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Lee DH, Park EG, Kim JM, Shin HJ, Lee YJ, Jeong HS, Roh HY, Kim WR, Ha H, Kim SW, Choi YH, Kim HS. Genomic analyses of intricate interaction of TE-lncRNA overlapping genes with miRNAs in human diseases. Genes Genomics 2024; 46:1313-1325. [PMID: 39215947 DOI: 10.1007/s13258-024-01547-1] [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: 05/09/2024] [Accepted: 07/09/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Transposable elements (TEs) are known to be inserted into genome to create transcript isoforms or to generate long non-coding RNA (lncRNA) sequences. The insertion of TEs generates a gene protein sequence within the genome, but also provides a microRNA (miRNA) regulatory region. OBJECTIVE To determine the effect of gene sequence changes caused by TE insertion on miRNA binding and to investigate the formation of an overlapping lncRNA that represses it. METHODS The distribution of overlapping regions between exons and TE regions with lncRNA was examined using the Bedtools. miRNAs that can bind to those overlapping regions were identified through the miRDB web program. For TE-lncRNA overlapping genes, bioinformatic analysis was conducted using DAVID web database. Differential expression analysis was conducted using data from the GEO dataset and TCGA. RESULTS Most TEs were distributed more frequently in untranslated regions than open reading frames. There were 30 annotated TE-lncRNA overlapping genes with same strand that could bind to the same miRNA. As a result of identifying the association between these 30 genes and diseases, TGFB2, FCGR2A, DCTN5, and IFI6 were associated with breast cancer, and HMGCS1, FRMD4A, EDNRB, and SNCA were associated with Alzheimer's disease. Analysis of the GEO and TCGA data showed that the relevant expression of miR-891a and miR-28, which bind to the TE overlapping region of DCTN5 and HMGCS1, decreased. CONCLUSION This study indicates that the interaction between TE-lncRNA overlapping genes and miRNAs can affect disease progression.
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Affiliation(s)
- Du Hyeong Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Eun Gyung Park
- Department of Integrated Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Jung-Min Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Hae Jin Shin
- Department of Integrated Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Yun Ju Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Hyeon-Su Jeong
- Department of Integrated Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Hyun-Young Roh
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, 46241, Republic of Korea
| | - Woo Ryung Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Hongseok Ha
- Institute of Endemic Disease, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea
| | - Sang-Woo Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, 46241, Republic of Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, 47227, Republic of Korea
| | - Heui-Soo Kim
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea.
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, 46241, Republic of Korea.
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Yadav V, Singh T, Sharma D, Garg VK, Chakraborty P, Ghatak S, Satapathy SR. Unraveling the Regulatory Role of HuR/microRNA Axis in Colorectal Cancer Tumorigenesis. Cancers (Basel) 2024; 16:3183. [PMID: 39335155 PMCID: PMC11430344 DOI: 10.3390/cancers16183183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/04/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health burden with high incidence and mortality. MicroRNAs (miRNAs) are small non-protein coding transcripts, conserved throughout evolution, with an important role in CRC tumorigenesis, and are either upregulated or downregulated in various cancers. RNA-binding proteins (RBPs) are known as essential regulators of miRNA activity. Human antigen R (HuR) is a prominent RBP known to drive tumorigenesis with a pivotal role in CRC. In this review, we discuss the regulatory role of the HuR/miRNA axis in CRC. Interestingly, miRNAs can directly target HuR, altering its expression and activity. However, HuR can also stabilize or degrade miRNAs, forming complex feedback loops that either activate or block CRC-associated signaling pathways. Dysregulation of the HuR/miRNA axis contributes to CRC initiation and progression. Additionally, HuR-miRNA regulation by other small non-coding RNAs, circular RNA (circRNAs), or long-non-coding RNAs (lncRNAs) is also explored here. Understanding this HuR-miRNA interplay could reveal novel biomarkers with better diagnostic or prognostic accuracy.
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Affiliation(s)
- Vikas Yadav
- Department of Translational Medicine, Clinical Research Centre, Lund University, 221 00 Malmö, Sweden;
| | - Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, University of Delhi, New Delhi 110021, India; (T.S.); (D.S.)
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences (INMAS-DRDO), New Delhi 110054, India
| | - Deepika Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, University of Delhi, New Delhi 110021, India; (T.S.); (D.S.)
| | - Vivek Kumar Garg
- Department of Medical Lab Technology, Chandigarh University, Gharuan, Mohali 140413, Punjab, India;
| | - Payel Chakraborty
- Amity Institute of Biotechnology, Amity University Kolkata, Kolkata 700135, West Bengal, India; (P.C.); (S.G.)
| | - Souvik Ghatak
- Amity Institute of Biotechnology, Amity University Kolkata, Kolkata 700135, West Bengal, India; (P.C.); (S.G.)
| | - Shakti Ranjan Satapathy
- Department of Translational Medicine, Clinical Research Centre, Lund University, 221 00 Malmö, Sweden;
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Fabijanec M, Hulina-Tomašković A, Štefanović M, Verbanac D, Ćelap I, Somborac-Bačura A, Grdić Rajković M, Demirović A, Ramić S, Krušlin B, Rumora L, Čeri A, Koržinek M, Petrik J, Ljubičić N, Baršić N, Barišić K. MicroRNA-193a-3p as a Valuable Biomarker for Discriminating between Colorectal Cancer and Colorectal Adenoma Patients. Int J Mol Sci 2024; 25:8156. [PMID: 39125725 PMCID: PMC11311302 DOI: 10.3390/ijms25158156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Specific markers for colorectal cancer (CRC), preceded by colorectal adenoma (pre-CRC), are lacking. This study aimed to investigate whether microRNAs (miR-19a-3p, miR-92a-3p, miR-193a-3p, and miR-210-3p) from tissues and exosomes are potential CRC biomarkers and compare them to existing biomarkers, namely carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9. MiRNA was isolated in the samples of 52 CRC and 76 pre-CRC patients. Expression levels were analyzed by RT-qPCR. When comparing pre-CRC and CRC tissue expression levels, only miR-193a-3p showed statistically significant result (p < 0.0001). When comparing the tissues and exosomes of CRC samples, a statistically significant difference was found for miR-193a-3p (p < 0.0001), miR-19a-3p (p < 0.0001), miR-92a-3p (p = 0.0212), and miR-210-3p (p < 0.0001). A receiver-operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate the diagnostic value of CEA, CA 19-9, and miRNAs. CEA and CA 19-9 had good diagnostic values (AUCs of 0.798 and 0.668). The diagnostic value only of miR-193a-3p was highlighted (AUC = 0.725). The final logistic regression model, in which we put a combination of CEA concentration and the miR-193a-3p expression level in tissues, showed that using these two markers can distinguish CRC and pre-CRC in 71.3% of cases (AUC = 0.823). MiR-193a-3p from tissues could be a potential CRC biomarker.
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Affiliation(s)
- Marija Fabijanec
- Center for Applied Medical Biochemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia;
| | - Andrea Hulina-Tomašković
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
| | - Mario Štefanović
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
- Department of Clinical Chemistry, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
| | - Donatella Verbanac
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
| | - Ivana Ćelap
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
- Department of Clinical Chemistry, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
| | - Anita Somborac-Bačura
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
| | - Marija Grdić Rajković
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
| | - Alma Demirović
- Department of Pathology and Cytology “Ljudevit Jurak”, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia; (A.D.); (B.K.)
| | - Snježana Ramić
- Department of Oncological Pathology, University Hospital for Tumors, Sestre Milosrdnice University Hospital Centre, 10000 Zagreb, Croatia;
| | - Božo Krušlin
- Department of Pathology and Cytology “Ljudevit Jurak”, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia; (A.D.); (B.K.)
| | - Lada Rumora
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
| | - Andrea Čeri
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
| | - Martha Koržinek
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
| | - József Petrik
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
| | - Neven Ljubičić
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia; (N.L.)
| | - Neven Baršić
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia; (N.L.)
| | - Karmela Barišić
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia; (M.Š.); (D.V.); (I.Ć.); (A.S.-B.); (M.G.R.); (L.R.); (A.Č.); (M.K.); (J.P.); (K.B.)
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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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5
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Yadollahi Farsani M, Amini Farsani Z, Teimuri S, Kolahdouzan M, Eshraghi Samani R, Teimori H. Deregulation of miR-1245b-5p and miR-92a-3p and their potential target gene, GATA3, in epithelial-mesenchymal transition pathway in breast cancer. Cancer Rep (Hoboken) 2024; 7:e1955. [PMID: 38173189 PMCID: PMC10849934 DOI: 10.1002/cnr2.1955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/30/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are small molecules that have prominent roles in tumor development and metastasis and can be used for diagnostic and therapeutic purposes. This study evaluated the expression of miR-92a-3p and miR-1245b-5p and their potential target gene, GATA3 in patients with breast cancer (BC). MATERIALS AND METHODS In the search for BC-related microRNAs, miR-124b-5p and miR-92a-3p were selected using Medline through PubMed, miR2disease, miRcancer and miRTarBase. Moreover, target gene GATA3 and their possible interaction in the regulating epithelial-mesenchymal transition (EMT) and invasion was evaluated using in silico tools including miRTarBase, TargetScan, STRING-db, and Cytoscape. The expression level of miR-92a-3p, miR1245b-5p, and GATA3 were assessed on extracted RNAs of tumor and nontumor tissues from 36 patients with BC using qPCR. Additionally, clinical-pathologic characteristics, such as tumor grade, tumor stage, lymph node were taken into consideration and the diagnostic power of these miRNAs and GATA3 was evaluated using the ROC curve analysis. RESULTS In silico evaluation of miR-92a-3p and miR-1245b-5p supports their potential association with EMT and invasion signaling pathways in BC pathogenesis. Comparing tumor tissues to nontumor tissues, we found a significant downregulation of miR-1245b-5p and miR-92a-3p and upregulation of GATA3. Patients with BC who had decreased miR-92a-3p expression also had higher rates of advanced stage/grade and ER expression, whereas decreased miR-1245b-5p expression was only linked to ER expression and was not associated with lymph node metastasis. The AUC of miR-1245b-5p, miR-92a-3p, and GATA3 using ROC curve was determined 0.6449 (p = .0239), 0.5980 (p = .1526), and 0.7415 (p < .0001), respectively, which showed a significant diagnostic accuracy of miR-1245b-5p and GATA3 between the BC patients and healthy individuals. CONCLUSION MiR-1245b-5p, miR-92a-3p, and GATA3 gene contribute to BC pathogenesis and they may be having potential regulatory roles in signaling pathways involved in invasion and EMT pathways in BC pathogenesis, as a result of these findings. More research is needed to determine the regulatory mechanisms that they control.
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Affiliation(s)
- Mahtab Yadollahi Farsani
- Department of Medical Biotechnology, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
| | - Zeinab Amini Farsani
- Cellular and Molecular Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
| | | | - Mohsen Kolahdouzan
- Department of Surgery, School of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Reza Eshraghi Samani
- Department of Surgery, School of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Hossein Teimori
- Cellular and Molecular Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
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Beaumont JEJ, Ju J, Barbeau LMO, Demers I, Savelkouls KG, Derks K, Bouwman FG, Wauben MHM, Zonneveld MI, Keulers TGH, Rouschop KMA. GABARAPL1 is essential in extracellular vesicle cargo loading and metastasis development. Radiother Oncol 2024; 190:109968. [PMID: 37898438 DOI: 10.1016/j.radonc.2023.109968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/04/2023] [Accepted: 10/22/2023] [Indexed: 10/30/2023]
Abstract
BACKGROUND AND PURPOSE Hypoxia is a common feature of tumours, associated with poor prognosis due to increased resistance to radio- and chemotherapy and enhanced metastasis development. Previously we demonstrated that GABARAPL1 is required for the secretion of extracellular vesicles (EV) with pro-angiogenic properties during hypoxia. Here, we explored the role of GABARAPL1+ EV in the metastatic cascade. MATERIALS AND METHODS GABARAPL1 deficient or control MDA-MB-231 cells were injected in murine mammary fat pads. Lungs were dissected and analysed for human cytokeratin 18. EV from control and GABARAPL1 deficient cells exposed to normoxia (21% O2) or hypoxia (O2 < 0.02%) were isolated and analysed by immunoblot, nanoparticle tracking analysis, high resolution flow cytometry, mass spectrometry and next-generation sequencing. Cellular migration and invasion were analysed using scratch assays and transwell-invasion assays, respectively. RESULTS The number of pulmonary metastases derived from GABARAPL1 deficient tumours decreased by 84%. GABARAPL1 deficient cells migrate slower but display a comparable invasive capacity. Both normoxic and hypoxic EV contain proteins and miRNAs associated with metastasis development and, in line, increase cancer cell invasiveness. Although GABARAPL1 deficiency alters EV content, it does not alter the EV-induced increase in cancer cell invasiveness. CONCLUSION GABARAPL1 is essential for metastasis development. This is unrelated to changes in migration and invasion and suggests that GABARAPL1 or GABARAPL1+ EV are essential in other processes related to the metastatic cascade.
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Affiliation(s)
- Joel E J Beaumont
- Department of Radiotherapy, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Jinzhe Ju
- Department of Radiotherapy, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Lydie M O Barbeau
- Department of Radiotherapy, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Imke Demers
- Department of Radiotherapy, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands; Department of Pathology, GROW-School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Kim G Savelkouls
- Department of Radiotherapy, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Kasper Derks
- Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Freek G Bouwman
- Department of Human Biology, NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Marca H M Wauben
- Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Marijke I Zonneveld
- Department of Radiotherapy, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Tom G H Keulers
- Department of Radiotherapy, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Kasper M A Rouschop
- Department of Radiotherapy, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands.
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Application of Bioinformatics Tools for the Prediction of Helper MicroRNAs for Improvement of Oncolytic Virus Efficacy. Cell Microbiol 2022. [DOI: 10.1155/2022/5756131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Purpose. Oncolytic Reoviruses, as a self-limiting virus, can be used in cancer treatment, because they have the ability to replicate in tumor cells selectively and destroy them. Studies show that some immune response proteins may interfere with the virus life cycle. So, the main aim of this bioinformatic study is to check which microRNA is able to target some reovirus inhibitory proteins. Experimental Design. By use of online bioinformatics software, the microRNAs that could target inhibitory genes were selected. Then, other features like content ++ score and cell type were checked and finally the eligible microRNAs were determined. Results. After choosing 15 inhibitory proteins, analysis was performed and finally 37 microRNAs which could target inhibitory proteins in colorectal cell lines were selected. In the end, by investigation of web-based tools, just two microRNAs were finalized. Conclusions and Clinical Relevance. This bioinformatic study shows that microRNA-140 and microRNA-92a have the potential to target some inhibitory proteins which interfere with oncolytic Reovirus replication and it may help in the optimal use of this virus as a cancer treatment. Because selective reproduction of Reovirus in tumor cells, as a nonchemical therapy, can be a good way to overcome this disease with broad advantages.
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Lu F, Zhao X, Zhang Z, Xiong M, Wang Y, Sun Y, He B, Zhu J. The diagnostic and prognostic value of the miR-17-92 cluster in hepatocellular carcinoma: A meta-analysis. Front Genet 2022; 13:927079. [PMID: 36118845 PMCID: PMC9480495 DOI: 10.3389/fgene.2022.927079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/02/2022] [Indexed: 11/23/2022] Open
Abstract
Previous studies demonstrated that microRNAs (miRNAs) could serve as biomarkers in various cancers. This meta-analysis aimed to determine the roles of a miR-17-92 cluster in hepatocellular carcinoma (HCC). Here, eligible included studies were searched through PubMed, Embase, and Wan Fang databases up to 1st February 2022. Relevant data were extracted from each eligible study to evaluate the relationship between miRNA-17-92 cluster miRNA expression and the diagnosis and prognosis of HCC. Finally, a total of 21 studies were pooled and included in the meta-analysis, of which four articles were used for diagnostic meta-analysis and eight articles were used for prognostic meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratios (DOR) of the miR17-92 cluster for diagnosis of HCC were 0.75 [95% confidence interval (CI): 0.64–0.83], 0.73 (95% CI: 0.65–0.79), and 7.87 (95% CI: 5.36–11.54), respectively. Also, the area under the curve (AUC) for the miR-17-92 cluster when diagnosing HCC was 0.79 (95% CI: 0.76–0.83). For prognostic analysis, hazard ratios (HRs) with 95% CIs were extracted from the included studies and pooled HRs were determined to assess the associations. Patients with increased expression of miR17-92 cluster miRNA were associated with poor overall survival (OS) and recurrence-free survival (RFS) (HR=1.86, 95% CI: 1.04–3.33; HR = 4.18, 95% CI: 3.02–5.77, respectively), but not progression-free survival (PFS) (HR = 0.43, 95% CI: 0.25–0.73), while no association of the miR-17-92 cluster high-expression was detected with disease-free survival (DFS) (HR: 0.95, 95% CI: 0.21–4.34). In short, current pieces of evidence suggested that the miR-17-92 cluster may serve as a novel diagnostic and prognostic biomarker for HCC. However, given the limited study number, larger-size, multi-center, and higher-quality studies are indispensable in the future.
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Affiliation(s)
- Fang Lu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Xianghong Zhao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Zhongqiu Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Mengqiu Xiong
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ying Wang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Yalan Sun
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Bangshun He
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Bangshun He, ; Junrong Zhu,
| | - Junrong Zhu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
- *Correspondence: Bangshun He, ; Junrong Zhu,
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9
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Jorgensen BG, Ro S. MicroRNAs and 'Sponging' Competitive Endogenous RNAs Dysregulated in Colorectal Cancer: Potential as Noninvasive Biomarkers and Therapeutic Targets. Int J Mol Sci 2022; 23:2166. [PMID: 35216281 PMCID: PMC8876324 DOI: 10.3390/ijms23042166] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 01/28/2022] [Accepted: 02/02/2022] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal (GI) tract in mammals is comprised of dozens of cell types with varied functions, structures, and histological locations that respond in a myriad of ways to epigenetic and genetic factors, environmental cues, diet, and microbiota. The homeostatic functioning of these cells contained within this complex organ system has been shown to be highly regulated by the effect of microRNAs (miRNA). Multiple efforts have uncovered that these miRNAs are often tightly influential in either the suppression or overexpression of inflammatory, apoptotic, and differentiation-related genes and proteins in a variety of cell types in colorectal cancer (CRC). The early detection of CRC and other GI cancers can be difficult, attributable to the invasive nature of prophylactic colonoscopies. Additionally, the levels of miRNAs associated with CRC in biofluids can be contradictory and, therefore, must be considered in the context of other inhibiting competitive endogenous RNAs (ceRNA) such as lncRNAs and circRNAs. There is now a high demand for disease treatments and noninvasive screenings such as testing for bloodborne or fecal miRNAs and their inhibitors/targets. The breadth of this review encompasses current literature on well-established CRC-related miRNAs and the possibilities for their use as biomarkers in the diagnoses of this potentially fatal GI cancer.
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Affiliation(s)
| | - Seungil Ro
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA;
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10
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Sehgal P, Lanauze C, Wang X, Hayer KE, Torres-Diz M, Leu NA, Sela Y, Stanger BZ, Lengner CJ, Thomas-Tikhonenko A. MYC Hyperactivates Wnt Signaling in APC/ CTNNB1-Mutated Colorectal Cancer Cells through miR-92a-Dependent Repression of DKK3. Mol Cancer Res 2021; 19:2003-2014. [PMID: 34593610 PMCID: PMC8642317 DOI: 10.1158/1541-7786.mcr-21-0666] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/18/2021] [Accepted: 09/20/2021] [Indexed: 11/16/2022]
Abstract
Activation of Wnt signaling is among the earliest events in colon cancer development. It is achieved either via activating mutations in the CTNNB1 gene encoding β-catenin, the key transcription factor in the Wnt pathway, or most commonly by inactivating mutations affecting APC, a major β-catenin binding partner and negative regulator. However, our analysis of recent Pan Cancer Atlas data revealed that CTNNB1 mutations significantly co-occur with those affecting Wnt receptor complex components (e.g., Frizzled and LRP6), underscoring the importance of additional regulatory events even in the presence of common APC/CTNNB1 mutations. In our effort to identify non-mutational hyperactivating events, we determined that KRAS-transformed murine colonocytes overexpressing direct β-catenin target MYC show significant upregulation of the Wnt signaling pathway and reduced expression of Dickkopf 3 (DKK3), a reported ligand for Wnt co-receptors. We demonstrate that MYC suppresses DKK3 transcription through one of miR-17-92 cluster miRNAs, miR-92a. We further examined the role of DKK3 by overexpression and knockdown and discovered that DKK3 suppresses Wnt signaling in Apc-null murine colonic organoids and human colon cancer cells despite the presence of downstream activating mutations in the Wnt pathway. Conversely, MYC overexpression in the same cell lines resulted in hyperactive Wnt signaling, acquisition of epithelial-to-mesenchymal transition markers, and enhanced migration/invasion in vitro and metastasis in a syngeneic orthotopic mouse colon cancer model. IMPLICATIONS: Our results suggest that the MYC→miR-92a-|DKK3 axis hyperactivates Wnt signaling, forming a feed-forward oncogenic loop.
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Affiliation(s)
- Priyanka Sehgal
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Claudia Lanauze
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xin Wang
- Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Katharina E Hayer
- The Bioinformatics Group, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Manuel Torres-Diz
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - N Adrian Leu
- Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yogev Sela
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ben Z Stanger
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Christopher J Lengner
- Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrei Thomas-Tikhonenko
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
- Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Pathology & Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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11
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Lin TA, Lin WS, Chou YC, Nagabhushanam K, Ho CT, Pan MH. Oxyresveratrol inhibits human colon cancer cell migration through regulating epithelial-mesenchymal transition and microRNA. Food Funct 2021; 12:9658-9668. [PMID: 34664597 DOI: 10.1039/d1fo01920a] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The major cause of death in colorectal cancer (CRC) patients is metastasis. Moreover, lots of studies have emphasized that the epithelial-mesenchymal transition (EMT) is a pivotal step in metastasis. Both transforming growth factor beta (TGF-β) and dysregulation of microRNAs (miRNAs) can induce or regulate EMT, promoting the loss of intercellular adhesion and increased motility of cancer cells. Therefore, it is necessary to prevent or inhibit the metastasis of colorectal cancer. Relatively little is known about the anti-metastatic effect of oxyresveratrol (OXY), a natural derivative of resveratrol (RES), compared to RES. Accordingly, RES was used as the positive control to investigate the effects of OXY on colon cancer cell migration. The results showed that OXY could significantly inhibit cell migration (67.17% ± 0.04, 64.89% ± 0.04) compared to RES (84.6% ± 0.07, 76.34% ± 0.08) in HCT116 cells and TGF-β-induced HT-29 cells, respectively, via Snail/E-cadherin expression. In addition, OXY improved EMT-related miRNA expression through, for example, lowering the levels of miR-3687 and miR-301a-3p while upregulating miR-3612 in TGF-β-induced HT-29 cells. In conclusion, OXY inhibits human colon cancer cell migration by regulating EMT and miRNAs. Based on these findings, it can be stated that OXY promotes anti-metastatic properties in CRC.
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Affiliation(s)
- Ting-Ann Lin
- Institute of Food Sciences and Technology, National Taiwan University, Taipei 10617, Taiwan.
| | - Wei-Sheng Lin
- Institute of Food Sciences and Technology, National Taiwan University, Taipei 10617, Taiwan.
| | - Ya-Chun Chou
- Institute of Food Sciences and Technology, National Taiwan University, Taipei 10617, Taiwan.
| | | | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Min-Hisung Pan
- Institute of Food Sciences and Technology, National Taiwan University, Taipei 10617, Taiwan. .,Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
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12
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Shen Y, Lu H, Song G. MiR-221-3p and miR-92a-3p enhances smoking-induced inflammation in COPD. J Clin Lab Anal 2021; 35:e23857. [PMID: 34097306 PMCID: PMC8274981 DOI: 10.1002/jcla.23857] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/29/2021] [Accepted: 04/10/2021] [Indexed: 12/23/2022] Open
Abstract
Background Smoking is likely to facilitate airway inflammation and finally contributes to chronic obstructive pulmonary disease (COPD). This investigation was intended to elucidate miRNAs that were involved in smoking‐induced COPD. Methods Altogether 155 COPD patients and 77 healthy volunteers were recruited, and their serum levels of miR‐221‐3p and miR‐92a‐3p were determined. Besides, human bronchial epithelial cells (16HBECs) were purchased, and they were treated by varying concentrations of cigarette smoke extract (CSE). The 16HBECs were, additionally, transfected by miR‐221‐3p mimic, miR‐92a‐3p mimic, miR‐221‐3p inhibitor or miR‐92a‐3p inhibitor, and cytokines released by them, including TNF‐α, IL‐8, IL‐1β, and TGF‐β1, were monitored using enzyme linked immunosorbent assay (ELISA) kits. Results Chronic obstructive pulmonary disease patients possessed higher serum levels of miR‐221‐3p and miR‐92a‐3p than healthy volunteers (p < 0.05), and both miR‐221‐3p and miR‐92a‐3p were effective biomarkers in diagnosing stable COPD from acute exacerbation COPD. Moreover, viability of 16HBECs was undermined by CSE treatment (p < 0.05), and exposure to CSE facilitated 16HBECs’ release of TNF‐α, IL‐8, IL‐1β, and TGF‐β1 (p < 0.05). Furthermore, miR‐221‐3p/miR‐92a‐3p expression in 16HBECs was significantly suppressed after transfection of miR‐221‐3p/miR‐92a‐3p inhibitor (p < 0.05), which abated CSE‐triggered increase in cytokine production and decline in viability of 16HBECs (p < 0.05). Conclusion MiR‐221‐3p and miR‐92a‐3p were involved in CSE‐induced hyperinflammation of COPD, suggesting that they were favorable alternatives in diagnosing COPD patients with smoking history.
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Affiliation(s)
- Yahui Shen
- Department of Respiratory and Critical Care Medicine, Taizhou Clinical Medical School of Nanjing Medical University (Taizhou People's Hospital), Taizhou, China
| | - Huiyu Lu
- Department of Respiratory and Critical Care Medicine, Taizhou Clinical Medical School of Nanjing Medical University (Taizhou People's Hospital), Taizhou, China
| | - Guixian Song
- Department of Cardiology, Taizhou Clinical Medical School of Nanjing Medical University (Taizhou People's Hospital), Taizhou, China
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13
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Long W, Liu S, Li XX, Shen X, Zeng J, Luo JS, Li KR, Wu AG, Yu L, Qin DL, Hu GQ, Yang J, Wu JM. Whole transcriptome sequencing and integrated network analysis elucidates the effects of 3,8-Di-O-methylellagic acid 2-O-glucoside derived from Sanguisorba offcinalis L., a novel differentiation inducer on erythroleukemia cells. Pharmacol Res 2021; 166:105491. [PMID: 33582247 DOI: 10.1016/j.phrs.2021.105491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/05/2020] [Accepted: 02/09/2021] [Indexed: 12/30/2022]
Abstract
Acute erythroid leukemia (AEL) is a rare and aggressive hematologic malignancy with no specific treatment. Sanguisorba officinalis L. (S. officinalis), a well-known traditional Chinese medicine, possesses potent anticancer activity. However, the active components of S. officinalis against AEL and the associated molecular mechanisms remain unknown. In this study, we predicted the anti-AML effect of S. officinalis based on network pharmacology. Through the identification of active components of S. officinalis, we found that 3,8-Di-O-methylellagic acid 2-O-glucoside (DMAG) not only significantly inhibited the proliferation of erythroleukemic cell line HEL, but also induced their differentiation to megakaryocytes. Furthermore, we demonstrated that DMAG could prolong the survival of AEL mice model. Whole-transcriptome sequencing was performed to elucidate the underlying molecular mechanisms associated with anti-AEL effect of DMAG. The results showed that the total of 68 miRNAs, 595 lncRNAs, 4030 mRNAs and 35 circRNAs were significantly differentially expressed during DMAG induced proliferation inhibition and differentiation of HEL cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed miRNAs, lncRNAs, mRNAs and circRNAs were mainly involved in metabolic, HIF-1, MAPK, Notch pathway and apoptosis. The co-expression networks showed that miR-23a-5p, miR-92a-1-5p, miR-146b and miR-760 regulatory networks were crucial for megakaryocyte differentiation induced by DMAG. In conclusion, our results suggest that DMAG, derived from S. officinalis might be a potent differentiation inducer of AEL cells and provide important information on the underlying mechanisms associated with its anti-AEL activity.
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MESH Headings
- Antineoplastic Agents, Phytogenic/chemistry
- Antineoplastic Agents, Phytogenic/pharmacology
- Cell Differentiation/drug effects
- Cell Line, Tumor
- Gene Expression Regulation, Leukemic/drug effects
- Humans
- Leukemia, Erythroblastic, Acute/drug therapy
- Leukemia, Erythroblastic, Acute/genetics
- Leukemia, Erythroblastic, Acute/pathology
- Network Pharmacology
- Sanguisorba/chemistry
- Transcriptome/drug effects
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Affiliation(s)
- Wang Long
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Sha Liu
- School of Preclinical Medicine, Southwest Medical University, Luzhou 646000, China
| | - Xiao-Xuan Li
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin 644000, China
| | - Xin Shen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Jing Zeng
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Jie-Si Luo
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Ke-Ru Li
- School of Preclinical Medicine, Southwest Medical University, Luzhou 646000, China
| | - An-Guo Wu
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China; Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou 646000, China
| | - Lu Yu
- School of Preclinical Medicine, Southwest Medical University, Luzhou 646000, China
| | - Da-Lian Qin
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China; Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou 646000, China
| | - Guang-Qiang Hu
- School of Preclinical Medicine, Southwest Medical University, Luzhou 646000, China.
| | - Jing Yang
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
| | - Jian-Ming Wu
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China; Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou 646000, China.
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14
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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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15
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The Role of miRNAs, miRNA Clusters, and isomiRs in Development of Cancer Stem Cell Populations in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22031424. [PMID: 33572600 PMCID: PMC7867000 DOI: 10.3390/ijms22031424] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/17/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) during development and altered expression can cause developmental defects and/or disease. Indeed, aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has been linked to many cancers. Mounting evidence also indicates a role for miRNAs in the development of the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current research on miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentially expressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genes to influence CSC phenotype. Accordingly, we discuss the specific miRNA cluster classifications and isomiRs that are predicted to target the ALDH1, CD166, BMI1, LRIG1, and LGR5 SC genes. miR-23b and miR-92A are of particular interest because our previously reported studies on miRNA expression in isolated normal versus malignant human colonic SCs showed that miR-23b and miR-92a are regulators of the LGR5 and LRIG1 SC genes, respectively. We also identify additional miRNAs whose expression inversely correlated with mRNA levels of their target genes and associated with CRC patient survival. Altogether, our deliberation on miRNAs, their clusters, and isomiRs in regulation of SC genes could provide insight into how dysregulation of miRNAs leads to the emergence of different CSC populations and SC overpopulation in CRC.
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16
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Saberinia A, Alinezhad A, Jafari F, Soltany S, Akhavan Sigari R. Oncogenic miRNAs and target therapies in colorectal cancer. Clin Chim Acta 2020; 508:77-91. [DOI: 10.1016/j.cca.2020.05.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 12/18/2022]
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17
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Brînzan C, Aşchie M, Cozaru G, Dumitru E, Mitroi A. The diagnostic value of miR-92a, -143, and -145 expression levels in patients with colorectal adenocarcinoma from Romania. Medicine (Baltimore) 2020; 99:e21895. [PMID: 32871920 PMCID: PMC7458237 DOI: 10.1097/md.0000000000021895] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
MicroRNAs (miRNAs) refers to a small, short non-coding RNA of endogenous class. They have shown to have an increasingly altered expression in many types of cancer, including colorectal cancer (CRC).In the present study, miRNA TaqManMGB and qRT-PCR was used to quantify the expression and clinical significance of 3 mature human miRNA in 82 pairs of colorectal adenocarcinoma tissues and normal adjacent tissue samples (NATS) collected from patients of the south-east part of Romania. Differences between CRC and NATS were analyzed using Wilcoxon test, while correlations between miRNAs expression levels and clinicopathological features were examined using non-parametric tests. In addition, the ability of selected miRNAs to function as biomarkers and, as potential indicators in CRC prognosis was also examined.When the miRNA expression was compared in CRC related NATS, miR-143, and miR-145 were significantly underexpressed (4.99 ± -1.02 vs -5.66 ± -1.66, P < .001; -4.85 ± -0.59 vs -9.27 ± -1.51, P < .001, respectively), while the pattern of miR-92a was significantly overexpressed (-5.55 ± -2.83 vs -4.92 ± -2.44, P < .001). Moreover, the expression levels of selected miRNAs were identified to be correlated with gradual increases in fold change expression with the depth of tumor invasion, lymph node invasion, and maximal increases with distant metastasis. Furthermore, the receiver operating characteristic analysis demonstrated that potential diagnostic of miR-143, miR-145, and miR-92a in discriminating CRC from NATS, with the area under the curve of 0.74, 0.85, and 0.84 respectively. The Kaplan-Meier and the log-rank test showed that a high level of miR-92a and low levels of miR-143 and miR-145 predicted poor survival rate in our cohorts.In conclusion, we can summarize that miR-145 and miR-143 are decreased, while miR-92 is increased in CRC compared to NATS, and associated with different stages of CRC pathogenesis. Thus, the expression of selected miRNAs can represent potential diagnostic and prognostic tools in patients with CRC from Romania.
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Affiliation(s)
- Costel Brînzan
- Pathology Department, Sf. Apostol Andrei Clinical Emergency County Hospital
- CEDMOG Center, Ovidius University
| | - Mariana Aşchie
- Pathology Department, Sf. Apostol Andrei Clinical Emergency County Hospital
| | - Georgeta Cozaru
- Pathology Department, Sf. Apostol Andrei Clinical Emergency County Hospital
- CEDMOG Center, Ovidius University
| | - Eugen Dumitru
- CEDMOG Center, Ovidius University
- Gastroenterology Department, Sf. Apostol Andrei Clinical Emergency County Hospital, Constanta, Romania
| | - Anca Mitroi
- Pathology Department, Sf. Apostol Andrei Clinical Emergency County Hospital
- CEDMOG Center, Ovidius University
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18
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Shi Y, Liu Z. Serum miR-92a-1 is a novel diagnostic biomarker for colorectal cancer. J Cell Mol Med 2020; 24:8363-8367. [PMID: 32562465 PMCID: PMC7412696 DOI: 10.1111/jcmm.15282] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 02/25/2020] [Accepted: 03/27/2020] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, with high mortality. Abnormally expressed microRNAs (miRNAs) are considered novel biomarkers in cancer diagnosis. The aim of this study was to investigate the diagnostic value of miR‐92a‐1 in patients with CRC. Serum samples were collected from 148 patients pathologically diagnosed with CRC and 68 gender‐ and age‐matched healthy volunteers. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to measure serum miR‐92a‐1 level. Relationship between miR‐92a‐1 and clinicopathological features of CRC cases was analysed via chi‐square test. Receiver operating characteristic (ROC) curve was plotted to estimate the diagnostic value of miR‐92a‐1 in CRC. Serum miR‐92a‐1 was significantly up‐regulated in CRC patients compared with healthy individuals (P < .001). Moreover, miR‐92a‐1 expression was correlated with TNM stage (P = .02), histological stage (P = .003), lymph node metastasis (P = .003) and distant metastasis (P < .001). ROC analysis showed that the area under the ROC curve (AUC) was 0.914, suggesting high diagnostic accuracy of miR‐92a‐1 in ROC. The optimal cut‐off value was 1.485, with a sensitivity of 81.8% and a specificity of 95.6%. MiR‐92a‐1 is increased in CRC patients and correlated with aggressive clinical characteristics. Serum miR‐92a‐1 may be a potential diagnostic biomarker for CRC.
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Affiliation(s)
- Ying Shi
- Department of Oncology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Zhibao Liu
- Department of Oncology, Cangzhou Central Hospital, Cangzhou, Hebei, China
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19
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MicroRNA Expression Profiling of Normal and Malignant Human Colonic Stem Cells Identifies miRNA92a as a Regulator of the LRIG1 Stem Cell Gene. Int J Mol Sci 2020; 21:ijms21082804. [PMID: 32316543 PMCID: PMC7216254 DOI: 10.3390/ijms21082804] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 04/13/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) have a critical role in regulating stem cells (SCs) during development, and because aberrant expression of miRNAs occurs in various cancers, our goal was to determine if dysregulation of miRNAs is involved in the SC origin of colorectal cancer (CRC). We previously reported that aldehyde dehydrogenase (ALDH) is a marker for normal and malignant human colonic SCs and tracks SC overpopulation during colon tumorigenesis. MicroRNA expression was studied in ALDH-positive SCs from normal and malignant human colon tissues by Nanostring miRNA profiling. Our findings show that: (1) A unique miRNA signature distinguishes ALDH-positive CRC cells from ALDH-positive normal colonic epithelial cells, (2) Expression of four miRNAs (miRNA200c, miRNA92a, miRNA20a, miRNA93) are significantly altered in CRC SCs compared to normal colonic SCs, (3) miRNA92a expression is also upregulated in ALDH-positive HT29 CRC SCs as compared to ALDH-negative SCs, (4) miRNA92a targets the 3′UTR of LRIG1 SC gene, and (5) miRNA92a modulates proliferation of HT29 CRC cells. Thus, our findings indicate that overexpression of miRNA92a contributes to the SC origin of CRC. Strategies designed to modulate miRNA expression, such as miRNA92a, may provide ways to target malignant SCs and to develop more effective therapies against CRC.
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Szczepaniak A, Fichna J, Zielińska M. Opioids in Cancer Development, Progression and Metastasis: Focus on Colorectal Cancer. Curr Treat Options Oncol 2020; 21:6. [PMID: 31970561 PMCID: PMC6976545 DOI: 10.1007/s11864-019-0699-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OPINION STATEMENT So far, opioids have been successfully used to reduce cancer pain in patients in order to improve their quality of life. However, the use of opioids leads to numerous side effects such as constipation, drowsiness, nausea, itching, increased sweating and hormonal changes. In this review, we described the action of opioids in several molecular pathways significant for maintenance of the intestinal homeostasis including the impact on the intestinal epithelium integrity, changes in microbiome composition, modulation of the immune system or induction of apoptosis and inhibition of angiogenesis. We summed up the role of individual opioids in the processes involved in the growth and development of cancer and elucidated if targeting opioid receptors may constitute novel therapeutic option in colon cancer.
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Affiliation(s)
- Adrian Szczepaniak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Marta Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
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21
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Guan NN, Wang CC, Zhang L, Huang L, Li JQ, Piao X. In silico prediction of potential miRNA-disease association using an integrative bioinformatics approach based on kernel fusion. J Cell Mol Med 2019; 24:573-587. [PMID: 31747722 PMCID: PMC6933403 DOI: 10.1111/jcmm.14765] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 08/13/2019] [Accepted: 09/20/2019] [Indexed: 12/18/2022] Open
Abstract
Accumulating experimental evidence has demonstrated that microRNAs (miRNAs) have a huge impact on numerous critical biological processes and they are associated with different complex human diseases. Nevertheless, the task to predict potential miRNAs related to diseases remains difficult. In this paper, we developed a Kernel Fusion-based Regularized Least Squares for MiRNA-Disease Association prediction model (KFRLSMDA), which applied kernel fusion technique to fuse similarity matrices and then utilized regularized least squares to predict potential miRNA-disease associations. To prove the effectiveness of KFRLSMDA, we adopted leave-one-out cross-validation (LOOCV) and 5-fold cross-validation and then compared KFRLSMDA with 10 previous computational models (MaxFlow, MiRAI, MIDP, RKNNMDA, MCMDA, HGIMDA, RLSMDA, HDMP, WBSMDA and RWRMDA). Outperforming other models, KFRLSMDA achieved AUCs of 0.9246 in global LOOCV, 0.8243 in local LOOCV and average AUC of 0.9175 ± 0.0008 in 5-fold cross-validation. In addition, respectively, 96%, 100% and 90% of the top 50 potential miRNAs for breast neoplasms, colon neoplasms and oesophageal neoplasms were confirmed by experimental discoveries. We also predicted potential miRNAs related to hepatocellular cancer by removing all known related miRNAs of this cancer and 98% of the top 50 potential miRNAs were verified. Furthermore, we predicted potential miRNAs related to lymphoma using the data set in the old version of the HMDD database and 80% of the top 50 potential miRNAs were confirmed. Therefore, it can be concluded that KFRLSMDA has reliable prediction performance.
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Affiliation(s)
- Na-Na Guan
- College of Big Data Statistics, Guizhou University of Finance and Economics, Guiyang, China.,College of Computer Science and Software Engineering, Shenzhen University, Shenzhen, China
| | - Chun-Chun Wang
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Li Zhang
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Li Huang
- Academy of Arts and Design, Tsinghua University, Beijing, China.,The Future Laboratory, Tsinghua University, Beijing, China
| | - Jian-Qiang Li
- College of Computer Science and Software Engineering, Shenzhen University, Shenzhen, China
| | - Xue Piao
- School of Medical Informatics, Xuzhou Medical University, Xuzhou, China
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22
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Peng Y, Huang D, Qing X, Tang L, Shao Z. Investigation of MiR-92a as a Prognostic Indicator in Cancer Patients: a Meta-Analysis. J Cancer 2019; 10:4430-4441. [PMID: 31413763 PMCID: PMC6691717 DOI: 10.7150/jca.30313] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 06/23/2019] [Indexed: 12/30/2022] Open
Abstract
Background: MiR-92a has been discovered to be involved in the malignant behavior of various types of cancers. However, the particular clinical and prognostic roles of miR-92a in tumors still need to be identified more precisely. The current meta-analysis assessed the prognostic value of miR-92a in various carcinomas. Methods: Systematic literature searches of PubMed, PMC, Web of Science (WOS), Embase in English and Wanfang, SinoMed and the China National Knowledge Infrastructure (CNKI) in Chinese up to Jan 15th 2019 were conducted for eligible studies. Twenty studies involving a total of 2573 patients were included in the analysis. Pooled hazard ratios (HR) for overall survival (OS) and disease-free survival (DFS), progression-free survival (PFS) and recurrence-free survival (RFS) were assessed using fixed-effects and random-effects models. Meta-regression and subgroup analyses were carried out to explore the source of heterogeneity. Odds ratio (OR) and 95%CIs were applied to evaluate the relationship between miR-92a expression levels and clinicopathological characteristics. Results: A significant association between miR-92a levels and OS (HR=2.18) was identified. The random pooling model also revealed significance of consistency (HR=2.14), indicating that the stability of the results. Subgroup analyses were performed and the corresponding significance was recognized in Chinese cancer patients (HR=2.35), studies of specimen derived from tissues (HR=2.43), non-hematological cancer (HR=2.35), osteosarcoma (HR=2.54), non-small cell lung cancer (HR=2.33), hepatocellular carcinoma (HR=2.40) and so on. There were significant relations observed of the expression level of miR-92a to tumor size (≥5 vs <5 cm) (OR=2.13), lymph node metastasis (present vs. absent) (OR=1.87), distant metastasis (present vs. absent) (OR=2.99) and so on. Conclusions: the over expression of miR-92a is associated with unfavorable prognosis of Chinese cancer patients. In addition, patients of elevated miR-92a expression level are likely to develop the cancers of more malignant behaviors.
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Affiliation(s)
- Yizhong Peng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Donghua Huang
- Musculoskeletal Tumor Center, Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Xiangcheng Qing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lu Tang
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Peng Q, Shen Y, Lin K, Zou L, Shen Y, Zhu Y. Identification of microRNA-92a and the related combination biomarkers as promising substrates in predicting risk, recurrence and poor survival of colorectal cancer. J Cancer 2019; 10:3154-3171. [PMID: 31289586 PMCID: PMC6603388 DOI: 10.7150/jca.30306] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 04/28/2019] [Indexed: 12/15/2022] Open
Abstract
Background: Previous studies demonstrated that microRNA-92a (miR-92a) may serve as a novel promising biomarker in colorectal cancer (CRC) patients. However, a comprehensive analysis of the contribution of miR-92a in CRC is lacking. We aimed to systematically summarize the diagnostic and prognostic values of miR-92a in CRC. Methods: The diagnostic and prognostic roles of individual miR-92a and the combination biomarkers based on miR-92a were evaluated through comprehensive meta-analyses. Meanwhile, the function and potential mechanisms of miR-92a were assessed by an integrative bioinformatics analysis. Results: According to the results, we found that miR-92a yielded a pooled area under ROC curve (AUC) of 0.82 (sensitivity: 76%, specificity: 75%) in discriminating CRC from controls. Notably, the combination biomarkers based on miR-92a increased the diagnostic performance, yielding an AUC of 0.91, with a sensitivity of 83% and a specificity of 87%. For the prognostic meta-analysis, patients with higher expression of miR-92a had significant shorter overall survival (pooled HR: 2.30; 95% CI: 1.03-5.12). In addition, the regulated genes of miR-92a were retrieved and enriched through gene ontology and pathway analysis, indicating their correlations with the initiation and progression of CRC. Furthermore, protein-protein interaction network was set up with miR-92a targets and screened for hub nodes and significant modules, which were confirmed strongly involved in the occurrence and development of CRC again. Conclusions: Current evidences suggest miR-92a is a promising biomarker for early detection and prognosis of CRC while miRNA combination biomarkers may be considered as the right way for clinical practice. However, more prospective studies are required to highlight the theoretical strengths.
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Affiliation(s)
- Qiliang Peng
- Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China
| | - Yi Shen
- Department of Radiation Oncology, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou Science & Technology Town Hospital, Suzhou, China
| | - Kaisu Lin
- Department of Oncology, Nantong Rich Hospital, Nantong, China
| | - Li Zou
- Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China
| | - Yuntian Shen
- Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China
| | - Yaqun Zhu
- Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China
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MiR-92a modulates proliferation, apoptosis, migration, and invasion of osteosarcoma cell lines by targeting Dickkopf-related protein 3. Biosci Rep 2019; 39:BSR20190410. [PMID: 30926679 PMCID: PMC6487267 DOI: 10.1042/bsr20190410] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 03/21/2019] [Accepted: 03/26/2019] [Indexed: 02/07/2023] Open
Abstract
Osteosarcoma (OS) is recognized as a common malignant tumor with a high trend of metastasis and diffusion. Despite the progresses that have been made in surgery, chemotherapy, and radiotherapy in the recent decades, the prognosis of patients with OS still remains poor. MiRNAs are being increasingly considered as new therapeutic targets for OS treatment. Our research aims to investigate the regulatory impact of miR-92a in the development of OS. Quantitative real-time PCR (qRT-PCR) results revealed that the expression of miR-92a was aberrantly overexpressed in human OS cell lines. By using cell counting kit-8 (CCK-8) assays, colony formation assays, flow cytometric analyses and Transwell assays, our data suggested that up-regulation of miR-92a promoted the proliferation, migration, and invasion of MNNG and U2OS cells, while inhibiting their apoptosis. In contrast, the knockdown of miR-92a effectively reversed these cellular biological behaviors. Furthermore, bioinformatics analysis indicated that Dickkopf-related protein 3 (DKK3) was a possible target of miR-92a. Subsequently, negative regulation of miR-92a on DKK3 was observed, which further supported the direct binding between them. In addition, silencing DKK3 rescued the inhibitory effect of miR-92a inhibitor on the development of OS. To sum up, our study revealed that miR-92a played a carcinogenic role in the growth of OS by promoting the tumorigenesis of OS cells via targeting of DKK3, thus revealing a new therapeutic target for OS.
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25
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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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26
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He F, Fang L, Yin Q. miR-363 acts as a tumor suppressor in osteosarcoma cells by inhibiting PDZD2. Oncol Rep 2019; 41:2729-2738. [PMID: 30896877 PMCID: PMC6448123 DOI: 10.3892/or.2019.7078] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 03/13/2019] [Indexed: 12/03/2022] Open
Abstract
PDZ domain containing 2 (PDZD2) is a multi-PDZ domain protein that promotes the proliferation of insulinoma cells, and is upregulated during prostate tumorigenesis. However, the function of PDZD2 in other cancers, including osteosarcoma (OS), remains unclear. Dysregulation of microRNAs (miRNAs) contributes to tumor initiation, proliferation and metastasis, via the regulation of their target genes. The present study investigated the functions of miR-363 and PDZD2 in MG-63 OS cells. The results revealed that MG-63 cells contained low levels of miR-363, and that overexpression of miR-363 in MG-63 cells significantly inhibited the vitality, proliferation, and colony formation ability of the cells, but promoted their apoptosis and G1/S arrest by regulating proliferating cell nuclear antigen (PCNA) and caspase-3 expression. Additionally, miR-363 impaired the migration and invasion of MG-63 cells by regulating the epithelial-mesenchymal transition (EMT) phenotype. Notably, a bioinformatics analysis and luciferase reporter assay indicated that PDZD2 was a direct target of miR-363. miR-363 overexpression reduced PDZD2 protein levels and knockdown of PDZD2 suppressed the colony formation, migration and invasion of MG-63 cells, but promoted their apoptosis by regulating expression of PCNA, caspase-3, and the EMT phenotype. In vivo studies further confirmed that miR-363 functioned as tumor suppressor, by inhibiting tumor growth, promoting cell apoptosis, and reducing PDZD2 and PCNA levels and the prevalence of the EMT phenotype in tumor tissues. The present data demonstrated that downregulation of the tumor suppressor miR-363 may be involved in the development of osteosarcoma via regulation of PDZD2.
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Affiliation(s)
- Fan He
- Department of Orthopedic, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Long Fang
- Department of Orthopedic, Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China
| | - Qingshui Yin
- Department of Orthopedic, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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Alcantara KMM, Garcia RL. MicroRNA‑92a promotes cell proliferation, migration and survival by directly targeting the tumor suppressor gene NF2 in colorectal and lung cancer cells. Oncol Rep 2019; 41:2103-2116. [PMID: 30816526 PMCID: PMC6412542 DOI: 10.3892/or.2019.7020] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 02/05/2019] [Indexed: 01/29/2023] Open
Abstract
Inactivation of the tumor suppressor protein Merlin leads to the development of benign nervous system tumors in neurofibromatosis type 2 (NF2). Documented causes of Merlin inactivation include deleterious mutations in the encoding neurofibromin 2 gene (NF2) and aberrant Merlin phosphorylation leading to proteasomal degradation. Rare somatic NF2 mutations have also been detected in common human malignancies not associated with NF2, including colorectal and lung cancer. Furthermore, tumors without NF2 mutations and with unaltered NF2 transcript levels, but with low Merlin expression, have been reported. The present study demonstrated that NF2 is also regulated by microRNAs (miRNAs) through direct interaction with evolutionarily conserved miRNA response elements (MREs) within its 3′-untranslated region (3′UTR). Dual-Luciferase assays in human colorectal carcinoma (HCT116) and lung adenocarcinoma (A549) cells revealed downregulation of NF2 by miR-92a-3p via its wild-type 3′UTR, but not NF2−3′UTR with mutated miR-92a-3p MRE. HCT116 cells overexpressing miR-92a-3p exhibited significant downregulation of endogenous NF2 mRNA and protein levels, which was rescued by co-transfection of a target protector oligonucleotide specific for the miR-92a-3p binding site within NF2−3′UTR. miR-92a-3p overexpression in HCT116 and A549 cells promoted migration, proliferation and resistance to apoptosis, as well as altered F-actin organization compared with controls. Knockdown of NF2 by siRNA phenocopied the oncogenic effects of miR-92a overexpression on HCT116 and A549 cells. Collectively, the findings of the present study provide functional proof of the unappreciated role of miRNAs in NF2 regulation and tumor progression, leading to enhanced oncogenicity.
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Affiliation(s)
- Krizelle Mae M Alcantara
- National Institute of Molecular Biology and Biotechnology, University of the Philippines, Diliman, Quezon City 1101, Philippines
| | - Reynaldo L Garcia
- National Institute of Molecular Biology and Biotechnology, University of the Philippines, Diliman, Quezon City 1101, Philippines
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Rezaei N, Talebi F, Ghorbani S, Rezaei A, Esmaeili A, Noorbakhsh F, Hakemi MG. MicroRNA-92a Drives Th1 Responses in the Experimental Autoimmune Encephalomyelitis. Inflammation 2019; 42:235-245. [PMID: 30411211 DOI: 10.1007/s10753-018-0887-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Dysregulation of microRNAs (miRNAs) has been linked to the progress of a number of autoimmune diseases including multiple sclerosis (MS), and its animal model, experimental autoimmune encephalomyelitis (EAE). IFN-γ-producing Th1 cells are major players in MS/EAE pathogenesis. It is known that differentiation of T cells towards the Th1 phenotype is influenced by various factors including miRNAs. The miR-92a shows substantial upregulation in MS; however, little is known about its role in the development of autoimmune and inflammatory responses. Herein, we investigated the role of miR-92a in the pathogenesis of MS, focusing on its potential effects on differentiation of Th1 cells. The expression levels of miR-92a were assessed in the spinal cord tissues and splenocytes from mice with EAE using real-time RT-PCR. Next, using transfection with miR-92a mimic sequences, the potential involvement of miR-92a in Th1 polarization was investigated by flow cytometric analysis. Moreover, the expression levels of miR-92a targets were explored in spinal cord tissues of EAE mice. miR-92a expression was enhanced in mouse spinal cord samples at the peak of EAE disease. Overexpression of miR-92a in splenocytes led to increased differentiation of Th1 cells compared with cells transfected with negative control sequences. Enhanced miR-92a expression was accompanied by reduced expression TSC1 or DUSP10, predicted miR-92a targets, in EAE spinal cords. Our data point to a potential role for miR-92a in neuroinflammatory responses in EAE. Our results indicate that miR-92a might affect Th1 differentiation, likely due to downregulation of TSC1 and DUSP10.
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Affiliation(s)
- Nahid Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farideh Talebi
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Ghorbani
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abolghasem Esmaeili
- Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Chen M, Xu R, Rai A, Suwakulsiri W, Izumikawa K, Ishikawa H, Greening DW, Takahashi N, Simpson RJ. Distinct shed microvesicle and exosome microRNA signatures reveal diagnostic markers for colorectal cancer. PLoS One 2019; 14:e0210003. [PMID: 30608951 PMCID: PMC6319712 DOI: 10.1371/journal.pone.0210003] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 12/14/2018] [Indexed: 12/31/2022] Open
Abstract
Extracellular vesicle (EV) microRNAs are of major interest as potential diagnostic biomarkers in all cancer types. This study aims to identify miRNA profiles of shed microvesicles (sMVs) and exosomes (Exos) secreted from the isogenic colorectal cancer (CRC) cell lines SW480 and SW620 and evaluate their ability to predict CRC. Deep sequencing of miRNAs in parental cell lysates (CLs) and highly-purified sMVs and Exos was performed. We focused on miRNAs enriched in EVs and dysregulated miRNAs in metastatic cells (SW620) relative to primary cancer cells (SW480). We investigated the ability of EV miRNA signatures to predict CRC tumours using 594 tumours (representing different pathological stages) and 11 normal samples obtained from TCGA. In SW480 and SW620 cells we identified 345 miRNAs, of which 61 and 73 were upregulated and downregulated in SW620-CLs compared to SW480-CLs, respectively. Selective distribution of cellular miRNAs into EVs results in distinct miRNA signatures for sMVs and Exos in each cell line. Cross cell line comparisons of EV miRNA profiles reveal a subset of miRNAs critical in CRC progression from primary carcinoma to metastasis. Many miRNAs non-detectable (<5 TPM) in CLs were significantly enriched (>1000 TPM) in secreted EVs. Strikingly, miR-7641 which is non-detectable in SW480-CL but upregulated in SW620-CL is highly enriched in EVs secreted from both cell lines. Pearson correlation analysis demonstrated that EV miRNA profiles can be used to predict CRC tumours with ~96% accuracy. Our findings suggest that EV miRNA profiles from CRC cell lines may allow prediction of CRC tumours, and that miR-7641 may serve as an attractive candidate for the specific, non-invasive diagnosis and prognosis of CRC.
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Affiliation(s)
- Maoshan Chen
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, Australia
- * E-mail: (MC); (RJS)
| | - Rong Xu
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, Australia
| | - Alin Rai
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, Australia
| | - Wittaya Suwakulsiri
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, Australia
| | - Keiichi Izumikawa
- Department of Applied Biological Science, Graduate School of Agriculture, and Global Innovation Research Organisation, Tokyo University of Agriculture and Technology, Tokyo Japan
| | - Hideaki Ishikawa
- Department of Applied Biological Science, Graduate School of Agriculture, and Global Innovation Research Organisation, Tokyo University of Agriculture and Technology, Tokyo Japan
| | - David W. Greening
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, Australia
| | - Nobuhiro Takahashi
- Department of Applied Biological Science, Graduate School of Agriculture, and Global Innovation Research Organisation, Tokyo University of Agriculture and Technology, Tokyo Japan
| | - Richard J. Simpson
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, Australia
- * E-mail: (MC); (RJS)
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30
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Guo J, Wen N, Yang S, Guan X, Cang S. MiR-92a regulates oral squamous cell carcinoma (OSCC) cell growth by targeting FOXP1 expression. Biomed Pharmacother 2018; 104:77-86. [DOI: 10.1016/j.biopha.2018.05.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 04/27/2018] [Accepted: 05/07/2018] [Indexed: 01/06/2023] Open
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Wu X, Wu Y, He L, Wu L, Wang X, Liu Z. Effects of the intestinal microbial metabolite butyrate on the development of colorectal cancer. J Cancer 2018; 9:2510-2517. [PMID: 30026849 PMCID: PMC6036887 DOI: 10.7150/jca.25324] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 05/02/2018] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is one of the major health threats in developed countries. Changes in dietary components, such as more protein and lipid intake, can increase the risk of CRC. Diet affects CRC in many ways. They regulate the composition and function of gut microbiota, which have an amazing metabolic capacity and can produce short chain fatty acids (SCFAs), such as propionate, acetate, and butyrate. Butyrate is a principal energy source for colonic epithelial cells and plays an important role in maintaining the stability of gut microbiota and the integrity of intestinal epithelium. However, there are few studies reviewing the anti-CRC potentials of butyrate. This review summarizes the recent research progresses in the effect of gut microbiota imbalance and the decrease in intestinal microbial metabolite butyrate caused by unbalanced diet on CRC development, and discusses the mechanisms of butyrate-induced anti-CRC activities, which may guide people to prevent CRC by improving diet structures.
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Affiliation(s)
- Xinqiang Wu
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Yuanbing Wu
- The First People's Hospital of Jiashan County, Jiaxing, Zhejiang, China
| | - Liangmei He
- The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Longhuo Wu
- College of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiangcai Wang
- The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Zhiping Liu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
- Ganzhou Cancer Precision Engineering Research Center, Ganzhou, Jiangxi, China
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32
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Jepsen RK, Novotny GW, Klarskov LL, Bang-Berthelsen CH, Haakansson IT, Hansen A, Christensen IJ, Riis LB, Høgdall E. Early metastatic colorectal cancers show increased tissue expression of miR-17/92 cluster members in the invasive tumor front. Hum Pathol 2018; 80:231-238. [PMID: 29902577 DOI: 10.1016/j.humpath.2018.05.027] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 04/28/2018] [Accepted: 05/22/2018] [Indexed: 01/05/2023]
Abstract
Accurate prediction of regional lymph node metastases (LNM) in endoscopically resected pT1 colorectal cancer (CRC) is crucial in treatment stratification for subsequent radical surgery. Several miRNAs have been linked to CRC invasion and metastasis, including the oncogenic miR-17/92 cluster, and expression levels might have predictive value in the risk assessment of early metastatic progression in CRC. We performed global miRNA microarray using tissue samples from the invasive front of pT1 CRC and investigated associations of the miR-17/92 cluster and presence of LNM. In total, 56 matched pT1 CRCs were thoroughly clinicopathologically characterized, and miRNA microarrays were performed on invasive front tissue samples. Global miRNA intensities were screened using paired t-tests between pT1pN+ and pT1pN0. Associations between miR-17/92 and histopathological features were analyzed using general linear models and tumor cell adjusted expression intensities. miR-17-3p and miR-92a were significantly higher expressed in the invasive front of tumors with LNM compared to those without, corresponding to 1.53-fold higher expression of miR-17-3p (95%CI: 1.04-2.24, P = .030) and 1.28-fold higher expression of miR-92a (95%CI: 1.01-1.68, P = .042). An inverse association between miR-19a and presence of high-grade tumor budding was observed (1.55-fold, 95%CI: 1.13-2.12, P = .008). We provide evidence for associations between early regional LNM and high expression levels of the miR-17/92 cluster members: miR-17-3p and miR-92a, in the invasive front of CRC. Our results support a role for the miR-17/92 cluster in early metastatic progression of CRC and calls for further investigation.
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Affiliation(s)
- Rikke Karlin Jepsen
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospitals, 2730 Herlev, Denmark.
| | - Guy Wayne Novotny
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospitals, 2730 Herlev, Denmark.
| | - Louise Laurberg Klarskov
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospitals, 2730 Herlev, Denmark.
| | - Claus Heiner Bang-Berthelsen
- Technical University of Denmark, National Food Institute, Research Group for Microbial Biotechnology and Biorefining, 2800 Kgs Lyngby, Denmark.
| | | | - Anker Hansen
- Medical Prognosis Institute A/S, 2970 Hørsholm, Denmark.
| | - Ib Jarle Christensen
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospitals, 2730 Herlev, Denmark.
| | - Lene Buhl Riis
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospitals, 2730 Herlev, Denmark.
| | - Estrid Høgdall
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospitals, 2730 Herlev, Denmark.
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33
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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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34
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Yin Z, Yang J, Ning R, Liu Y, Feng M, Gu C, Fei J, Li Y. Signal pathways, diseases, and functions associated with the miR-19a/92a cluster and the use of berberine to modulate the expression of this cluster in multiple myeloma cells. J Biochem Mol Toxicol 2018; 32:e22057. [PMID: 29687521 DOI: 10.1002/jbt.22057] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 03/27/2018] [Accepted: 04/02/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Berberine downregulated miR-19a/92a cluster expression in multiple myeloma (MM) cells. METHODS The cell viability of MM cells after berberine treatment was measured by CCK8 assay. qRT-PCR assay validated miR-19a/92a expression in multiple myeloma cells. TAM database analyzed miR-19a/92a-associated disease. miREnvironment database revealed that effects of environmental factors on the miR-19a/92a cluster. By targeting the seed region in the miRNA, the role of t-anti-miR-19a/92a cluster was evaluated by cell proliferation, migration, and colony formation. RESULTS Berberine inhibited the cell viability of MM cells and downregulated the expression of miR-19a/92a. Seven kinds of hematological malignancies are closely associated with miR-19a/92a expression. By targeting the seed region of the miRNA, t-anti-miR-19a/92a significantly inhibits multiple myeloma cell proliferation, migration, and colony formation. CONCLUSION Our findings may exhibit that miR-19a/92a cluster is a therapeutic target for MM and provide new mechanistic insight into the anti-MM effects of certain compounds in traditional Chinese herbal medicines.
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Affiliation(s)
- Zhao Yin
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China.,Engineering Technology Research Center of drug development for small nucleic acid, Guangdong, China.,Institute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China.,Antisense Biopharmaceutical technology co., Ltd., Guangzhou, China
| | - Juhua Yang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China.,Engineering Technology Research Center of drug development for small nucleic acid, Guangdong, China
| | - Rong Ning
- Department of Clinical Medicine, Medical College of Jinan University, Guangzhou 510632, China
| | - Yanjun Liu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China
| | - Maoxiao Feng
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China
| | - Chunmin Gu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China.,Engineering Technology Research Center of drug development for small nucleic acid, Guangdong, China.,Institute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China
| | - Jia Fei
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China.,Engineering Technology Research Center of drug development for small nucleic acid, Guangdong, China.,Institute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China.,Department of Clinical Medicine, Medical College of Jinan University, Guangzhou 510632, China
| | - Yumin Li
- Antisense Biopharmaceutical technology co., Ltd., Guangzhou, China.,Medical Laboratory of Shen zhen Luohu People's Hospital
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35
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Chen W, Lin G, Yao Y, Chen J, Shui H, Yang Q, Wang X, Weng X, Sun L, Chen F, Yang S, Yang Y, Zhou Y. MicroRNA hsa-let-7e-5p as a potential prognosis marker for rectal carcinoma with liver metastases. Oncol Lett 2018; 15:6913-6924. [PMID: 29731866 DOI: 10.3892/ol.2018.8181] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 01/19/2018] [Indexed: 12/20/2022] Open
Abstract
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that target mRNAs for translational repression or cleavage. The present study was conducted to identify differentially expressed miRNAs in primary tumor tissues of rectal carcinoma (RC) that may be associated with heterochrony hepatic metastasis (HHM). Samples were collected exclusively from patients with RC but not colon cancer (CC); Next-generation high-throughput sequencing technology and bioinformatics tools were used to profile and analyze small RNAs and their corresponding targets in primary tumor tissues with HHM (n=2) or without metastases (non-metastatic, NM; n=2). A total of 24 known miRNAs were identified to be differentially expressed (P<0.01; absolute value of log2-fold change ≥1). Hsa-let-7e-5p exhibited the most significant elevation in tissues with HHM (log2-fold change=2.62). By combining online informatics resources and previous mRNA sequencing data, it was identified that 54 validated target genes of let-7e were downregulated in primary tumor tissues with HHM. A number of these target genes have been demonstrated to be directly involved in tumor metastasis (including MYC proto-oncogene, bHLH transcription factor, high-mobility group AT-Hook 2, peptidase inhibitor 3, KIT proto-oncogene receptor tyrosine kinase, Jun proto-oncogene, AP-1 transcription factor subunit and ribonuclease T2), or have physiological associations to immunity (including C-C motif chemokine receptor 4 and cluster of differentiation 40 ligand) and cellular metabolism (including peroxisome proliferator-activated receptor γ, coactivator 1 α). Next, 14 target genes were selected for reverse transcription-quantitative polymerase chain reaction analysis in non-sequenced samples, and the downregulation of 10 target genes in RC samples with HHM was confirmed. In addition, it was demonstrated that hsa-let-7e-5p stimulated colorectal cancer cell migration in vitro. The miRNA hsa-let-7e-5p may serve as a potential biomarker for rectal carcinoma-associated HHM, facilitating the identification of patients with RC who are at risk of developing HHM.
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Affiliation(s)
- Wenfeng Chen
- Institute of Life Sciences, College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Guosheng Lin
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yizhou Yao
- Institute of Life Sciences, College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Jishen Chen
- Institute of Life Sciences, College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Hanli Shui
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Qinghai Yang
- Department of Molecular Pathology, Fuzhou Maixin Biotech., Co., Ltd., Fuzhou, Fujian 350001, P.R. China
| | - Xiaoya Wang
- Department of Molecular Pathology, Fuzhou Maixin Biotech., Co., Ltd., Fuzhou, Fujian 350001, P.R. China
| | - Xiaoyuan Weng
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Ling Sun
- Institute of Life Sciences, College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Fei Chen
- Institute of Life Sciences, College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Sheng Yang
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yufeng Yang
- Institute of Life Sciences, College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Yongjian Zhou
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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36
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Zhang X, Li Y, Qi P, Ma Z. Biology of MiR-17-92 Cluster and Its Progress in Lung Cancer. Int J Med Sci 2018; 15:1443-1448. [PMID: 30443163 PMCID: PMC6216058 DOI: 10.7150/ijms.27341] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 07/29/2018] [Indexed: 12/18/2022] Open
Abstract
MicroRNAs, a class of short endogenous RNAs, acting as post-transcriptional regulators of gene expression, mostly silence gene expression via binding imperfectly matched sequences in the 3'UTR of target mRNA. MiR-17-92, a highly conserved gene cluster, has 6 members including miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92a. The miR-17-92 cluster, regarded as oncogene, is overexpressed in human cancers. Lung cancer is the leading cause of death all over the world. The molecular mechanism of lung cancer has been partly known at the levels of genes and proteins in last decade. However, new prognosis biomarkers and more target drugs should be developed in future. Therefore, noncoding RNAs, especially miRNAs, make them as new potentially clinical biomarkers for diagnosis and prognosis. In this review, we focus the current progress of miR-17-92 cluster in lung cancer.
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Affiliation(s)
- Xinju Zhang
- Lab for Noncoding RNA & Cancer, School of Life Sciences Shanghai University, Shanghai 200444
| | - Yanli Li
- Lab for Noncoding RNA & Cancer, School of Life Sciences Shanghai University, Shanghai 200444
| | - Pengfei Qi
- Lab for Noncoding RNA & Cancer, School of Life Sciences Shanghai University, Shanghai 200444
| | - Zhongliang Ma
- Lab for Noncoding RNA & Cancer, School of Life Sciences Shanghai University, Shanghai 200444
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37
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Zhang GJ, Li LF, Yang GD, Xia SS, Wang R, Leng ZW, Liu ZL, Tian HP, He Y, Meng CY, Liu DZ, Hou SL, Tang XG, Zhou T. MiR-92a promotes stem cell-like properties by activating Wnt/β-catenin signaling in colorectal cancer. Oncotarget 2017; 8:101760-101770. [PMID: 29254202 PMCID: PMC5731912 DOI: 10.18632/oncotarget.21667] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 09/18/2017] [Indexed: 12/11/2022] Open
Abstract
We previously reported the oncogenic function of miR-92a in colorectal cancer. This study identified that miR-92a was upregulated in chemoresistant colorectal cancer cells and tissues. Ectopic expression of miR-92a conferred resistance to 5-fluorouracil-induced apoptosis in vitro, while antagomiR-92a significantly enhanced chemosensitivity in vivo. Moreover, Overexpression of miR-92a promoted the tumor sphere formation and the expression of stem cell markers. MiR-92a overexpression also displayed higher tumourigenesis in vivo. Furthermore, we demonstrated that miR-92a upregulates the Wnt/β-catenin signaling activity via directly targeting KLF4, GSK3β and DKK3, which are multiple level negative regulators of the Wnt/β-catenin signaling cascade. In addition, our results indicate IL-6/STAT3 pathway increases miR-92a expression by directly targeting its promoter, resulting in Wnt/β-catenin signaling activation and consequent promotion of stem-like phenotypes of colorectal cancer cells. Our present results suggest the essential role of IL-6/STAT3/miR-92a/Wnt/β-catenin pathway in regulating the stem cell-like traits of colorectal cancer cells and provide a potential target for colorectal cancer therapy.
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Affiliation(s)
- Guang-Jun Zhang
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.,Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Li-Fa Li
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.,Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Guo-Dong Yang
- Department of Gastroenterology, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Shu-Sen Xia
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Rong Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou, China
| | - Zheng-Wei Leng
- Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Zuo-Liang Liu
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Hong-Peng Tian
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yi He
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Chang-Yuan Meng
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Dai-Zhi Liu
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Song-Lin Hou
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xue-Gui Tang
- Anorectal Department of Integrated Traditional Chinese and Western Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Tong Zhou
- The Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.,Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, China
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38
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Lv M, Chen H, Shao Y, Li C, Zhang W, Zhao X, Jin C, Xiong J. miR-92a regulates coelomocytes apoptosis in sea cucumber Apostichopus japonicus via targeting Aj14-3-3ζ in vivo. FISH & SHELLFISH IMMUNOLOGY 2017; 69:211-217. [PMID: 28860073 DOI: 10.1016/j.fsi.2017.08.033] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 08/21/2017] [Accepted: 08/27/2017] [Indexed: 06/07/2023]
Abstract
miR-92a, a well-documented oncogene, was previously found to be differentially expressed in diseased sea cucumber Apostichopus japonicus by high-throughput sequencing. In this study, we identified Aj14-3-3ζ as a novel target of miR-92a in this species and investigated their regulatory roles in vivo. The negative expression profiles between miR-92a and Aj14-3-3ζ protein were detected in both LPS-exposed primary coelomocytes and Vibrio splendidus-challenged sea cucumbers. Over-expression of miR-92a by injection of miR-92a agomir significantly depressed the mRNA and protein expression of Aj14-3-3ζ and promoted coelomocytes apoptosis with 5.04-fold increase in vivo, which was consistent with those from siRNA-mediated Aj14-3-3ζ knockdown assay. In contrast, miR-92a antagomir significantly elevated the mRNA and protein expression of Aj14-3-3ζ and decreased coelomocytes apoptosis. Taken together, our result confirmed that miR-92a is involved in apoptotic signaling pathway regulation perhaps via targeting Aj14-3-3ζ in sea cucumbers, which will enhance our understanding of miR-92a regulatory roles in sea cucumber pathogenesis.
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Affiliation(s)
- Miao Lv
- School of Marine Sciences, Ningbo University, PR China
| | - Huahui Chen
- School of Marine Sciences, Ningbo University, PR China
| | - Yina Shao
- School of Marine Sciences, Ningbo University, PR China
| | - Chenghua Li
- School of Marine Sciences, Ningbo University, PR China.
| | - Weiwei Zhang
- School of Marine Sciences, Ningbo University, PR China
| | - Xuelin Zhao
- School of Marine Sciences, Ningbo University, PR China
| | - Chunhua Jin
- School of Marine Sciences, Ningbo University, PR China
| | - Jinbo Xiong
- School of Marine Sciences, Ningbo University, PR China
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39
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Fang LL, Wang XH, Sun BF, Zhang XD, Zhu XH, Yu ZJ, Luo H. Expression, regulation and mechanism of action of the miR-17-92 cluster in tumor cells (Review). Int J Mol Med 2017; 40:1624-1630. [PMID: 29039606 PMCID: PMC5716450 DOI: 10.3892/ijmm.2017.3164] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 09/11/2017] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs), a class of short, single-stranded non-coding RNAs, regulate and control gene expression in eukaryotes by degrading mRNA at the post-transcriptional level. Regulation by miRNAs involves a plethora of biological processes, such as cell differentiation, proliferation, metastasis, metabolism, apoptosis, tumorigenesis and others. miRNAs also represent a powerful tool in disease diagnosis and prognosis. The miR-17-92 cluster, one of the most extensively investigated microRNA clusters, comprises six mature miRNA members, including miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a. Originally identified as being involved in tumorigenesis, it is currently evident that the expression of the miR-17-92 cluster is upregulated in a wide range of tumor cells and cancer types; thus, this cluster has been identified as a potential oncogene. Considering the growing interest in the field of miR-17-92 research, we herein review recent advances in the expression and regulation of this cluster in various cancer cells, discuss the proposed mechanism of action for tumorigenesis and tumor development, and propose clinical and therapeutic applications for miR-17-92 cluster members, such as potential cancer biomarkers.
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Affiliation(s)
- Li-Li Fang
- Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Xing-Hui Wang
- Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, Guizhou 550004, P.R. China
| | - Bao-Fei Sun
- Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Xiao-Dong Zhang
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Xu-Hui Zhu
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Zi-Jiang Yu
- Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Heng Luo
- Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, Guizhou 550004, P.R. China
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40
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Zhang K, Zhang L, Zhang M, Zhang Y, Fan D, Jiang J, Ye L, Fang X, Chen X, Fan S, Chao M, Liang C. Prognostic value of high-expression of miR-17-92 cluster in various tumors: evidence from a meta-analysis. Sci Rep 2017; 7:8375. [PMID: 28827775 PMCID: PMC5567103 DOI: 10.1038/s41598-017-08349-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 07/10/2017] [Indexed: 12/18/2022] Open
Abstract
The prognostic value of miR-17-92 cluster high-expression in various tumors remains controversial. Therefore, we conducted this meta-analysis by searching literatures in PubMed, Embase, Cochrane Library, China Biology Medicine disc, China National Knowledge Infrastructure to identify eligible studies. Eventually, we analyzed 36 articles that examined 17 tumor types from 4965 patients. Consequently, high-expression of miR-17-92 cluster in various tumors was associated with unfavorable overall survival in both univariate (HR = 2.05, 95%CI: 1.58-2.65, P<0.001) and multivariate (HR = 2.14, 95%CI: 1.75-2.61, P<0.001) analyses. Likewise, similar results were found in different subgroups of country, test method, miR-17-92 cluster component, sample source and size. Additionally, high-expression of miR-17-92 cluster was linked with poor disease-free survival (Univariate: HR = 1.96, 95%CI: 1.55-2.48, P<0.001; Multivariate: HR = 2.18, 95%CI: 1.63-2.91, P<0.001), favorable progression-free survival (Univariate: HR = 0.36, 95%CI: 0.16-0.80, P = 0.012; Multivariate: HR = 1.55, 95%CI: 0.79-3.05, P = 0.201) and poor cancer specific survival in univariate rather than multivariate analyses (Univariate: HR = 1.77, 95%CI: 1.21-2.60, P = 0.004; Multivariate: HR = 1.77, 95%CI: 0.80-3.92, P = 0.160). However, no association of miR-17-92 cluster high-expression was detected with recurrence or relapse-free survival. In summary, this meta-analysis towards high-expression of miR-17-92 cluster has indicated poor prognosis of various cancers. Notably, future studies comprising large cohort size from multicenter are required to confirm our conclusions.
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Affiliation(s)
- Kaiping Zhang
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Li Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China
| | - Meng Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China
| | - Yin Zhang
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Dengxin Fan
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Jiabin Jiang
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Liqin Ye
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Xiang Fang
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Xianguo Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China
| | - Song Fan
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China
| | - Min Chao
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China.
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China.
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Islam F, Gopalan V, Vider J, Wahab R, Ebrahimi F, Lu CT, Kasem K, Lam AKY. MicroRNA-186-5p overexpression modulates colon cancer growth by repressing the expression of the FAM134B tumour inhibitor. Exp Cell Res 2017; 357:260-270. [PMID: 28549913 DOI: 10.1016/j.yexcr.2017.05.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 05/21/2017] [Accepted: 05/23/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The role and underlying mechanism of miR-186-5p in colorectal cancer remain unknown. The present study aims to examine the various cellular effects of miR-186-5p in the carcinogenesis of colorectal cancer. Also, the interacting targets and association of clinicopathological factors with miR-186-5p expression in patients with colorectal cancer were analysed. METHODS The miR-186-5p expression levels in colorectal cancer tissues (n=126) and colon cancer cell lines (n=3) were analysed by real-time PCR. Matched non-neoplastic colorectal tissues and a non-neoplastic colonic epithelial cell line were used as controls. Various in vitro assays such as cell proliferation, wound healing and colony formation assays were performed to examine the miR-186-5p specific cellular effects. Western blots and immunohistochemistry analysis were performed to examine the modulation of FAM134B, PARP9 and KLF7 proteins expression. RESULTS Significant high expression of miR-186-5p was noted in cancer tissues (p< 0.001) and cell lines (p<0.05) when compared to control tissues and cells. The majority of the patients with colorectal cancer (88/126) had shown overexpression of miR-186-5p. This miR-186-5p overexpression was predominantly noted with in cancer with distant metastasis (p=0.001), lymphovascular permeation (p=0.037), microsatellite instability (MSI) stable (p=0.015), in distal colorectum (p=0.043) and with associated adenomas (p=0.047). Overexpression of miR-186-5p resulted in increased cell proliferation, colony formation, wound healing capacities and induced alteration of cell cycle kinetics in colon cancer cells. On the other hand, inhibition of endogenous miR-186-5p reduced the cancer growth properties. miR-186-5p overexpression reduced FAM134B expression significantly in the cancer cells (p<0.01). Also, FAM134B and miR-186-5p expressions are inversely correlated in colorectal cancer tissues and cells. CONCLUSION The miR-186-5p expression promotes colorectal cancer pathogenesis by regulating tumour suppressor FAM134B. Reduced cancer cells growth followed by inhibition of miR-186-5p highlights the potential of miR-186-5p inhibitor as a novel strategy for targeting colorectal cancer initiation and progression.
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Affiliation(s)
- Farhadul Islam
- Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia; Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Jelena Vider
- School of Medical Science and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Riajul Wahab
- Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Faeza Ebrahimi
- Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Cu-Tai Lu
- Department of Surgery, Gold Coast Hospital, Gold Coast, Queensland, Australia
| | - Kais Kasem
- Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Alfred K Y Lam
- Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia.
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Gu Y, Si J, Xiao X, Tian Y, Yang S. miR-92a Inhibits Proliferation and Induces Apoptosis by Regulating Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) Expression in Acute Myeloid Leukemia. Oncol Res 2017; 25:1069-1079. [PMID: 28059050 PMCID: PMC7841081 DOI: 10.3727/096504016x14829256525028] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Aberrant expression of microRNA-92a (miR-92a) has been investigated in various cancers. However, the function and mechanism of miR-92a in acute myeloid leukemia (AML) remain to be elucidated. Our data showed that miR-92a was evidently downregulated and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was remarkably upregulated in AML cell lines HL-60 and THP-1. Dual luciferase reporter assay revealed that MTHFD2 was a direct target of miR-92a. Gain- and loss-of-function analysis demonstrated that MTHFD2 knockdown or miR-92a overexpression notably inhibited proliferation and promoted apoptosis of AML cell lines. Restoration of MTHFD2 expression reversed proliferation inhibition and apoptosis induction of AML cells triggered by miR-92a. Moreover, an implanted tumor model in mice indicated that miR-92a overexpression dramatically decreased tumor growth and MTHFD2 expression in vivo. Taken together, our results suggest that miR-92a inhibits proliferation and induces apoptosis by directly regulating MTHFD2 expression in AML. miR-92a may act as a tumor suppressor in AML, providing a promising therapeutic target for AML patients.
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Affiliation(s)
- Yueli Gu
- *Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
| | - Jinchun Si
- †Department of Surgery Teaching and Research Section, Shangqiu Medical College, Shangqiu, P.R. China
| | - Xichun Xiao
- *Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
| | - Ying Tian
- *Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
| | - Shuo Yang
- *Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
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Prognostic role of miR-17-92 family in human cancers: evaluation of multiple prognostic outcomes. Oncotarget 2017; 8:69125-69138. [PMID: 28978185 PMCID: PMC5620325 DOI: 10.18632/oncotarget.19096] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 06/20/2017] [Indexed: 12/31/2022] Open
Abstract
Recent evidence indicates that miR-17–92 family might be an essential prognostic biomarker for human cancers. However, results are still inconsistent. We therefore performed a meta-analysis to evaluate the predictive role of miR-17–92 family in human cancer prognosis. We searched literatures published before March 31th, 2017 inPubMed, Cochrane and Embase databases. Twenty six studies were included in our analyses. The overall hazard ratios (HRs) showed that high expression level of miR-17-92 family was a predictor of poor overall survival (OS): adjusted HRs = 1.71, 95% confidence intervals (CIs): 1.39–2.11, p < 0.00001, and poor disease-free survival (DFS): adjusted HRs = 2.29, 95% CIs: 1.41–3.72, p = 0.0008. However, no association between miR-17-92 family expression and cancer progress-free survival (PFS) was found (p > 0.05). Subgroup analyses showed that high expression of miR-17-92 family was associated with poor OS (adjusted HRs = 1.89, 95% CIs: 1.43–2.49, p < 0.00001) and DFS (adjusted HRs = 2.83, 95% CIs: 1.59–5.04, p = 0.0003) among the Asian, and no association was found for the Caucasian (p > 0.05). Besides, the HRs of miR-17-92 family high expression in tissue and serum samples was 1.68 (1.35–2.09) and 2.20 (1.08–4.46) for OS, and 1.73 (0.80–3.74) and 3.37 (2.25–5.02) for DFS. It also found that high expression of miR-17-92 family predicted a poor OS in breast cancer, esophageal squamous cell carcinoma, lymphoma and other cancers. Findings suggest that miR-17-92 family can be an effective predictor for prognosis prediction in cancer patients.
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Elshafei A, Shaker O, Abd El-Motaal O, Salman T. The expression profiling of serum miR-92a, miR-375, and miR-760 in colorectal cancer: An Egyptian study. Tumour Biol 2017; 39:1010428317705765. [PMID: 28618945 DOI: 10.1177/1010428317705765] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Dysregulation in microRNA expression is a common feature in colorectal cancer. Due to the inconsistent results regarding serum miR-92a expression pattern and the insufficient studies on serum miR-375 and miR-760, we aimed in this study to investigate their expression profile and diagnostic and prognostic power in Egyptian colorectal cancer patients. The expression profile of miR-92a, miR-375, and miR-760 was determined in the sera of 64 colorectal cancer patients using quantitative real-time reverse transcription polymerase chain reaction in comparison to 27 healthy control subjects. The expression fold change of the studied microRNAs was correlated with patients' clinicopathological features. Receiver operating characteristic curve analysis was done to determine the role of these microRNAs in colorectal cancer diagnosis and follow-up according to the yielded area under the curve. The expression pattern of miR-92a was significantly upregulated (3.38 ± 2.52, p < 0.0001), while both of miR-375 and 760 were significantly downregulated (-1.250 ± 1.80, p< 0.0001; -1.710 ± 1.88, p < 0.0001, respectively) in colorectal cancer than the control. MiR-92a was positively correlated ( r = 0.671, p = 0.0001), while miR-375 and miR-760 were inversely correlated ( r = -0.414, p = 0.001; r = -0.644, p = 0.0001) with advanced colorectal cancer stages. Receiver operating characteristic curve analysis disclosed the highest diagnostic potential for miR-760 to discriminate colorectal cancer patients and early-stage colorectal cancer from the control (area under the curve = 0.922 and 0.875, respectively), while the highest prognostic potential for discrimination between colorectal cancer stages was for miR-92a. In conclusion, serum level of miR-92a, miR-375, and miR-760 may serve as biomarkers of colorectal cancer in Egyptian patients with high diagnostic power for miR-760 and high prognostic power for miR-92a.
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Affiliation(s)
- Ahmed Elshafei
- 1 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Olfat Shaker
- 2 Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ossama Abd El-Motaal
- 1 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Tarek Salman
- 1 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
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Xiao J, Yu W, Hu K, Li M, Chen J, Li Z. miR-92a promotes tumor growth of osteosarcoma by targeting PTEN/AKT signaling pathway. Oncol Rep 2017; 37:2513-2521. [PMID: 28260104 DOI: 10.3892/or.2017.5484] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 02/20/2017] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs) play critical roles in human cancers including osteosarcoma (OS). miR-92a has been found to be a cancer-related miRNA in many cancer types and it is upregulated in OS cell lines. However, the expression and biological function of miR-92a in OS have not been investigated. In this study, we showed that miR-92a expression was increased in OS tissues, and its high expression was correlated with clinical stage, T classification and histological differentiation. Furthermore, patients with high expression of miR-92a had a significantly poorer survival rate. Functionally, miR-92a overexpression promoted the proliferation and cell cycle progression, and inhibited apoptosis in MG-63 cells. While inhibition of miR-92a showed contrary effects with reduced proliferation, cell cycle arrest at G1 phase and increased apoptosis in U2OS cells. Moreover, we confirmed that miR-92a inhibition reversed the tumor growth of OS cells in nude mice. Phosphatase and tensin homolog (PTEN), a well-known tumor suppressor, was confirmed to be the direct downstream target of miR-92a in OS. Notably, miR-92a consequently regulated the expression of the downstream targets of PTEN/AKT signaling pathway including p-Akt(Ser473), mTOR, p-p27(Thr157) and p-MDM2(Ser166). Furthermore, PTEN knockdown abrogated the functional effects of miR-92a silencing on the proliferation, apoptosis and cell cycle progression in OS cells. Thus, miR-92a that exerts an oncogenic role by targeting PTEN/AKT pathway in OS potentially acts as a biomarker and drug-target.
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Affiliation(s)
- Jie Xiao
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China
| | - Weifeng Yu
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China
| | - Kongzu Hu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Maoqiang Li
- Department of Orthopaedic Surgery, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
| | - Jianwei Chen
- Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China
| | - Zhanchun Li
- Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China
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The Structure and Clinical Roles of MicroRNA in Colorectal Cancer. Gastroenterol Res Pract 2016; 2016:1360348. [PMID: 28115926 PMCID: PMC5225333 DOI: 10.1155/2016/1360348] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 10/11/2016] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent types of malignancies, particularly among individuals aged between 50 and 75. The global incidence of CRC has been steadily on the rise due in no small part to an aging population and a shift in lifestyle as well as eating habits. MicroRNAs are a group of small, noncoding, and endogenous RNA molecules that have recently emerged as key players in a broad range of pathological pathways. Moreover, dysregulation of microRNAs has been implicated in cancer development and metastasis. This review is intended to provide a brief overview of the structure, functions, and clinical roles of microRNAs. In particular, the review will focus on the discovery, the underlying mechanistic roles, and the diagnostic as well as therapeutic potentials of CRC-specific miRNAs.
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Wang H, Ke C, Ma X, Zhao Q, Yang M, Zhang W, Wang J. MicroRNA-92 promotes invasion and chemoresistance by targeting GSK3β and activating Wnt signaling in bladder cancer cells. Tumour Biol 2016; 37:16295–16304. [PMID: 27830467 DOI: 10.1007/s13277-016-5460-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 09/23/2016] [Indexed: 12/27/2022] Open
Abstract
miR-92 has been reported to be upregulated in several human cancers. Until now, its expression pattern and biological roles in human bladder cancer still remains unexplored. The present study aims to clarify its expression, function, and potential molecular mechanisms in bladder cancer. Using real-time PCR, we found that miR-92 was upregulated in bladder cancer tissues compared with normal bladder tissues. We transfected miR-92 mimic and inhibitor in T24 and 5637 bladder cancer cells separately. We found that miR-92 mimic promoted T24 proliferation and invasion, with increased expression of cyclin D1, c-myc, and MMP7 at both mRNA and protein levels. Further investigation found that miR-92 could also promote epithelial-mesenchymal transition by downregulating E-cadherin protein and upregulating vimentin. In addition, miR-92 mimic also promoted activation of Wnt signaling. Meanwhile, miR-92 inhibitor displayed the opposite effects in 5637 cell line. By use of bioinformatic prediction software and luciferase reporter assay, we discovered that GSK3β acted as a direct target of miR-92. Additionally, GSK3β siRNA abrogated the effects of miR-92 mimic on cyclin D1 and MMP7. Moreover, we observed a negative correlation between GSK3β and miR-92 in bladder cancer tissues. In conclusion, our study demonstrated that upregulation of miR-92 is closely related with malignant progression of bladder cancer and miR-92 promotes proliferation, invasion, and Wnt/c-myc/MMP7 signaling by targeting GSK3β.
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Affiliation(s)
- Haifeng Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Changxing Ke
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Xingyong Ma
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Qinghua Zhao
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Mingying Yang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Wei Zhang
- Department of Urology, Affiliated Hospital of Hebei University, Baoding, 071000, China.
| | - Jiansong Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China.
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Bigagli E, De Filippo C, Castagnini C, Toti S, Acquadro F, Giudici F, Fazi M, Dolara P, Messerini L, Tonelli F, Luceri C. DNA copy number alterations, gene expression changes and disease-free survival in patients with colorectal cancer: a 10 year follow-up. Cell Oncol (Dordr) 2016; 39:545-558. [PMID: 27709558 DOI: 10.1007/s13402-016-0299-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2016] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND DNA copy number alterations (CNAs) and gene expression changes have amply been encountered in colorectal cancers (CRCs), but the extent at which CNAs affect gene expression, as well as their relevance for tumor development, are still poorly defined. Here we aimed at assessing the clinical relevance of these parameters in a 10 year follow-up study. METHODS Tumors and normal adjacent colon mucosa, obtained at primary surgery from 21 CRC patients, were subjected to (i) high-resolution array CGH (a-CGH) for the detection of CNAs and (ii) microarray-based transcriptome profiling for the detection of gene expression (GE) changes. Correlations between these genomic and transcriptomic changes and their associations with clinical and histopathological parameters were assessed with the aim to identify molecular signatures associated with disease-free survival of the CRC patients during a 10 year follow-up. RESULTS DNA copy number gains were frequently detected in chromosomes 7, 8q, 13, 19, 20q and X, whereas DNA copy number losses were frequently detected in chromosomes 1p, 4, 8p, 15, 17p, 18, 19 and 22q. None of these alterations were observed in all samples. In addition, we found that 2,498 genes were up- and that 1,094 genes were down-regulated in the tumor samples compared to their corresponding normal mucosa (p < 0.01). The expression of 65 genes was found to be significantly associated with prognosis (p < 0.01). Specifically, we found that up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, were strongly associated with a poor survival. Subsequent integrated analyses revealed that increased expression levels of the MMP9, BMP7, UBE2C, I-CAM, NOTCH3, NOTCH1, PTGES2, HMGB1 and ERBB3 genes were associated with copy number gains, whereas decreased expression levels of the MUC1, E2F2, HRAS and SIRT3 genes were associated with copy number losses. Pathways related to cell cycle progression, eicosanoid metabolism, and TGF-β and apoptosis signaling, were found to be most significantly affected. CONCLUSIONS Our results suggest that CNAs in CRC tumor tissues are associated with concomitant changes in the expression of cancer-related genes. In other genes epigenetic mechanism may be at work. Up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, appear to be associated with a poor survival. These alterations may, in addition to Dukes' staging, be employed as new prognostic biomarkers for the prediction of clinical outcome in CRC patients.
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Affiliation(s)
- Elisabetta Bigagli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
| | - Carlotta De Filippo
- Institute of Biometeorology (IBIMET), National Research Council (CNR), Florence, Italy
| | - Cinzia Castagnini
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | | | - Francesco Acquadro
- Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
| | - Francesco Giudici
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Marilena Fazi
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Piero Dolara
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Francesco Tonelli
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Cristina Luceri
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
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The impact of RNA binding motif protein 4-regulated splicing cascade on the progression and metabolism of colorectal cancer cells. Oncotarget 2016; 6:38046-60. [PMID: 26506517 PMCID: PMC4741983 DOI: 10.18632/oncotarget.5710] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 10/06/2015] [Indexed: 01/17/2023] Open
Abstract
Dysregulated splicing of pre-messenger (m)RNA is considered a molecular occasion of carcinogenesis. However, the underlying mechanism is complex and remains to be investigated. Herein, we report that the upregulated miR-92a reduced the RNA-binding motif 4 (RBM4) protein expression, leading to the imbalanced expression of the neuronal polypyrimidine tract-binding (nPTB) protein through alternative splicing-coupled nonsense mediated decay (NMD) mechanism. Increase in nPTB protein enhances the relative level of fibroblast growth factor receptor 2 IIIc (FGFR2) and pyruvate kinase M2 (PKM2) transcripts which contribute to the progression and metabolic signature of CRC cells. Expression profiles of RBM4 and downstream alternative splicing events are consistently observed in cancerous tissues compared to adjacent normal tissues. These results constitute a mechanistic understanding of RBM4 on repressing the carcinogenesis of colorectal cells.
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Jepsen RK, Novotny GW, Klarskov LL, Christensen IJ, Høgdall E, Riis LB. Investigating intra-tumor heterogeneity and expression gradients of miR-21, miR-92a and miR-200c and their potential of predicting lymph node metastases in early colorectal cancer. Exp Mol Pathol 2016; 101:187-196. [PMID: 27565378 DOI: 10.1016/j.yexmp.2016.08.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 12/18/2022]
Abstract
INTRODUCTION miR-21, miR-92a and miR-200c are regulators of pathways involved in migration, intravasation and metastasis, and their tumor expression levels have been proposed as potential prognostic markers in colorectal cancer (CRC). In two parallel cohorts we examine intra-tumor expression levels in early stage CRC tissue in order to determine intra-tumor heterogeneity, potential systematic intra-tumor expression gradients of the miRNAs and to investigate the association to metastatic disease in early stage CRC. MATERIAL AND METHODS Two parallel studies on archived formalin-fixed paraffin-embedded (FFPE) CRC tissue. Intra-tumor and inter-patient variances were analyzed in 9 early metastatic CRCs by measuring expression levels by qRT-PCR on isolated tissue samples from luminal, central and invasive border zones. Associations between miRNA expression levels and early metastasizing tumors was investigated in FFPE tissue from invasive border and central tumor zones from 47 early metastatic CRCs matched with 47 non-metastatic CRCs. Intra-tumor expression gradients were analyzed on both cohorts. RESULTS Mean intra-tumor coefficient of variation in the heterogeneity cohort was 38.5% (range: 33.1-49.0%) only slightly less than variation between patients (45.1%, range 37.0-49.5%). We demonstrated systematic expression gradients between tumor zones equal to a 3.23 (p=0.003) and 1.36 (p=0.014) fold lower expression in invasive areas for miR-200c, 1.52 (p<0.001) and 1.27 (p=0.021) fold lower expression in invasive areas for miR-92a. For miR-21 we found a 1.75 (p<0.001) and 1.21 (p=0.064) fold higher expression in invasive areas compared to luminal and central zones, respectively. No significant difference in expression levels between metastatic and non-metastatic tumors was demonstrated, nor a difference in intra-tumor gradients between metastatic and non-metastatic tumors. CONCLUSION This study provides evidence for moderate intra-tumor and inter-patient heterogeneities of three well-described potential prognostic markers in CRC. We demonstrate intra-tumor expression gradients indicating a differentiated expression of the target miRNAs between functional tumor zones, but the potential role as markers of early metastatic disease is still not fully clarified.
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Affiliation(s)
- Rikke Karlin Jepsen
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
| | - Guy Wayne Novotny
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark
| | - Louise Laurberg Klarskov
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark
| | - Ib Jarle Christensen
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark
| | - Estrid Høgdall
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark
| | - Lene Buhl Riis
- Department of Pathology and Molecular Unit, University of Copenhagen, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark
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