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Andrade F, German-Cortés J, Montero S, Carcavilla P, Baranda-Martínez-Abascal D, Moltó-Abad M, Seras-Franzoso J, Díaz-Riascos ZV, Rafael D, Abasolo I. The Nanotechnology-Based Approaches against Kirsten Rat Sarcoma-Mutated Cancers. Pharmaceutics 2023; 15:1686. [PMID: 37376135 DOI: 10.3390/pharmaceutics15061686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/18/2023] [Accepted: 05/27/2023] [Indexed: 06/29/2023] Open
Abstract
Kirsten rat sarcoma (KRAS) is a small GTPase which acts as a molecular switch to regulate several cell biological processes including cell survival, proliferation, and differentiation. Alterations in KRAS have been found in 25% of all human cancers, with pancreatic cancer (90%), colorectal cancer (45%), and lung cancer (35%) being the types of cancer with the highest mutation rates. KRAS oncogenic mutations are not only responsible for malignant cell transformation and tumor development but also related to poor prognosis, low survival rate, and resistance to chemotherapy. Although different strategies have been developed to specifically target this oncoprotein over the last few decades, almost all of them have failed, relying on the current therapeutic solutions to target proteins involved in the KRAS pathway using chemical or gene therapy. Nanomedicine can certainly bring a solution for the lack of specificity and effectiveness of anti-KRAS therapy. Therefore, nanoparticles of different natures are being developed to improve the therapeutic index of drugs, genetic material, and/or biomolecules and to allow their delivery specifically into the cells of interest. The present work aims to summarize the most recent advances related to the use of nanotechnology for the development of new therapeutic strategies against KRAS-mutated cancers.
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Affiliation(s)
- Fernanda Andrade
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Departament de Farmàcia i Tecnologia Farmacèutica i Fisicoquímica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona (UB), 08028 Barcelona, Spain
| | - Júlia German-Cortés
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - Sara Montero
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - Pilar Carcavilla
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - Diego Baranda-Martínez-Abascal
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
| | - Marc Moltó-Abad
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Joaquín Seras-Franzoso
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
| | - Zamira Vanessa Díaz-Riascos
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Diana Rafael
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Ibane Abasolo
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, 08035 Barcelona, Spain
- Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Clinical Biochemistry Service, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
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Kalita A, Sikora-Skrabaka M, Nowakowska-Zajdel E. Role of Some microRNA/ADAM Proteins Axes in Gastrointestinal Cancers as a Novel Biomarkers and Potential Therapeutic Targets—A Review. Curr Issues Mol Biol 2023; 45:2917-2936. [PMID: 37185715 PMCID: PMC10136553 DOI: 10.3390/cimb45040191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/16/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Gastrointestinal (GI) cancers are some of the most common cancers in the world and their number is increasing. Their etiology and pathogenesis are still unclear. ADAM proteins are a family of transmembrane and secreted metalloproteinases that play a role in cancerogenesis, metastasis and neoangiogenesis. MicroRNAs are small single-stranded non-coding RNAs that take part in the post-transcriptional regulation of gene expression. Some ADAM proteins can be targets for microRNAs. In this review, we analyze the impact of microRNA/ADAM protein axes in GI cancers.
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Affiliation(s)
- Agnieszka Kalita
- Department of Nutrition-Related Disease Prevention, Department of Metabolic Disease Prevention, Faculty of Health Sciences in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
- Department of Clinical Oncology, No. 4 Provincial Specialist Hospital, 41-902 Bytom, Poland
| | - Magdalena Sikora-Skrabaka
- Department of Nutrition-Related Disease Prevention, Department of Metabolic Disease Prevention, Faculty of Health Sciences in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
- Department of Clinical Oncology, No. 4 Provincial Specialist Hospital, 41-902 Bytom, Poland
| | - Ewa Nowakowska-Zajdel
- Department of Nutrition-Related Disease Prevention, Department of Metabolic Disease Prevention, Faculty of Health Sciences in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
- Department of Clinical Oncology, No. 4 Provincial Specialist Hospital, 41-902 Bytom, Poland
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Habault J, Thonnart N, Ram-Wolff C, Bagot M, Bensussan A, Poyet JL, Marie-Cardine A. Validation of AAC-11-Derived Peptide Anti-Tumor Activity in a Single Graft Sézary Patient-Derived Xenograft Mouse Model. Cells 2022; 11:cells11192933. [PMID: 36230895 PMCID: PMC9564267 DOI: 10.3390/cells11192933] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/12/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma with poor prognosis mainly characterized by the expansion of a tumor CD4+ T cell clone in both skin and blood. So far, the development of new therapeutic strategies has been hindered by a lack of reproducible in vivo models closely reflecting patients’ clinical features. We developed an SS murine model consisting of the intravenous injection of Sézary patients’ PBMC, together with a mixture of interleukins, in NOD-SCID-gamma mice. Thirty-four to fifty days after injection, mice showed skin disorders similar to that observed in patients, with the detection of epidermis thickening and dermal tumor T cell infiltrates. Although experimental variability was observed, Sézary cells could be tracked in the blood stream, confirming that our model could efficiently exhibit both skin and blood involvement. Using this model, we evaluated the therapeutic potential of RT39, a cell-penetrating peptide derived from the survival protein anti-apoptosis clone 11 (AAC-11), that we previously characterized as specifically inducing apoptosis of Sézary patients’ malignant clone ex vivo. Systemic administration of RT39 led to cutaneous tumor T cells depletion, demonstrating efficient malignant cells’ targeting and a favorable safety profile. These preclinical data confirmed that RT39 might be an innovative therapeutic tool for Sézary syndrome.
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Affiliation(s)
- Justine Habault
- INSERM U976 Team 1, Onco-Dermatology and Therapies, 75010 Paris, France
- Saint Louis Research Institute, Université Paris Cité, 75010 Paris, France
| | - Nicolas Thonnart
- INSERM U976 Team 1, Onco-Dermatology and Therapies, 75010 Paris, France
- Saint Louis Research Institute, Université Paris Cité, 75010 Paris, France
| | - Caroline Ram-Wolff
- INSERM U976 Team 1, Onco-Dermatology and Therapies, 75010 Paris, France
- Saint Louis Research Institute, Université Paris Cité, 75010 Paris, France
- Department of Dermatology, Saint Louis Hospital, AP-HP, 75010 Paris, France
| | - Martine Bagot
- INSERM U976 Team 1, Onco-Dermatology and Therapies, 75010 Paris, France
- Saint Louis Research Institute, Université Paris Cité, 75010 Paris, France
- Department of Dermatology, Saint Louis Hospital, AP-HP, 75010 Paris, France
| | - Armand Bensussan
- INSERM U976 Team 1, Onco-Dermatology and Therapies, 75010 Paris, France
- Saint Louis Research Institute, Université Paris Cité, 75010 Paris, France
| | - Jean-Luc Poyet
- INSERM U976 Team 1, Onco-Dermatology and Therapies, 75010 Paris, France
- Saint Louis Research Institute, Université Paris Cité, 75010 Paris, France
| | - Anne Marie-Cardine
- INSERM U976 Team 1, Onco-Dermatology and Therapies, 75010 Paris, France
- Saint Louis Research Institute, Université Paris Cité, 75010 Paris, France
- Correspondence:
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Small RNA-Seq Reveals Similar miRNA Transcriptome in Children and Young Adults with T-ALL and Indicates miR-143-3p as Novel Candidate Tumor Suppressor in This Leukemia. Int J Mol Sci 2022; 23:ijms231710117. [PMID: 36077521 PMCID: PMC9456032 DOI: 10.3390/ijms231710117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/21/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
We aimed to identify miRNAs and pathways specifically deregulated in adolescent and young adult (AYA) T-ALL patients. Small RNA-seq showed no major differences between AYA and pediatric T-ALL, but it revealed downregulation of miR-143-3p in T-ALL patients. Prediction algorithms identified several known and putative oncogenes targeted by this miRNA, including KRAS, FGF1, and FGF9. Pathway analysis indicated signaling pathways related to cell growth and proliferation, including FGFR signaling and PI3K-AKT signaling, with the majority of genes overrepresented in these pathways being predicted targets of hsa-miR-143-3p. By luciferase reporter assays, we validated direct interactions of this miRNA with KRAS, FGF1 and FGF9. In cell proliferation assays, we showed reduction of cell growth upon miR-143-3p overexpression in two T-ALL cell lines. Our study is the first description of the miRNA transcriptome in AYA T-ALL patients and the first report on tumor suppressor potential of miR-143-3p in T-ALL. Downregulation of this miRNA in T-ALL patients might contribute to enhanced growth and viability of leukemic cells. We also discuss the potential role of miR-143-3p in FGFR signaling. Although this requires more extensive validation, it might be an interesting direction, since FGFR inhibition proved promising in preclinical studies in various cancers.
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Herrera-Pulido JA, Guerrero OR, Forero JA, Moreno-Acosta P, Romero-Rojas A, Sanabria C, Hernández G, Serrano ML. KRAS Promoter Methylation Status and miR-18a-3p and miR-143 Expression in Patients With Wild-type KRAS Gene in Colorectal Cancer. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:576-584. [PMID: 36060016 PMCID: PMC9425578 DOI: 10.21873/cdp.10145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/25/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND/AIM Although some mutations of KRAS proto-oncogene, GTPase (KRAS) have been associated with the prognosis and therapeutic management of colorectal cancer (CRC), the epigenetic mechanisms (DNA methylation and microRNA expression) that regulate wild-type KRAS expression in patients with CRC are poorly known. The aim of this study was to establish whether there is a relationship between the expression of the wild-type KRAS gene, the methylation status of its distal promoter, and miR-143 and miR-18a-3p levels in samples of sporadic CRC. PATIENTS AND METHODS A total of 51 cases of sporadic CRC with wild-type KRAS were analyzed. The expression levels of KRAS mRNA, miR-18a-3p, miR-143, and KRAS protein, as well as methylation in the distal promoter of the KRAS gene were evaluated. RESULTS In the analyzed cases, KRAS mRNA expression was detected in 51.1%; wild-type KRAS protein was found in the membrane in 31.4% and in the cytoplasm in 98% of cases. An inverse relationship of marginal significance was observed between miR-18a-3p and KRAS protein expression in the cytoplasm (odds ratio=0.14, 95% confidence interval=0.012-1.092; p=0.08). The methylation status of the distal promoter of KRAS at four CpG islands was analyzed in 30 cases (58.8%): partial methylation of the four CpG islands evaluated was observed in two cases (6.7%). In these cases, KRAS protein expression was not evidenced at the membrane level; miR-18a-3p expression was not detected either but high expression of miR-143 was observed. CONCLUSION No association was found between the expression levels of KRAS mRNA, miR-18a-3p, miR-143 and methylation status. Methylation status was detected with low frequency, thus being the first report of methylation in wild-type KRAS.
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Affiliation(s)
- Jehison Alirio Herrera-Pulido
- Cancer Biology Research Group, National Cancer Institute, Bogotá, Colombia
- Master's Program in Human Genetics, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
| | | | - Jinneth Acosta Forero
- Department of Pathology, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Pablo Moreno-Acosta
- Cancer Biology Research Group, National Cancer Institute, Bogotá, Colombia
- Clinical, Molecular and Cellular Radiobiology Research Group, National Cancer Institute, Bogotá, Colombia
| | | | - Carolina Sanabria
- Cancer Biology Research Group, National Cancer Institute, Bogotá, Colombia
| | - Gustavo Hernández
- Public Health and Cancer Epidemiology Group, National Cancer Institute, Bogotá, Colombia
| | - Martha Lucía Serrano
- Cancer Biology Research Group, National Cancer Institute, Bogotá, Colombia
- Chemistry Department, Faculty of Sciences, Universidad Nacional de Colombia, Bogotá, Colombia
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The Insulin-like Growth Factor System and Colorectal Cancer. LIFE (BASEL, SWITZERLAND) 2022; 12:life12081274. [PMID: 36013453 PMCID: PMC9410426 DOI: 10.3390/life12081274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/29/2022]
Abstract
Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated molecules, they participate in numerous pathophysiological processes, including cancer development. Colorectal cancer (CRC) is a disease with high incidence and mortality rates worldwide, whose etiology usually represents a combination of the environmental and genetic factors. IGFs are most often increased in CRC, enabling excessive autocrine/paracrine stimulation of the cell growth. Overexpression or increased activation/accessibility of IGF receptors is a coinciding step which transmits IGF-related signals. A number of molecules and biochemical mechanisms exert modulatory effects shaping the final outcome of the IGF-stimulated processes, frequently leading to neoplastic transformation in the case of irreparable disbalance. The IGF system and related molecules and pathways which participate in the development of CRC are the focus of this review.
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The Clinical Assessment of MicroRNA Diagnostic, Prognostic, and Theranostic Value in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13122916. [PMID: 34208056 PMCID: PMC8230660 DOI: 10.3390/cancers13122916] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/29/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary MiRNAs are of great interest within colorectal cancers in diagnosis, prognosis, and within the field of personalized treatments; they are present within different biological fluids such as blood and can lead to specific information for daily clinical use. Herein, we review the current literature focusing on miRNAs as potential diagnostic and prognostic biomarkers in patients treated for colorectal cancers. Detection and analysis of miRNA expression are cost-effective and lead to high sensitivity and specificity rates. However, it is now necessary to highlight the most sensitive and specific miRNAs for each goal, either diagnostic, prognostic, or theranostic, thanks to multicentric prospective studies. Abstract MiRNAs have recently become a subject of great interest within cancers and especially colorectal cancers in diagnosis, prognosis, and therapy decisions; herein we review the current literature focusing on miRNAs in colorectal cancers, and we discuss future challenges to use this tool on a daily clinical basis. In liquid biopsies, miRNAs seem easily accessible and can give important information toward each step of the management of colorectal cancers. However, it is now necessary to highlight the most sensitive and specific miRNAs for each goal thanks to multicentric prospective studies. Conclusions: by their diversity and the feasibility of their use, miRNAs are getting part of the armamentarium of healthcare management of colorectal cancers.
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Habault J, Thonnart N, Pasquereau-Kotula E, Bagot M, Bensussan A, Villoutreix BO, Marie-Cardine A, Poyet JL. PAK1-Dependent Antitumor Effect of AAC-11‒Derived Peptides on Sézary Syndrome Malignant CD4 + T Lymphocytes. J Invest Dermatol 2021; 141:2261-2271.e5. [PMID: 33745910 DOI: 10.1016/j.jid.2021.01.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/10/2020] [Accepted: 01/08/2021] [Indexed: 01/08/2023]
Abstract
Sézary syndrome is an aggressive form of cutaneous T-cell lymphoma characterized by the presence of a malignant CD4+ T-cell clone in both blood and skin. Its pathophysiology is still poorly understood, and the development of targeted therapies is hampered by the absence of specific target proteins. AAC-11 plays important roles in cancer cell progression and survival and thus has been considered as an anticancer therapeutic target. In this study, we show that a peptide called RT39, comprising a portion of AAC-11‒binding site to its protein partners coupled to the penetratin sequence, induces the specific elimination of the malignant T-cell clone both ex vivo on the circulating cells of patients with Sézary syndrome and in vivo in a subcutaneous xenograft mouse model. RT39 acts by direct binding to PAK1 that is overexpressed, located in the plasma membrane, and constitutively activated in Sézary cells, resulting in their selective depletion by membranolysis. Along with the absence of toxicity, our preclinical efficacy evidence suggests that RT39 might represent a promising alternative therapeutic tool for Sézary syndrome because it spares the nonmalignant immune cells and, contrary to antibody-based immunotherapies, does not require the mobilization of the cellular immunity that shows heavy deficiencies at advanced stages of the disease.
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Affiliation(s)
- Justine Habault
- Onco-Dermatology and Therapies, INSERM UMRS976, Hôpital Saint Louis, Paris, France; Institut de Recherche Saint Louis, Université de Paris, Paris, France
| | - Nicolas Thonnart
- Onco-Dermatology and Therapies, INSERM UMRS976, Hôpital Saint Louis, Paris, France; Institut de Recherche Saint Louis, Université de Paris, Paris, France
| | - Ewa Pasquereau-Kotula
- Onco-Dermatology and Therapies, INSERM UMRS976, Hôpital Saint Louis, Paris, France; Institut de Recherche Saint Louis, Université de Paris, Paris, France
| | - Martine Bagot
- Onco-Dermatology and Therapies, INSERM UMRS976, Hôpital Saint Louis, Paris, France; Institut de Recherche Saint Louis, Université de Paris, Paris, France; Département de Dermatologie, Hôpital Saint Louis, AP-HP, Paris, France
| | - Armand Bensussan
- Onco-Dermatology and Therapies, INSERM UMRS976, Hôpital Saint Louis, Paris, France; Institut de Recherche Saint Louis, Université de Paris, Paris, France
| | - Bruno O Villoutreix
- INSERM U1141, NeroDiderot, Hôpital Robert-Debré, Paris, France; c-Dithem, Inserm Consortium for Discovery and Innovation in Therapy and Medicine, Paris, France
| | - Anne Marie-Cardine
- Onco-Dermatology and Therapies, INSERM UMRS976, Hôpital Saint Louis, Paris, France; Institut de Recherche Saint Louis, Université de Paris, Paris, France
| | - Jean-Luc Poyet
- Onco-Dermatology and Therapies, INSERM UMRS976, Hôpital Saint Louis, Paris, France; Institut de Recherche Saint Louis, Université de Paris, Paris, France; c-Dithem, Inserm Consortium for Discovery and Innovation in Therapy and Medicine, Paris, France.
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MicroRNA-Based Therapeutics for Drug-Resistant Colorectal Cancer. Pharmaceuticals (Basel) 2021; 14:ph14020136. [PMID: 33567635 PMCID: PMC7915952 DOI: 10.3390/ph14020136] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/29/2021] [Accepted: 02/04/2021] [Indexed: 12/13/2022] Open
Abstract
Although therapeutic approaches for patients with colorectal cancer (CRC) have improved in the past decades, the problem of drug resistance still persists and acts as a major obstacle for effective therapy. Many studies have shown that drug resistance is related to reduced drug uptake, modification of drug targets, and/or transformation of cell cycle checkpoints. A growing body of evidence indicates that several microRNAs (miRNAs) may contribute to the drug resistance to chemotherapy, targeted therapy, and immunotherapy by regulating the drug resistance-related target genes in CRC. These drug resistance-related miRNAs may be used as promising biomarkers for predicting drug response or as potential therapeutic targets for treating patients with CRC. In this review, we summarized the recent discoveries regarding anti-cancer drug-related miRNAs and their molecular mechanisms in CRC. Furthermore, we discussed the challenges associated with the clinical application of miRNAs as biomarkers for the diagnosis of drug-resistant patients and as therapeutic targets for CRC treatment.
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Eslamizadeh S, Zare AA, Talebi A, Tabaeian SP, Eshkiki ZS, Heydari-Zarnagh H, Akbari A. Differential Expression of miR-20a and miR-145 in Colorectal Tumors as Potential Location-specific miRNAs. Microrna 2020; 10:66-73. [PMID: 33349227 DOI: 10.2174/2211536609666201221123604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/16/2020] [Accepted: 11/27/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs), as tissue specific regulators of gene transcription, may be served as biomarkers for Colorectal Cancer (CRC). OBJECTIVE This study aimed to investigate the potential role of the cancer-related hsa-miRNAs as biomarkers in Colon Cancer (CC) and Rectal Cancer (RC). METHODS A total of 148 CRC samples (74 rectum and 74 colon) and 74 adjacent normal tissues were collected to examine the differential expression of selected ten hsa-miRNAs using quantitative Reverse Transcriptase PCR (qRT-PCR). RESULTS The significantly elevated levels of miR-21, miR-133b, miR-18a, miR-20a, and miR-135b, and decreased levels of miR-34a, miR-200c, miR-145, and let-7g were detected in colorectal tumors compared to the healthy tissues (P<0.05). Hsa-miR-20a was significantly overexpressed in rectum compared to colon (p =0.028) from a cut-off value of 3.15 with a sensitivity of 66% and a specificity of 60% and an AUC value of 0.962. Also, hsa-miR-145 was significantly overexpressed in colon compared to the rectum (p =0.02) from a cut-off value of 3.9 with a sensitivity of 55% and a specificity of 61% and an AUC value of 0.91. CONCLUSION In conclusion, hsa-miR-20a and hsa-miR-145, as potential tissue-specific biomarkers for distinguishing RC and CC, improve realizing the molecular differences between these local tumors.
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Affiliation(s)
- Sara Eslamizadeh
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Zare
- Young Researchers and Elites club, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Atefeh Talebi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Zahra Shokati Eshkiki
- Alimentary Tract Research Center, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hafez Heydari-Zarnagh
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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Bull CJ, Bell JA, Murphy N, Sanderson E, Davey Smith G, Timpson NJ, Banbury BL, Albanes D, Berndt SI, Bézieau S, Bishop DT, Brenner H, Buchanan DD, Burnett-Hartman A, Casey G, Castellví-Bel S, Chan AT, Chang-Claude J, Cross AJ, de la Chapelle A, Figueiredo JC, Gallinger SJ, Gapstur SM, Giles GG, Gruber SB, Gsur A, Hampe J, Hampel H, Harrison TA, Hoffmeister M, Hsu L, Huang WY, Huyghe JR, Jenkins MA, Joshu CE, Keku TO, Kühn T, Kweon SS, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, May AM, Milne RL, Moreno V, Newcomb PA, Offit K, Ogino S, Phipps AI, Platz EA, Potter JD, Qu C, Quirós JR, Rennert G, Riboli E, Sakoda LC, Schafmayer C, Schoen RE, Slattery ML, Tangen CM, Tsilidis KK, Ulrich CM, van Duijnhoven FJB, van Guelpen B, Visvanathan K, Vodicka P, Vodickova L, Wang H, White E, Wolk A, Woods MO, Wu AH, Campbell PT, Zheng W, Peters U, Vincent EE, Gunter MJ. Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study. BMC Med 2020; 18:396. [PMID: 33327948 PMCID: PMC7745469 DOI: 10.1186/s12916-020-01855-9] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/12/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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Affiliation(s)
- Caroline J Bull
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK.
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
| | - Joshua A Bell
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Neil Murphy
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Eleanor Sanderson
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - George Davey Smith
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Nicholas J Timpson
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stéphane Bézieau
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - D Timothy Bishop
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | | | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Cancer Centre Hamburg (UCCH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK
| | - Albert de la Chapelle
- Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Steven J Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Susan M Gapstur
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Stephen B Gruber
- Department of Preventive Medicine & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria
| | - Jochen Hampe
- Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Corinne E Joshu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea
| | | | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Annika Lindblom
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Vicente Martín
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Biomedicine Institute (IBIOMED), University of León, León, Spain
| | - Anne M May
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Victor Moreno
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - Kenneth Offit
- Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- University of Washington, Seattle, WA, USA
- Centre for Public Health Research, Massey University, Wellington, New Zealand
- Health Sciences Centre, University of Canterbury, Christchurch, New Zealand
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Clemens Schafmayer
- Department of General Surgery, University Hospital Rostock, Rostock, Germany
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Catherine M Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Kostas K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Cornelia M Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | | | - Bethany van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Hansong Wang
- University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michael O Woods
- Discipline of Genetics, Memorial University of Newfoundland, St John's, Canada
| | - Anna H Wu
- University of Southern California, Preventative Medicine, CA, Los Angeles, USA
| | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Emma E Vincent
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Marc J Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
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12
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Huang L, Sun T, Hu L, Hu S, Sun H, Zhao F, Wu B, Yang S, Ji F, Zhou D. Elevated miR-124-3p in the aging colon disrupts mucus barrier and increases susceptibility to colitis by targeting T-synthase. Aging Cell 2020; 19:e13252. [PMID: 33040455 PMCID: PMC7681053 DOI: 10.1111/acel.13252] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 08/31/2020] [Accepted: 09/13/2020] [Indexed: 12/22/2022] Open
Abstract
The risk of colitis and colorectal cancer increases markedly throughout adult life, endangering the health and lives of elderly individuals. Previous studies have proposed that bacterial translocation and infection are the main risk factors for these diseases. Therefore, in the present study, we aimed to identify the underlying mechanism by focusing on the mucus barrier function and mucin‐type O‐glycosylation. We evaluated alterations in the colon mucus layer in 2‐, 16‐, and 24‐month‐old mice and aged humans. Aged colons showed defective intestinal mucosal barrier and changed mucus properties. The miR‐124‐3p expression level was significantly increased in the aged distal colonic mucosa, which was accompanied by an increase in pathogens and bacterial translocation. Meanwhile, T‐synthase, the rate‐limiting enzyme in O‐glycosylation, displayed an age‐related decline in protein expression. Further experiments indicated that miR‐124‐3p modulated O‐glycosylation by directly targeting T‐synthase. Moreover, young mice overexpressing miR‐124‐3p exhibited abnormal glycosylation, early‐onset, and more severe colitis. These data suggest that miR‐124‐3p predisposes to senile colitis by reducing T‐synthase, and the miR‐124‐3p/T‐synthase/O‐glycans axis plays an essential role in maintaining the physiochemical properties of colonic mucus and intestinal homeostasis.
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Affiliation(s)
- Li Huang
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
| | - Ting‐yi Sun
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research Beijing China
- Cancer Institute of Capital Medical University Beijing China
| | - Liang‐jun Hu
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
| | - Shi‐long Hu
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
| | - Hai‐mei Sun
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research Beijing China
- Cancer Institute of Capital Medical University Beijing China
| | - Fu‐qian Zhao
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
| | - Bo Wu
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research Beijing China
- Cancer Institute of Capital Medical University Beijing China
| | - Shu Yang
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research Beijing China
- Cancer Institute of Capital Medical University Beijing China
| | - Feng‐qing Ji
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research Beijing China
- Cancer Institute of Capital Medical University Beijing China
| | - De‐shan Zhou
- Department of Histology and Embryology, School of Basic Medical Sciences Capital Medical University Beijing China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research Beijing China
- Cancer Institute of Capital Medical University Beijing China
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13
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Lan S, Albinsson S. Regulation of IRS-1, insulin signaling and glucose uptake by miR-143/145 in vascular smooth muscle cells. Biochem Biophys Res Commun 2020; 529:119-125. [PMID: 32560812 DOI: 10.1016/j.bbrc.2020.05.148] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 05/20/2020] [Indexed: 11/25/2022]
Abstract
Regulation of insulin signaling by microRNAs in smooth muscle cells may contribute to diabetic vascular disease. The two smooth muscle enriched miRNAs miR-143 and miR-145 have been reported to target mediators of insulin signaling in non-smooth muscle cells. In this study, we aimed to determine the importance of this regulation in vascular smooth muscle cells, where expression of miR-143/145 is much higher than in other cell types. Smooth muscle cells deficient of the miR-143/145 cluster were used, as well as smooth muscle cells transfected with mimics/inhibitors for either miR-143 or miR-145. We found that deletion of miR-143/145 in smooth muscle results in a dramatic upregulation IRS-1 expression and insulin signaling, and an increased insulin-induced glucose uptake. Furthermore, specific modulation of either miR-145 or miR-143 expression regulated specific targets (IRS-1, ORP8 and the IGF-1 receptor) in the insulin signaling pathway. Consequently, transient inhibition or overexpression of either miR-143 or miR-145 was sufficient to regulate insulin signaling in smooth muscle cells. In conclusion, the results of this study support an important role for both miR-143 and miR-145 in the regulation of insulin signaling and glucose uptake in vascular smooth muscle cells.
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MESH Headings
- Animals
- Biological Transport, Active
- Cells, Cultured
- Glucose/metabolism
- Insulin/metabolism
- Insulin Receptor Substrate Proteins/metabolism
- Mice
- Mice, Knockout
- MicroRNAs/antagonists & inhibitors
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/metabolism
- Receptor, IGF Type 1/metabolism
- Signal Transduction
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Affiliation(s)
- Susan Lan
- Department of Experimental Medical Science, Lund University, Lund, Sweden
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14
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Wang L, Zhang S, Cheng G, Mei C, Li S, Zhang W, Junjvlieke Z, Zan L. MiR-145 reduces the activity of PI3K/Akt and MAPK signaling pathways and inhibits adipogenesis in bovine preadipocytes. Genomics 2020; 112:2688-2694. [DOI: 10.1016/j.ygeno.2020.02.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/31/2020] [Accepted: 02/29/2020] [Indexed: 12/29/2022]
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15
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Luo Q, Song H, Deng X, Li J, Jian W, Zhao J, Zheng X, Basnet S, Ge H, Daniel T, Xu B, Fang L. A Triple-Regulated Oncolytic Adenovirus Carrying MicroRNA-143 Exhibits Potent Antitumor Efficacy in Colorectal Cancer. MOLECULAR THERAPY-ONCOLYTICS 2020; 16:219-229. [PMID: 32123722 PMCID: PMC7036723 DOI: 10.1016/j.omto.2020.01.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 01/13/2020] [Indexed: 12/24/2022]
Abstract
The cancer-targeting gene virotherapy might be a useful strategy for the treatment of cancer, because it could combine the advantages of both gene therapy and virotherapy. This study aimed to construct a triple-regulated oncolytic adenovirus, Ad-RGD-Survivin-ZD55-miR-143, carrying the therapeutic gene miR-143 and evaluate its possible antitumor effect in colorectal cancer. We observed that miR-143 was lowly expressed in patients with colorectal cancer. The upregulation of miR-143 could inhibit cell proliferation and induce cell apoptosis by targeting KRAS in colorectal cancer cells. Then, Ad-RGD-Survivin-ZD55-miR-143 was successfully constructed in this study. Cells infected with Ad-RGD-Survivin-ZD55-miR-143 could inhibit cell proliferation, suppress cell migration and invasion, arrest cells at the G1 phase, and induce cellular apoptosis. At the same time, Ad-RGD-Survivin-ZD55-miR-143 decreased the expression of PARP-1 and KRAS protein in vitro. In a HCT116 xenograft model, intratumoral injection of Ad-RGD-Survivin-ZD55-miR-143 resulted in reduced tumor growth. Furthermore, Ad-RGD-Survivin-ZD55-miR-143 induced apoptosis and decreased the expression level of KRAS in HCT116 xenograft cells. Our results suggested that Ad-RGD-Survivin-ZD55-miR-143 produced a strong antitumor effect by targeting KRAS and that this strategy could broaden the therapeutic options for treating colorectal cancer.
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Affiliation(s)
- Qifeng Luo
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
| | - Hongming Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China.,Breast Disease Center, The Affiliated Hospital of Qingdao University, Shandong 266000, P. R. China
| | - Xiaochong Deng
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
| | - Jiayi Li
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
| | - Wei Jian
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
| | - Junyong Zhao
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
| | - Xueyu Zheng
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
| | - Shiva Basnet
- Department of Gastrointestinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P. R. China
| | - Haiyan Ge
- Department of Gastrointestinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P. R. China
| | - Twingle Daniel
- Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia
| | - Bin Xu
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
| | - Lin Fang
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China
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16
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Yoshikawa Y, Taniguchi K, Tsujino T, Heishima K, Inamoto T, Takai T, Minami K, Azuma H, Miyata K, Hayashi K, Kataoka K, Akao Y. Anti-cancer Effects of a Chemically Modified miR-143 on Bladder Cancer by Either Systemic or Intravesical Treatment. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 13:290-302. [PMID: 30911586 PMCID: PMC6416526 DOI: 10.1016/j.omtm.2019.02.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 02/13/2019] [Indexed: 12/29/2022]
Abstract
We developed a novel chemically modified miR-143 (miR-143#12), and with it we investigated the contribution of miR-143 to the pathogenesis of bladder cancer (BC), in which miR-143 is extremely downregulated. Since miR-143 silenced K-RAS and RAS effector-signaling molecules Erk and Akt, we performed the ectopic expression of miR-143 in human BC 253J-BV cells, and we examined the growth inhibition and the mechanism of it in vitro and in orthotopic model mice. As a result, miR-143#12 induced a marked growth inhibition with apoptosis through impairing RAS-signaling networks, including SOS1, which exchanges guanosine diphosphate (GDP)/RAS for active guanosine triphosphate (GTP)/RAS. In the in vivo study, miR-143#12 exhibited a marked anti-tumor activity by either systemic or intravesical administration with polyionic copolymer (PIC) as the carrier, compared with the activity obtained by use of lipofection. These findings raised the possibility that the chemically modified miR-143#12 would be a candidate of microRNA (miRNA) medicine for BC delivered by intravesical infusion.
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Affiliation(s)
- Yuki Yoshikawa
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.,Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Kohei Taniguchi
- Translational Research Program, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Takuya Tsujino
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.,Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Kazuki Heishima
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
| | - Teruo Inamoto
- Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Tomoaki Takai
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.,Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Koichiro Minami
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.,Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Haruhito Azuma
- Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Kanjiro Miyata
- Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Kotaro Hayashi
- Inovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Kazunori Kataoka
- Inovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.,Policy Alternatives Research Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yukihiro Akao
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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17
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Diagnostic value of serum miR197 and miR145 in non-small cell lung cancer. Oncol Lett 2019; 17:3247-3252. [PMID: 30867756 PMCID: PMC6396217 DOI: 10.3892/ol.2019.9958] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 01/14/2019] [Indexed: 02/06/2023] Open
Abstract
Diagnostic value of microRNA (miR)-197 and miR-145 in non-small cell lung cancer (NSCLC) and their relationship with the clinicopathological parameters of NSCLC patients were investigated. Seventy-six patients with NSCLC admitted to Jimo Hospital of Traditional Chinese Medicine from July 2016 to March 2018 were enrolled in group A, while 60 healthy who received health examinations during the same period were enrolled in group B. The relative expression levels of serum miR-197 and miR-145 were detected by RT-qPCR. The relative expression of serum miR-197 in group A was significantly higher than that in group B (P<0.001); the relative expression of serum miR-145 in group A was significantly lower than that in group B (P<0.001); serum miR-197 in group A showed association with the clinical stage of NSCLC patients (P<0.001); serum miR-145 in group A was associated with the clinical stage and pathological differentiation of patients with NSCLC (P<0.001). The AUC of serum miR-197 diagnosis of NSCLC was 0.864 (95% CI: 0.804-0.924), with a diagnostic sensitivity of 73.68% and a specificity of 85.00%; the AUC of serum miR-145 diagnosis of NSCLC was 0.879 (95% CI: 0.824-0.934), with a diagnostic sensitivity of 84.21% and a specificity of 71.67%; the AUC of the diagnosis of the combination of serum miR-197 and miR-145 for NSCLC was 0.952 (95% CI: 0.919-0.984), with a diagnostic sensitivity of 92.10% and a specificity of 78.33%. miR-197 and miR-145 are potential new biomarkers in the diagnosis of NSCLC due to their possible involvement in the occurrence and development of NSCLC. With good sensitivity and specificity of single miR-197 and single miR-145 for the diagnosis of NSCLC, the combined detection of miR-197 and miR-145 can achieve a better sensitivity in the diagnosis of NSCLC.
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18
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Javadian M, Gharibi T, Shekari N, Abdollahpour‐Alitappeh M, Mohammadi A, Hossieni A, Mohammadi H, Kazemi T. The role of microRNAs regulating the expression of matrix metalloproteinases (MMPs) in breast cancer development, progression, and metastasis. J Cell Physiol 2018; 234:5399-5412. [DOI: 10.1002/jcp.27445] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Mahsa Javadian
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Najibeh Shekari
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | | | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Arezoo Hossieni
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Hamed Mohammadi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
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19
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Li Q, Zhang Y, Sun J, Bo Q. Paeonol-mediated apoptosis of hepatocellular carcinoma cells by NF-κB pathway. Oncol Lett 2018; 17:1761-1767. [PMID: 30675235 PMCID: PMC6341580 DOI: 10.3892/ol.2018.9730] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 10/25/2018] [Indexed: 01/25/2023] Open
Abstract
The aim of the study was to investigate the effect of paeonol on the apoptosis of hepatocellular carcinoma cells and to explore the possible mechanism of its effect. During the experiment, the human hepatoma (Huh7) cell line was cultured and treated with different concentrations of paeonol. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect the effects of paeonol at different concentrations on the proliferation of Huh7 cells after 24 h, and the optimal concentration of paeonol was selected for follow-up experiments. Huh7 cells were divided into the blank control group (C group), parthenolide [(an inhibitor of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)] group (CE group), paeonol group (PO group), and paeonol + tumor necrosis factor-α (TNF-α) (an activator of NF-κB) group (PN group). The effect of paeonol on the apoptosis of Huh7 cells was detected via flow cytometry and Hoechst staining, respectively. The expression levels of NF-κB and protein apoptosis inhibitor-5 (p-API-5) were detected by semi-quantitative polymerase chain reaction (PCR) and western blot analysis, respectively, and the activity of NF-κB in cells was measured by NF-κB p65/50. After determination of the effects of paeonol at different concentrations on Huh7 cells by MTT assay, it was found that paeonol at the concentration of 200–800 µM could inhibit the proliferation of Huh7 cells (P<0.01), with 500 µM phenol being selected as the treatment concentration for follow-up experiments. Results of flow cytometry and Hoechst staining showed that the apoptotic levels of Huh7 cells in the PO and CE groups were significantly increased compared with that in the C group, and that in the PO group was higher than that in the PN group. The differences were statistically significant (P<0.01). Results of semi-quantitative PCR and western blot analysis revealed that the expression levels of NF-κB and p-API-5 in the PO and CE groups were significantly lower than those in the C group, and those in the PO group were lower than those in the PN group. The differences were statistically significant (P<0.01). The expression level of NF-κB p65/50 in the PO group was significantly lower than that in the C group (P<0.01). The results suggest that paeonol can significantly increase the apoptosis rate of Huh7 cells, and the possible mechanism of inducing apoptosis is related to the downregulation of NF-κB and p-API-5 and inhibition of the NF-κB signaling pathway.
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Affiliation(s)
- Qiang Li
- Department of Pharmacy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Ying Zhang
- Department of Pharmacy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jing Sun
- Department of Pharmacy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Qiyu Bo
- Department of First Operating Room, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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20
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Infection of Epstein⁻Barr Virus in Type III Latency Modulates Biogenesis of Exosomes and the Expression Profile of Exosomal miRNAs in the Burkitt Lymphoma Mutu Cell Lines. Cancers (Basel) 2018; 10:cancers10070237. [PMID: 30029522 PMCID: PMC6071279 DOI: 10.3390/cancers10070237] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 12/15/2022] Open
Abstract
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is associated with various malignancies in B lymphocytes and epithelial cells. EBV encodes 49 microRNAs in two separated regions, termed the BART and BHRF1 loci. Although accumulating evidence demonstrates that EBV infection regulates the profile of microRNAs in the cells, little is known about the microRNAs in exosomes released from infected cells. Here, we characterized the expression profile of intracellular and exosomal microRNAs in EBV-negative, and two related EBV-infected Burkitt lymphoma cell lines having type I and type III latency by next-generation sequencing. We found that the biogenesis of exosomes is upregulated in type III latently infected cells compared with EBV-negative and type I latently infected cells. We also observed that viral and several specific host microRNAs were predominantly incorporated in the exosomes released from the cells in type III latency. We confirmed that multiple viral microRNAs were transferred to the epithelial cells cocultured with EBV-infected B cells. Our findings indicate that EBV infection, in particular in type III latency, modulates the biogenesis of exosomes and the profile of exosomal microRNAs, potentially contributing to phenotypic changes in cells receiving these exosomes.
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21
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Clark RJ, Craig MP, Agrawal S, Kadakia M. microRNA involvement in the onset and progression of Barrett's esophagus: a systematic review. Oncotarget 2018; 9:8179-8196. [PMID: 29487725 PMCID: PMC5814292 DOI: 10.18632/oncotarget.24145] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 12/22/2017] [Indexed: 12/13/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that develops from Barrett's esophagus (BE), an intestinal metaplasia of the distal esophagus. microRNAs (miRNAs), short non-coding regulatory RNAs, are frequently dysregulated in BE and are thought to play key roles in the onset of BE and its progression to EAC. miRNAs thus have potential diagnostic and prognostic value and are increasingly being used as cancer biomarkers. This review summarizes the current literature related to miRNAs that are dysregulated in BE within the context of Hedgehog, Notch, MAPK, NF kappa-B, Wnt and epithelial-mesenchymal transition (EMT) signaling which are thought to drive BE onset and progression. This comprehensive analysis of miRNAs and their associated signaling in the regulation of BE provides an overview of vital discoveries in this field and highlights gaps in our understanding of BE pathophysiology that warrant further investigation.
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Affiliation(s)
- Reilly J Clark
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
| | - Michael P Craig
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
| | | | - Madhavi Kadakia
- Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA
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22
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Xie H, Ren X, Xin S, Lan X, Lu G, Lin Y, Yang S, Zeng Z, Liao W, Ding YQ, Liang L. Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer. Oncotarget 2018; 7:26680-91. [PMID: 27058418 PMCID: PMC5042007 DOI: 10.18632/oncotarget.8589] [Citation(s) in RCA: 361] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 03/07/2016] [Indexed: 12/14/2022] Open
Abstract
Circular RNAs (circRNAs), a large class of RNAs, have recently shown huge capabilities as gene regulators in mammals. Some of them bind with microRNAs (miRNAs) and act as natural miRNA sponges to inhibit related miRNAs’ activities. Here we showed that hsa_circ_001569 acted as a positive regulator in cell proliferation and invasion of colorectal cancer (CRC). Moreover, hsa_circ_001569 was identified as a sponge of miR-145 and up-regulated miR-145 functional targets E2F5, BAG4 and FMNL2. In CRC tissues, circ_001569 negatively correlated with miR-145, and miR-145 correlated negatively with E2F5, BAG4 and FMNL2 expressions. Our study reveals a novel regulatory mechanism of circ_001569 in cell proliferation and invasion in CRC, provides a comprehensive landscape of circ_001569 that will facilitate further biomarker discoveries in the progression of CRC.
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Affiliation(s)
- Huijun Xie
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Xiaoli Ren
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Sainan Xin
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Xiaoliang Lan
- Department of General Surgery, Nanfang Hospital, Guangzhou, Guangdong, China
| | - Guifeng Lu
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yuan Lin
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Shaoshan Yang
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Zhicheng Zeng
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Wenting Liao
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yan-Qing Ding
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Li Liang
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
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23
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Abstract
Prostate cancer still represents a major health problem for men worldwide. Due to the specific limitation of the currently used clinical biomarkers for prostate cancer, there is a need to identify new and more accurate prostate-specific biomarkers, both for diagnosis and prediction. Small noncoding species of RNAs called microRNAs (miRNAs) have emerged as possible biomarkers in cancer tissues as well as biological fluids, including for prostate cancer. Moreover, it has been shown that miRNAs could be used as therapeutic targets in different cancer types, including prostate cancer, playing an important role in improving diagnosis and prognosis; and miRNAs have the potential to be clinically useful as predictors of response to personalized cancer therapy and as predictors of prognosis. The analysis of miRNAs in prostate tissue is rather straightforward and has been routinely done on fresh tissue. In addition, due to the more stable nature of miRNAs, they are amenable to be analyzed in archived formalin fixed paraffin embedded tissue as well, and also in serum, plasma and urine, using various analytical platforms including microarrays, next generation sequencing and real time PCR. Moreover, although the existence or prostasomes (microvesicles secreted by prostate cells including prostate cancer cells) has been known for years and they were studied as a source of biomarkers for prostate cancer, only recently it has been described that these vesicles also contain miRNAs that could be used as biomarkers in prostate cancer. This chapter underscores the feasibility of current technologies for miRNA analysis and their importance in prostate cancer biology. Moreover, elucidating the specific alteration of miRNA expression and how to modulate it in prostate tissue will open new avenues for developing therapeutic strategies for prostate cancer treatment.
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Affiliation(s)
- Ovidiu Balacescu
- Department of Functional Genomics, Proteomics and Experimental Pathology, The Oncology Institute "Prof. Dr. Ion Chiricuta", Cluj-Napoca, Romania
| | | | - Catalin Marian
- Department of Biochemistry and Pharmacology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania.
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24
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Yang Y, Du Y, Liu X, Cho WC. Involvement of Non-coding RNAs in the Signaling Pathways of Colorectal Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 937:19-51. [PMID: 27573893 DOI: 10.1007/978-3-319-42059-2_2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the most common diagnosed cancers worldwide. The metastasis and development of resistance to anti-cancer treatment are major challenges in the treatment of CRC. Understanding mechanisms underpinning the pathogenesis is therefore critical in developing novel agents for CRC treatments. A large number of evidence has demonstrated that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs have functional roles in both the physiological and pathological processes by regulating the expression of their target genes. These molecules are engaged in the pathobiology of neoplastic diseases and are targets for the diagnosis, prognosis and therapy of a variety of cancers, including CRC. In this regard, ncRNAs have emerged as one of the hallmarks of CRC pathogenesis and they also play key roles in metastasis, drug resistance and the stemness of CRC stem cell by regulating various signaling networks. Therefore, a better understanding the ncRNAs involved in the signaling pathways of CRC may lead to the development of novel strategy for diagnosis, prognosis and treatment of CRC. In this chapter, we summarize the latest findings on ncRNAs, with a focus on miRNAs and lncRNAs involving in signaling networks and in the regulation of pathogenic signaling pathways in CRC.
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Affiliation(s)
- Yinxue Yang
- The General Hospital, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yong Du
- The General Hospital, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Xiaoming Liu
- The General Hospital, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.
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25
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Van Raay T, Allen-Vercoe E. Microbial Interactions and Interventions in Colorectal Cancer. Microbiol Spectr 2017; 5:10.1128/microbiolspec.bad-0004-2016. [PMID: 28643625 PMCID: PMC11687491 DOI: 10.1128/microbiolspec.bad-0004-2016] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Indexed: 12/14/2022] Open
Abstract
Recently, several lines of evidence that indicate a strong link between the development of colorectal cancer (CRC) and aspects of the gut microbiota have become apparent. However, it remains unclear how changes in the gut microbiota might influence carcinogenesis or how regional organization of the gut might influence the microbiota. In this review, we discuss several leading theories that connect gut microbial dysbiosis with CRC and set this against a backdrop of what is known about proximal-distal gut physiology and the pathways of CRC development and progression. Finally, we discuss the potential for gut microbial modulation therapies, for example, probiotics, antibiotics, and others, to target and improve gut microbial dysbiosis as a strategy for the prevention or treatment of CRC.
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Affiliation(s)
- Terence Van Raay
- Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada
| | - Emma Allen-Vercoe
- Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada
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26
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Colorectal Cancer: From the Genetic Model to Posttranscriptional Regulation by Noncoding RNAs. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7354260. [PMID: 28573140 PMCID: PMC5442347 DOI: 10.1155/2017/7354260] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/16/2017] [Indexed: 12/11/2022]
Abstract
Colorectal cancer is the third most common form of cancer in developed countries and, despite the improvements achieved in its treatment options, remains as one of the main causes of cancer-related death. In this review, we first focus on colorectal carcinogenesis and on the genetic and epigenetic alterations involved. In addition, noncoding RNAs have been shown to be important regulators of gene expression. We present a general overview of what is known about these molecules and their role and dysregulation in cancer, with a special focus on the biogenesis, characteristics, and function of microRNAs. These molecules are important regulators of carcinogenesis, progression, invasion, angiogenesis, and metastases in cancer, including colorectal cancer. For this reason, miRNAs can be used as potential biomarkers for diagnosis, prognosis, and efficacy of chemotherapeutic treatments, or even as therapeutic agents, or as targets by themselves. Thus, this review highlights the importance of miRNAs in the development, progression, diagnosis, and therapy of colorectal cancer and summarizes current therapeutic approaches for the treatment of colorectal cancer.
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27
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Bailey KL, Agarwal E, Chowdhury S, Luo J, Brattain MG, Black JD, Wang J. TGFβ/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells. PLoS One 2017; 12:e0176096. [PMID: 28414818 PMCID: PMC5393866 DOI: 10.1371/journal.pone.0176096] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 04/05/2017] [Indexed: 01/15/2023] Open
Abstract
In this study, we have uncovered a novel crosstalk between TGFβ and IGF-1R signaling pathways. We show for the first time that expression and activation of IRS-1, an IGF-1R adaptor protein, is decreased by TGFβ/Smad3 signaling. Loss or attenuation of TGFβ activation leads to elevated expression and phosphorylation of IRS-1 in colon cancer cells, resulting in enhanced cell proliferation, decreased apoptosis and increased tumor growth in vitro and in vivo. Downregulation of IRS-1 expression reversed Smad3 knockdown-mediated oncogenic phenotypes, indicating that TGFβ/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression and activation. Additionally, the TGFβ/Smad3/IRS-1 signaling axis regulates expression of cyclin D1 and XIAP, which may contribute to TGFβ/Smad3/IRS-1-mediated cell cycle progression and survival. Given that loss of TGFβ signaling occurs frequently in colon cancer, an important implication of our study is that IRS-1 could be a potential therapeutic target for colon cancer treatment.
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Affiliation(s)
- Katie L. Bailey
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Ekta Agarwal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States of America
- Wistar Institute, Philadelphia, Pennsylvania
| | - Sanjib Chowdhury
- Section of Gastroenterology, Department of Medicine, Boston University Medical Center, Boston, Massachusetts, United States of America
| | - Jiangtao Luo
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Michael G. Brattain
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States of America
| | - Jennifer D. Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Jing Wang
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States of America
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
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28
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Yan W, Chen ZY, Chen JQ, Chen HM. BMP2 promotes the differentiation of neural stem cells into dopaminergic neurons in vitro via miR-145-mediated upregulation of Nurr1 expression. Am J Transl Res 2016; 8:3689-3699. [PMID: 27725851 PMCID: PMC5040669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 07/10/2016] [Indexed: 06/06/2023]
Abstract
BACKGROUND Neural stem cells (NSCs) are pluripotent and self-renewing cells which could differentiate into diverse types of neural cells, such as dopaminergic (DA) neurons, the loss of which is the typical characteristic of Parkinson's disease (PD). This study aimed to examine the molecular mechanisms of BMP2-mediating NSCs differentiation into DA neurons. METHODS Different concentrations of BMP2 were used to induce the differentiation of NSCs into DA neurons, which were characterized by the number and the neurite lengths of tyrosine hydroxylase (TH)+ and dopamine transporter (DAT)+ neurons by immunocytochemistry. qRT-PCR and Western blot were performed to explore the expression of miR-145 and Nurr1. The methylation level of miR-145 promoter was examined by DNA methylation analyses. The regulation of miR-145 on Nurr1 was detected by Dual-Luciferase reporter assay. RESULTS The number of TH+ and DAT+ neurons were significantly increased in NSCs treated with 20 and 100 ng/ml of BMP2, as well as the neurite lengths of TH+ and DAT+ neurons. The reduced level of miR-145 and up-regulated Nurr1 were observed in NSCs induced by BMP2. The hypermethylation level of miR-145 promoter down-regulated the expression of miR-145 in NSCs pretreated with BMP2, which was regulated by DNMT3b. Luciferase reporter assay showed that Nurr1 was a direct target of miR-145. miR-145 overexpression restrained the differentiating effect of BMP2. Moreover, overexpression of Nurr1 abrogated this effect of miR-145 overexpression. CONCLUSION Our results showed that BMP2 promoted the differentiation of NSCs into DA neurons in vitro and miR-145 and Nurr1 were involved in the neurotrophic effects of BMP2.
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Affiliation(s)
- Wang Yan
- Neurological Department of Internal Medicine, Ningbo No. 2 Hospital Ningbo 315000, China
| | - Zhao-Ying Chen
- Neurological Department of Internal Medicine, Ningbo No. 2 Hospital Ningbo 315000, China
| | - Jia-Qi Chen
- Neurological Department of Internal Medicine, Ningbo No. 2 Hospital Ningbo 315000, China
| | - Hui-Min Chen
- Neurological Department of Internal Medicine, Ningbo No. 2 Hospital Ningbo 315000, China
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29
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Jagot-Lacoussiere L, Kotula E, Villoutreix BO, Bruzzoni-Giovanelli H, Poyet JL. A Cell-Penetrating Peptide Targeting AAC-11 Specifically Induces Cancer Cells Death. Cancer Res 2016; 76:5479-90. [DOI: 10.1158/0008-5472.can-16-0302] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 06/24/2016] [Indexed: 11/16/2022]
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30
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MicroRNA-145 functions as a tumor suppressor by targeting matrix metalloproteinase 11 and Rab GTPase family 27a in triple-negative breast cancer. Cancer Gene Ther 2016; 23:258-65. [PMID: 27364572 DOI: 10.1038/cgt.2016.27] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 05/04/2016] [Accepted: 05/04/2016] [Indexed: 12/26/2022]
Abstract
Although increasing evidence has documented that microRNA-145 (miR-145) acts as a tumor suppressor in breast cancer, its exact role in triple-negative breast cancer (TNBC) remains poorly defined. In this study, the expression of miR-145 in human TNBC cells and samples from 30 patients was analyzed by stem-loop real-time PCR. We found that miR-145 was significantly downregulated in TNBC tissues and cells. Upregulating miR-145 in HCC1937 cells dramatically suppressed cell proliferation and induced G1-phase arrest, whereas MDA-MB-231 cells did not show growth inhibition. MiR-145 exhibited an inhibitory role in cell invasion through the post-transcriptional regulation of the novel targets MMP11 and Rab27a in TNBC cells. Additionally, miR-145 silencing could be reversed by 5-aza-2'-deoxycytidine (DAC). These results demonstrated that miR-145 has an inhibitory role in TNBC malignancy by targeting MMP11 and Rab27a, which might be potential therapeutic and diagnostic targets for TNBC.
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Azizian A, Gruber J, Ghadimi BM, Gaedcke J. MicroRNA in rectal cancer. World J Gastrointest Oncol 2016; 8:416-426. [PMID: 27190581 PMCID: PMC4865709 DOI: 10.4251/wjgo.v8.i5.416] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Revised: 12/01/2015] [Accepted: 03/09/2016] [Indexed: 02/05/2023] Open
Abstract
In rectal cancer, one of the most common cancers worldwide, the proper staging of the disease determines the subsequent therapy. For those with locally advanced rectal cancer, a neoadjuvant chemoradiotherapy (CRT) is recommended before any surgery. However, response to CRT ranges from complete response (responders) to complete resistance (non-responders). To date we are not able to separate in advance the first group from the second, due to the absence of a valid biomarker. Therefore all patients receive the same therapy regardless of whether they reap benefits. On the other hand almost all patients receive a surgical resection after the CRT, although a watch-and-wait procedure or an endoscopic resection might be sufficient for those who responded well to the CRT. Being highly conserved regulators of gene expression, microRNAs (miRNAs) seem to be promising candidates for biomarkers. Many studies have been analyzing the miRNAs expressed in rectal cancer tissue to determine a specific miRNA profile for the ailment. Unfortunately, there is only a small overlap of identified miRNAs between different studies, posing the question as to whether different methods or differences in tissue storage may contribute to that fact or if the results simply are not reproducible, due to unknown factors with undetected influences on miRNA expression. Other studies sought to find miRNAs which correlate to clinical parameters (tumor grade, nodal stage, metastasis, survival) and therapy response. Although several miRNAs seem to have an impact on the response to CRT or might predict nodal stage, there is still only little overlap between different studies. We here aimed to summarize the current literature on rectal cancer and miRNA expression with respect to the different relevant clinical parameters.
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Jiang SB, He XJ, Xia YJ, Hu WJ, Luo JG, Zhang J, Tao HQ. MicroRNA-145-5p inhibits gastric cancer invasiveness through targeting N-cadherin and ZEB2 to suppress epithelial-mesenchymal transition. Onco Targets Ther 2016; 9:2305-15. [PMID: 27143926 PMCID: PMC4846054 DOI: 10.2147/ott.s101853] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
MicroRNA (miR)-145-5p has been reported to function as a suppressor of cancer and plays an important role in cancer invasiveness. Epithelial-mesenchymal transition (EMT) is an important process in cancer invasion and migration. However, the involvement of miR-145-5p in EMT in human gastric cancer (GC) remains unclear. In this study, we aimed to investigate the molecular mechanisms by which miR-145-5p regulates EMT in GC invasiveness. We used quantitative real-time polymerase chain reaction to investigate the miR-145-5p expression level in GC and matched normal tissues. The effects of miR-145-5p on GC cell invasion and migration abilities were evaluated using Transwell models. The relationships among miR-145-5p and zinc-finger E-box binding homeobox 2 (ZEB2), E-cadherin, and N-cadherin were analyzed by quantitative real-time polymerase chain reaction and Western blot analyses. miR-145-5p levels in primary GC tissues obtained from 60 patients were significantly downregulated, compared to those in paired normal tissues. Lauren classification, depth of tumor invasion, lymph node metastasis, lymphatic invasion, and tumor-node-metastasis stage were associated with miR-145-5p expression. miR-145-5p inhibits the expression of the candidate target gene ZEB2 to delay the invasion and migration of GC cells. ZEB2 acts as transcriptional repressor of E-cadherin, while miR-145-5p is known to suppress N-cadherin directly to regulate EMT. Therefore, we concluded that miR-145-5p may target N-cadherin and ZEB2 directly to influence EMT.
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Affiliation(s)
- Shi-Bin Jiang
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Xu-Jun He
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Ying-Jie Xia
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Wei-Jian Hu
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Jun-Gang Luo
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Jun Zhang
- Wenzhou Medical University, Wenzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Hou-Quan Tao
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
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Moreno-Sánchez R, Saavedra E, Gallardo-Pérez JC, Rumjanek FD, Rodríguez-Enríquez S. Understanding the cancer cell phenotype beyond the limitations of current omics analyses. FEBS J 2015; 283:54-73. [DOI: 10.1111/febs.13535] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 08/24/2015] [Accepted: 09/25/2015] [Indexed: 12/27/2022]
Affiliation(s)
- Rafael Moreno-Sánchez
- Departamento de Bioquímica; Instituto Nacional de Cardiología Ignacio Chávez; Tlalpan Mexico
| | - Emma Saavedra
- Departamento de Bioquímica; Instituto Nacional de Cardiología Ignacio Chávez; Tlalpan Mexico
| | | | | | - Sara Rodríguez-Enríquez
- Departamento de Bioquímica; Instituto Nacional de Cardiología Ignacio Chávez; Tlalpan Mexico
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Mousa L, Salem ME, Mikhail S. Biomarkers of Angiogenesis in Colorectal Cancer. BIOMARKERS IN CANCER 2015; 7:13-9. [PMID: 26543385 PMCID: PMC4624093 DOI: 10.4137/bic.s25250] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 09/17/2015] [Accepted: 09/23/2015] [Indexed: 12/18/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and accounts for 10% of all new cancer diagnoses. Angiogenesis is a tightly regulated process that is mediated by a group of angiogenic factors such as vascular endothelial growth factor and its receptors. Given the widespread use of antiangiogenic agents in CRC, there has been considerable interest in the development of methods to identify novel markers that can predict outcome in the treatment of this disease with angiogenesis inhibitors. Multiple biomarkers are in various phases of development and include tissue, serum, and imaging biomarkers. The complexity of the angiogenesis pathway and the overlap between the various angiogenic factors present a significant challenge to biomarker discovery. In our review, we discuss the angiogenesis pathway and the most promising evolving concepts in biomarker discovery, as well as highlight the landmark studies that identify subgroups of patients with CRC who may preferentially benefit from angiogenesis inhibitors.
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Affiliation(s)
- Luay Mousa
- The Medstar Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | - Mohamed E Salem
- Medstar Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC, USA
| | - Sameh Mikhail
- The Medstar Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
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Liu X, Gong J, Xu B. miR-143 down-regulates TLR2 expression in hepatoma cells and inhibits hepatoma cell proliferation and invasion. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:12738-12747. [PMID: 26722463 PMCID: PMC4680408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 09/28/2015] [Indexed: 06/05/2023]
Abstract
Hepatoma is a tumor with high degree of malignancy. A number of oncogenes and tumor suppressor genes play certain roles in tumorigenesis and progression. Among which, miRNA, as an important class of gene regulators, play important roles in regulating tumorigenesis and development of hepatoma. So know well the unique molecular pathway is very important. Here, we showed that there is a different miR-143 expression patterns in different hepatoma tissues, and that miR-143 expressions contribute disease progress. By contrast, we down-regulated the expression of miR-143 with miR-143 mimics in HepG2 cells resulting in decreased proliferation. And the decreased proliferations of HepG2 cells were due to a G0/G1 arrest of cell cycle. During this progress, the increased apoptosis may be another major cause for decreased proliferation of HepG2 cells. And then, we found miR-143 down-regulation induced decreased mRNA and protein expressions of TLR2 and NF-κB. These results show that HepG2 cells depend to a greater extent on miR-143 for proliferation, and miR-143 down-regulation may induce a cell cycle arrest though TLR and NF-κB pathway. miR-143 blockade may be beneficial in therapy of Hepatoma.
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Affiliation(s)
- Xing Liu
- Department of Infectious Disease, Linyi People’s HospitalLinyi 276000, China
| | - Junling Gong
- Department of Obstetrics and Gynecology, Linyi People’s HospitalLinyi 276000, China
| | - Baoli Xu
- Department of General Surgery, Linyi People’s HospitalLinyi 276000, China
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Liang Y, Sun R, Li L, Yuan F, Liang W, Wang L, Nie X, Chen P, Zhang L, Gao L. A Functional Polymorphism in the Promoter of MiR-143/145 Is Associated With the Risk of Cervical Squamous Cell Carcinoma in Chinese Women: A Case-Control Study. Medicine (Baltimore) 2015; 94:e1289. [PMID: 26252302 PMCID: PMC4616598 DOI: 10.1097/md.0000000000001289] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
MiR-143/145 is down-regulated in cervical cancer, which may serve as a tumor suppressor by targeting KRAS and Ras-responsive element-binding protein (RREB1). Activated KRAS leads to down-regulation of miR-143/145 transcription in a RREB1-dependent manner, establishing a miR-143/145-KRAS-RREB1 feedback loop. A polymorphism rs4705343C/T in the promoter of miR-143/145 might influence the binding of TATA-binding protein. We hypothesized that the miR-143/145 rs4705343 and KRAS rs712 may be related to the occurrence of cervical squamous cell carcinoma (CSCC). In this study, we genotyped the 2 polymorphisms in 415 patients with CSCC and 504 controls using polymerase chain reaction-restriction fragment length polymorphism. The promoter activities were measured by the Dual-Luciferase Reporter Assay System. We found that the rs4705343TC genotype was associated with an increased risk of CSCC (adjusted odds ratio [OR] = 1.37; 95% confidence interval [CI], 1.05-1.80). The significantly increased association was also observed in a dominant genetic model (adjusted OR = 1.32; 95% CI, 1.01-1.72). Combined analysis showed that individuals carrying the genotypes of rs4705343 TC/CC and rs712GT/TT had a 1.47-fold increased risk of CSCC (adjusted OR = 1.47; 95% CI, 1.01-2.15). By using multifactor dimensionality reduction software method, we identified a significant interaction between the miR-143/145 rs4705343 and KRAS rs712. Dual-Luciferase Reporter Assay showed that the luciferase activity was significantly lower in cells transfected with the rs4705343C allele than that of the rs4705343T allele. These findings indicate that miR-143/145 rs4705343 and KRAS rs712 may contribute to the etiology of CSCC in Chinese women.
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Affiliation(s)
- Yundan Liang
- From the Laboratory of Molecular and Translational Medicine, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China (YL, RS, LL, FY, XN, LZ, LG); Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, P.R. China (YL, RS, LL, FY, XN, LZ, LG); Central Laboratory, Yunnan University of Chinese Traditional Medicine, Kunming, Yunnan, P.R. China (RS); and Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China (LW, PC, LZ)
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MicroRNAs as Regulator of Signaling Networks in Metastatic Colon Cancer. BIOMED RESEARCH INTERNATIONAL 2015; 2015:823620. [PMID: 26064956 PMCID: PMC4438141 DOI: 10.1155/2015/823620] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 04/06/2015] [Accepted: 04/06/2015] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are a class of small, noncoding RNA molecules capable of regulating gene expression translationally and/or transcriptionally. A large number of evidence have demonstrated that miRNAs have a functional role in both physiological and pathological processes by regulating the expression of their target genes. Recently, the functionalities of miRNAs in the initiation, progression, angiogenesis, metastasis, and chemoresistance of tumors have gained increasing attentions. Particularly, the alteration of miRNA profiles has been correlated with the transformation and metastasis of various cancers, including colon cancer. This paper reports the latest findings on miRNAs involved in different signaling networks leading to colon cancer metastasis, mainly focusing on miRNA profiling and their roles in PTEN/PI3K, EGFR, TGFβ, and p53 signaling pathways of metastatic colon cancer. The potential of miRNAs used as biomarkers in the diagnosis, prognosis, and therapeutic targets in colon cancer is also discussed.
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