to mammalian reproductive ability and the development of ovarian follicles. However, little is currently known about the role of SMAD4 in mammalian follicular granulosa cell (GC) apoptosis or its regulation by miRNAs. Here, we found that the porcine SMAD4 protein was expressed at high levels in GCs and oocytes from primary, preantral, and antral follicles, and only slightly expressed in theca cells; its expression level was down-regulated in apoptotic ovarian GCs, suggesting that SMAD4 may be involved in ovary development and selection. Overexpression and knockdown of SMAD4 increased the proliferation and apoptosis of cultured porcine GCs, respectively. In addition, the use of miRNA mimics and luciferase reporter assays revealed that miRNA-26b (miR-26b) functions as a proapoptotic factor in porcine follicular GCs by targeting the 3'-untranslated region of the SMAD4 gene. Overexpression of miR-26b in follicular GCs suppressed SMAD4 mRNA and protein levels, resulting in down-regulation of the antiapoptotic BCL-2 gene and the promotion of GC apoptosis. Furthermore, transforming growth factor beta 1 (TGF-beta1) down-regulates miR-26b expression in porcine GCs. Taken together, these data suggest that SMAD4 plays a critical role in porcine follicular GC apoptosis and follicular atresia and that miR-26b may have a proapoptotic role in GCs by regulating the expression of SMAD4 in the transforming growth factor beta signaling pathway.
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Affiliation(s)
- Jiying Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, P.R. China
| | - Xing Du
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, P.R. China
| | - Jilong Zhou
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, P.R. China
| | - Zengxiang Pan
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, P.R. China
| | - Honglin Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, P.R. China
| | - Qifa Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, P.R. China
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