|
1
|
Sharma A, Hanisha, Rana A, Sharma I. Molecular Crosstalk by miR-449a and miR-34b in endometrial and ovarian cancer cells in vitro. Gene 2025; 947:149337. [PMID: 39965746 DOI: 10.1016/j.gene.2025.149337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 02/08/2025] [Accepted: 02/14/2025] [Indexed: 02/20/2025]
Abstract
AIMS Endometrial and ovarian cancers, the sixth and eighth most prevalent cancers in women globally, account for nearly 8% of all new female cancer cases annually. MicroRNAs (miRNAs) have emerged as a promising field in cancer treatment, offering new avenues for targeted therapies and diagnostic tools. Recent miRNA-based cancer research has uncovered various miRNAs commonly dysregulated in cancer and which possess tumor-suppressive functions. These miRNAs influence genes crucial for cellular differentiation, proliferation, apoptosis, and metabolism. MAIN METHODS In the present study, the researchers investigated the effect of dysregulation of two such miRNAs, miR-449a and miR-34b, on the oncogenes involved in the progression of endometrial and ovarian cancer using the respective RL95-2 and SKOV3 cell lines. The transcriptional gene expression analysis was done by Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). KEY FINDINGS It was found that the overexpression of miR-449a and miR-34b downregulated HIF-1α, VEGF, c-Myc, COX-2, and TNF-α while upregulating TP53 in both cancer types. Conversely, inhibiting these miRNAs increased the levels of HIF-1α, VEGF, c-Myc, COX-2, and TNF-α, and decreased TP53. However, co-transfection with both mimic and inhibitor had varying effects. SIGNIFICANCE The study demonstrated that these miRNAs could influence critical processes such as angiogenesis, proliferation, inflammation, tumorigenesis, and apoptosis in cancer cells, highlighting their potential as therapeutic targets. However, the varied effects observed with the co-transfection of mimics and inhibitors suggest a complex interplay that requires further investigation.
Collapse
Affiliation(s)
- Anuradha Sharma
- Department of Zoology, Panjab University, Chandigarh 160014, INDIA.
| | - Hanisha
- Department of Zoology, Panjab University, Chandigarh 160014, INDIA.
| | - Akanksha Rana
- Department of Zoology, Panjab University, Chandigarh 160014, INDIA.
| | - Indu Sharma
- Department of Zoology, Panjab University, Chandigarh 160014, INDIA.
| |
Collapse
|
|
2
|
Saadh MJ, Hussain QM, Alazzawi TS, Fahdil AA, Athab ZH, Yarmukhamedov B, Al-Nuaimi AMA, Alsaikhan F, Farhood B. MicroRNA as Key Players in Hepatocellular Carcinoma: Insights into Their Role in Metastasis. Biochem Genet 2025; 63:1014-1062. [PMID: 39103713 DOI: 10.1007/s10528-024-10897-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
Liver cancer or hepatocellular carcinoma (HCC) remains the most common cancer in global epidemiology. Both the frequency and fatality of this malignancy have shown an upward trend over recent decades. Liver cancer is a significant concern due to its propensity for both intrahepatic and extrahepatic metastasis. Liver cancer metastasis is a multifaceted process characterized by cell detachment from the bulk tumor, modulation of cellular motility and invasiveness, enhanced proliferation, avoidance of the immune system, and spread either via lymphatic or blood vessels. MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) playing a crucial function in the intricate mechanisms of tumor metastasis. A number of miRNAs can either increase or reduce metastasis via several mechanisms, such as control of motility, proliferation, attack by the immune system, cancer stem cell properties, altering the microenvironment, and the epithelial-mesenchymal transition (EMT). Besides, two other types of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can competitively bind to endogenous miRNAs. This competition results in the impaired ability of the miRNAs to inhibit the expression of the specific messenger RNAs (mRNAs) that are targeted. Increasing evidence has shown that the regulatory axis comprising circRNA/lncRNA-miRNA-mRNA is correlated with the regulation of HCC metastasis. This review seeks to present a thorough summary of recent research on miRNAs in HCC, and their roles in the cellular processes of EMT, invasion and migration, as well as the metastasis of malignant cells. Finally, we discuss the function of the lncRNA/circRNA-miRNA-mRNA network as a crucial modulator of carcinogenesis and the regulation of signaling pathways or genes that are relevant to the metastasis of HCC. These findings have the potential to offer valuable insight into the discovery of novel therapeutic approaches for management of liver cancer metastasis.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | - Tuqa S Alazzawi
- College of Dentist, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Ali A Fahdil
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Bekhzod Yarmukhamedov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | | | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
- School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| |
Collapse
|
|
3
|
Chauhan M, Singh K, Chongtham C, A G A, Sharma P. miR-449a mediated repression of the cell cycle machinery prevents neuronal apoptosis. J Biol Chem 2024; 300:107698. [PMID: 39173945 PMCID: PMC11419829 DOI: 10.1016/j.jbc.2024.107698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/18/2024] [Accepted: 08/08/2024] [Indexed: 08/24/2024] Open
Abstract
Aberrant activation of the cell cycle of terminally differentiated neurons results in their apoptosis and is known to contribute to neuronal loss in various neurodegenerative disorders like Alzheimer's Disease. However, the mechanisms that regulate cell cycle-related neuronal apoptosis are poorly understood. We identified several miRNA that are dysregulated in neurons from a transgenic APP/PS1 mouse model for AD (TgAD). Several of these miRNA are known to and/or are predicted to target cell cycle-related genes. Detailed investigation on miR-449a revealed the following: a, it promotes neuronal differentiation by suppressing the neuronal cell cycle; b, its expression in cortical neurons was impaired in response to amyloid peptide Aβ42; c, loss of its expression resulted in aberrant activation of the cell cycle leading to apoptosis. miR-449a may prevent cell cycle-related neuronal apoptosis by targeting cyclin D1 and protein phosphatase CDC25A, which are important for G1-S transition. Importantly, the lentiviral-mediated delivery of miR-449a in TgAD mouse brain significantly reverted the defects in learning and memory, which are associated with AD.
Collapse
Affiliation(s)
- Monika Chauhan
- Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi, India.
| | - Komal Singh
- Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi, India
| | - Chen Chongtham
- Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India
| | - Aneeshkumar A G
- Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India
| | - Pushkar Sharma
- Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi, India.
| |
Collapse
|
|
4
|
Ricciardiello F, Falco M, Scarpa A, Motta G, Viola P, Bocchetti M, Caraglia M, Alfieri N, Oliva F, Tammaro C, Tortoriello G, Radici M, Camaioni A, Misso G, De Luca P. Tissue expression of miR-449a as risk factor for occult neck metastasis in patients with cT3-T4 N0 laryngeal cancer. A pilot study. Eur Arch Otorhinolaryngol 2024; 281:5015-5020. [PMID: 38771342 DOI: 10.1007/s00405-024-08743-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 05/16/2024] [Indexed: 05/22/2024]
Abstract
OBJECTIVE To explore the potential role of miR-449a as biomarker for laryngeal squamous cell carcinoma (LSCC), especially in the decision strategy of neck dissection (ND). METHODS Each patient underwent total laryngectomy and bilateral ND (levels II-IV); during surgery, tissue samples of around 1 × 0.5 cm were extracted from both healthy tissue adjacent to the tumor and the visibly affected tumor tissue. The extraction of total RNA, encompassing miRNA, was performed using a mirVana PARIS kit. To detect miR449a, cDNA was synthesized from 200 ng of RNA using a TaqMan miRNA reverse transcription kit. RESULTS The study group was formed of 66 patients (62 males, and 4 females) with LSCC, aged between 39 and 77 years (mean 60 + 14.56 yr). MiR-449a was up-regulated in twenty-eight tumors (42%), while it was down-regulated in 38 samples (58%). In the present study, there was a statistical relevance for miR-449a tissue expression for pN staging (p = 0.017), and PNI (p = 0.005). Eight tumors (12%) cN0 became pN + showing occult cervical lymph node metastases at the final histopathological examination, and all of these patients showed miR-449a downregulation. CONCLUSION Super-selective ND (sparing the sub evels IIb and IV) might be the approach to cT3-T4 N0 LSCCs with upregulation of miR-449a; on the other hand, to ensure and effective control of occult neck metastases it would be appropriate to reserve elective ND (including sublevels IIb and IV) for cT3-T4 N0 LSCCs with miR-449a downregulation. Although promising, due to the small size of the cohort, the results of this work can be considered preliminary and need to be confirmed by prospective and larger studies.
Collapse
Affiliation(s)
| | - Michela Falco
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Alfonso Scarpa
- Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy
| | - Giovanni Motta
- Department of Mental, Physical Health and Preventive Medicine, University of Campania, "Luigi Vanvitelli", Naples, Italy
| | - Pasquale Viola
- Department of Experimental and Clinical Medicine, Unit of Audiology, Regional Centre for Cochlear Implants and ENT Diseases, Magna Graecia University, Catanzaro, Italy
| | - Marco Bocchetti
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Nello Alfieri
- Department of Anesthesia and Intensive Care, AORN Cardarelli, Naples, Italy
| | - Flavia Oliva
- Otolaryngology Department, AORN Cardarelli, Naples, Italy
| | - Chiara Tammaro
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Marco Radici
- Otolaryngology Department, Fatebenefratelli Isola Tiberina, Gemelli Isola, Rome, Italy
| | - Angelo Camaioni
- Otolaryngology Department, San Giovanni-Addolorata Hospital, Rome, Italy
| | - Gabriella Misso
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Pietro De Luca
- Otolaryngology Department, Fatebenefratelli Isola Tiberina, Gemelli Isola, Rome, Italy.
| |
Collapse
|
|
5
|
Barati T, Mirzaei Z, Ebrahimi A, Shekari Khaniani M, Mansoori Derakhshan S. miR-449a: A Promising Biomarker and Therapeutic Target in Cancer and Other Diseases. Cell Biochem Biophys 2024; 82:1629-1650. [PMID: 38809350 DOI: 10.1007/s12013-024-01322-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2024] [Indexed: 05/30/2024]
Abstract
In the regulation of gene expression, epigenetic factors like non-coding RNAs (ncRNAs) play an equal role in genetics. The role of microRNAs (miRNAs), which are members of the ncRNA family, in post-transcriptional gene regulation is well-documented and has important implications for both normal and abnormal biological processes, such as angiogenesis, proliferation, survival, and apoptosis. The purpose of this study was to synthesize previous research on miR-449a by analyzing published results from various databases, as there have been a number of investigations on miR-449's potential involvement in the development of human disorders. Based on our findings, miR-449 is strongly dysregulated in a wide range of diseases, from various cancers to cardiovascular diseases, cognitive impairments, and respiratory diseases, and it may play a pivotal role in the development of these problems. In addition, miR-449a functions as a crucial regulator of the expression of several well-known genes, including E2F-3, BCL2, NOTCH1, and SOX4. This, in turn, modulates various pathways and processes related to cancer, including Notch, PI3K, and TGF-β, and contributes to the improvement of cancer drug sensitivity. Curiously, abnormalities in the expression of this miRNA may serve as diagnostic or prognostic indicators for distinguishing between healthy people and patients or to evaluate the survival rates for specific disorders. This article provides a synopsis of the current understanding of miR-449a's role in human disease development through its regulation of gene expression and the biological processes related to these genes and their linked processes. In addition, we have covered the topic of miR-449a's potential as a clinical feature (diagnosis and prognosis) indicator for a range of disorders, both neoplastic and non-neoplastic. In general, our goal was to gain a thorough comprehension of the numerous functions of miR-449a in different disorders.
Collapse
Affiliation(s)
- Tahereh Barati
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Mirzaei
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Ebrahimi
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahmoud Shekari Khaniani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Sima Mansoori Derakhshan
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
6
|
Torres-Ruiz S, Garrido-Cano I, Lameirinhas A, Burgués O, Hernando C, Martínez MT, Rojo F, Bermejo B, Tapia M, Carbonell-Asins JA, Peña CJ, Lluch A, Cejalvo JM, Tormo E, Eroles P. MiRNA-449 family is epigenetically repressed and sensitizes to doxorubicin through ACSL4 downregulation in triple-negative breast cancer. Cell Death Discov 2024; 10:372. [PMID: 39174500 PMCID: PMC11341569 DOI: 10.1038/s41420-024-02128-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/25/2024] [Accepted: 07/31/2024] [Indexed: 08/24/2024] Open
Abstract
Despite progress in breast cancer treatment, a significant portion of patients still relapse because of drug resistance. The involvement of microRNAs in cancer progression and chemotherapy response is well established. Therefore, this study aimed to elucidate the dysregulation of the microRNA-449 family (specifically, microRNA-449a, microRNA-449b-5p, and microRNA-449c-5p) and its impact on resistance to doxorubicin, a commonly used chemotherapeutic drug for the treatment of triple-negative breast cancer. We found that the microRNA-449 family is downregulated in triple-negative breast cancer and demonstrated its potential as a diagnostic biomarker. Besides, our findings indicate that the downregulation of the microRNA-449 family is mediated by the microRNAs-449/SIRT1-HDAC1 negative feedback loop. Moreover, it was found that the microRNA-449 family dysregulates the fatty acid metabolism by targeting ACSL4, which is a potential prognostic biomarker that mediates doxorubicin response through regulation of the drug extrusion pump ABCG2. Altogether, our results suggest that the microRNA-449 family might be a potential therapeutic target for the treatment of triple-negative breast cancer since it is implicated in doxorubicin response through ACSL4/ABCG2 axis regulation. Ultimately, our results also highlight the value of microRNAs-449 and ACSL4 as diagnostic and prognostic biomarkers in triple-negative breast cancer. Proposed model of miRNAs-449 downregulation in TNBC and doxorubicin response. MiRNAs-449 are downregulated in TNBC through a negative feedback loop with SIRT1 and HDAC1. Moreover, ACSL4 increases ABCG2 expression, thus diminishing the intracellular doxorubicin concentration and promoting doxorubicin resistance. MiRNAs-449 overexpression downregulates the ACSL4/ABCG2 axis and sensitizes doxorubicin-resistant cells to doxorubicin. Created with BioRender. TNBC: triple-negative breast cancer; DOX: doxorubicin; SIRT1: Sirtuin 1; HDAC1: Histone deacetylase 1; ACSL4: Acyl-CoA Synthetase Long-Chain Family Member 4; ABCG2: ATP-binding cassette superfamily G member 2.
Collapse
Affiliation(s)
| | - Iris Garrido-Cano
- INCLIVA Biomedical Research Institute, Valencia, Spain
- Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM), Universidad politécnica de Valencia, Universidad de Valencia, Valencia, Spain
- Bioengineering, Biomaterials and Nanomedicine Networking Biomedical Research Centre (CIBER-BBN), Madrid, Spain
| | | | - Octavio Burgués
- INCLIVA Biomedical Research Institute, Valencia, Spain
- Department of Pathology, Hospital Clínico Universitario de València, Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain
| | - Cristina Hernando
- INCLIVA Biomedical Research Institute, Valencia, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia, Spain
| | - María Teresa Martínez
- INCLIVA Biomedical Research Institute, Valencia, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia, Spain
| | - Federico Rojo
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain
- Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain
| | - Begoña Bermejo
- INCLIVA Biomedical Research Institute, Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia, Spain
| | - Marta Tapia
- INCLIVA Biomedical Research Institute, Valencia, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia, Spain
| | | | | | - Ana Lluch
- INCLIVA Biomedical Research Institute, Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia, Spain
- Department of Medicine, Universidad de Valencia, Valencia, Spain
| | - Juan Miguel Cejalvo
- INCLIVA Biomedical Research Institute, Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia, Spain
| | - Eduardo Tormo
- INCLIVA Biomedical Research Institute, Valencia, Spain.
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain.
| | - Pilar Eroles
- INCLIVA Biomedical Research Institute, Valencia, Spain.
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid, Spain.
- Department of Physiology, Universidad de Valencia, Valencia, Spain.
| |
Collapse
|
|
7
|
Chen J, He F, Peng H, Guo J. The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma. Front Mol Biosci 2024; 11:1378386. [PMID: 38584703 PMCID: PMC10995332 DOI: 10.3389/fmolb.2024.1378386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/04/2024] [Indexed: 04/09/2024] Open
Abstract
The consistent notion holds that hepatocellular carcinoma (HCC) initiation, progression, and clinical treatment failure treatment failure are affected by the accumulation of various genetic and epigenetic alterations. MicroRNAs (miRNAs) play an irreplaceable role in a variety of physiological and pathological states. meanwhile, epithelial-mesenchymal transition (EMT) is a crucial biological process that controls the development of HCC. miRNAs regulate the intermediation state of EMTor mesenchymal-epithelial transition (MTE)thereby regulating HCC progression. Notably, miRNAs regulate key HCC-related molecular pathways, including the Wnt/β-catenin pathway, PTEN/PI3K/AKT pathway, TGF-β pathway, and RAS/MAPK pathway. Therefore, we comprehensively reviewed how miRNAs produce EMT effects by multiple signaling pathways and their potential significance in the pathogenesis and treatment response of HCC. emphasizing their molecular pathways and progression in HCC initiation. Additionally, we also pay attention to regulatory mechanisms that are partially independent of signaling pathways. Finally, we summarize and propose miRNA-targeted therapy and diagnosis and defense strategies forHCC. The identification of the mechanism leading to the activation of EMT programs during HCC disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Consequently, we summarize the latest progress in this direction, with a promising path for further insight into this fast-moving field.
Collapse
Affiliation(s)
- Juan Chen
- Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Fuguo He
- Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Peng
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Jinjun Guo
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
8
|
Abdolahi M, Ghaedi Talkhounche P, Derakhshan Nazari MH, Hosseininia HS, Khoshdel-Rad N, Ebrahimi Sadrabadi A. Functional Enrichment Analysis of Tumor Microenvironment-Driven Molecular Alterations That Facilitate Epithelial-to-Mesenchymal Transition and Distant Metastasis. Bioinform Biol Insights 2024; 18:11779322241227722. [PMID: 38318286 PMCID: PMC10840405 DOI: 10.1177/11779322241227722] [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: 01/06/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
Nowadays, hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths, and identifying the effective factors in causing this disease can play an important role in its prevention and treatment. Tumors provide effective agents for invasion and metastasis to other organs by establishing appropriate communication between cancer cells and the microenvironment. Epithelial-to-mesenchymal transition (EMT) can be mentioned as one of the effective phenomena in tumor invasion and metastasis. Several factors are involved in inducing this phenomenon in the tumor microenvironment, which helps the tumor survive and migrate to other places. It can be effective to identify these factors in the use of appropriate treatment strategies and greater patient survival. This study investigated the molecular differences between tumor border cells and tumor core cells or internal tumor cells in HCC for specific EMT genes. Expression of NOTCH1, ID1, and LST1 genes showed a significant increase at the HCC tumor border. Targeting these genes can be considered as a useful therapeutic strategy to prevent distant metastasis in HCC patients.
Collapse
Affiliation(s)
- Mahnaz Abdolahi
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University, Tehran, Iran
| | - Parnian Ghaedi Talkhounche
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mohammad Hossein Derakhshan Nazari
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Haniyeh Sadat Hosseininia
- Department of Cellular and Molecular Biology, Faculty of Advanced Medical Science, Islamic Azad University of Medical Sciences, Tehran, Iran
- Cytotech & Bioinformatics Research Group, Bioinformatics Department, Tehran, Iran
| | - Niloofar Khoshdel-Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amin Ebrahimi Sadrabadi
- Cytotech & Bioinformatics Research Group, Bioinformatics Department, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran
| |
Collapse
|
|
9
|
Chanchal S, Sharma S, Mohd S, Sultan A, Mishra A, Ashraf MZ. Unraveling Epigenetic Interplay between Inflammation, Thrombosis, and Immune-Related Disorders through a Network Meta-analysis. TH OPEN 2024; 8:e81-e92. [PMID: 38313596 PMCID: PMC10837039 DOI: 10.1055/a-2222-9126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/25/2023] [Indexed: 02/06/2024] Open
Abstract
Inflammation and thrombosis are two distinct yet interdependent physiological processes. The inflammation results in the activation of the coagulation system that directs the immune system and its activation, resulting in the initiation of the pathophysiology of thrombosis, a process termed immune-thrombosis. Still, the shared underlying molecular mechanism related to the immune system and coagulation has not yet been explored extensively. Inspired to answer this, we carried out a comprehensive gene expression meta-analysis using publicly available datasets of four diseases, including venous thrombosis, systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. A total of 609 differentially expressed genes (DEGs) shared by all four datasets were identified based on the combined effect size approach. The pathway enrichment analysis of the DEGs showed enrichment of various epigenetic pathways such as histone-modifying enzymes, posttranslational protein modification, chromatin organization, chromatin-modifying enzymes, HATs acetylate proteins. Network-based protein-protein interaction analysis showed epigenetic enzyme coding genes dominating among the top hub genes. The miRNA-interacting partner of the top 10 hub genes was determined. The predomination of epitranscriptomics regulation opens a layout for the meta-analysis of miRNA datasets of the same four diseases. We identified 30 DEmiRs shared by these diseases. There were 9 common DEmiRs selected from the list of miRNA-interacting partners of top 10 hub genes and shared significant DEmiRs from microRNAs dataset acquisition. These common DEmiRs were found to regulate genes involved in epigenetic modulation and indicate a promising epigenetic aspect that needs to be explored for future molecular studies in the context of immunothrombosis and inflammatory disease.
Collapse
Affiliation(s)
- Shankar Chanchal
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, Delhi, India
| | - Swati Sharma
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, Delhi, India
| | - Syed Mohd
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, Delhi, India
| | - Armiya Sultan
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, Delhi, India
| | - Aastha Mishra
- Cardio Respiratory Disease unit, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
| | - Mohammad Zahid Ashraf
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, Delhi, India
| |
Collapse
|
|
10
|
Toro AU, Shukla SK, Bansal P. Emerging role of MicroRNA-Based theranostics in Hepatocellular Carcinoma. Mol Biol Rep 2023; 50:7681-7691. [PMID: 37418086 DOI: 10.1007/s11033-023-08586-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023]
Abstract
Hepatocellular carcinoma (HCC), with its high mortality and short survival rate, continues to be one of the deadliest malignancies despite relentless efforts and several technological advances. The poor prognosis of HCC and the few available treatments are to blame for the low survival rate, which emphasizes the importance of creating new, effective diagnostic markers and innovative therapy strategies. In-depth research is being done on the potent biomarker miRNAs, a special class of non-coding RNA and has shown encouraging results in the early identification and treatment of HCC in order to find more viable and successful therapeutics for the disease. It is beyond dispute that miRNAs control cell differentiation, proliferation, and survival and, depending on the genes they target, can either promote tumorigenesis or suppress it. Given the vital role miRNAs play in the biological system and their potential to serve as ground-breaking treatments for HCC, more study is required to fully examine their theranostic potential.
Collapse
Affiliation(s)
- Abdulhakim Umar Toro
- Department of Biomedical Engineering, Shobhit institute of Engineering and Technology (Deemed to-be-University), Modipuram, Meerut, 250110, India
| | - Sudheesh K Shukla
- Department of Biomedical Engineering, Shobhit institute of Engineering and Technology (Deemed to-be-University), Modipuram, Meerut, 250110, India.
| | - Parveen Bansal
- University Centre of Excellence in Research, Baba Farid University of Health Sciences, Faridkot, 151203, India.
| |
Collapse
|
|
11
|
Ali R, Laskar SA, Khan NJ, Wahab S, Khalid M. Non-coding RNA's prevalence as biomarkers for prognostic, diagnostic, and clinical utility in breast cancer. Funct Integr Genomics 2023; 23:195. [PMID: 37270446 DOI: 10.1007/s10142-023-01123-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/19/2023] [Accepted: 05/25/2023] [Indexed: 06/05/2023]
Abstract
Noncoding RNAs (ncRNAs), which make up a significant portion of the mammalian transcriptome and plays crucial regulatory roles in expression of genes and other biological processes, have recently been found. The most extensively researched of the sncRNAs, microRNAs (miRNAs), have been characterized in terms of their synthesis, roles, and significance in the tumor development. Its crucial function in the stem cell regulation, another class of sncRNAs known as aspirRNAs, has attracted attention in cancer research. The investigations have shown that long non-coding RNAs have a crucial role in controlling developmental stages, such as mammary gland development. Additionally, it has been discovered that lncRNA dysregulation precedes the development of several malignancies, including breast cancer. The functions of sncRNAs (including miRNAs and piRNAs) and lncRNAs in the onset and development of the breast cancer are described in this study. Additionally, future perspectives of various ncRNA-based diagnostic, prognostic, and therapeutic approaches also discussed.
Collapse
Affiliation(s)
- Rafat Ali
- Department of Biosciences, Jamia Millia Islamia University, New Delhi, India
| | - Sorforaj A Laskar
- Department of Biosciences, Jamia Millia Islamia University, New Delhi, India
| | - Nida Jamil Khan
- Department of Biosciences, Jamia Millia Islamia University, New Delhi, India.
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia
| | - Mohammad Khalid
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj, 11942, Saudi Arabia
| |
Collapse
|
|
12
|
Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
Collapse
Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| |
Collapse
|
|
13
|
Li L, Xun C, Yu CH. Role of microRNA-regulated cancer stem cells in recurrent hepatocellular carcinoma. World J Hepatol 2022; 14:1985-1996. [PMID: 36618329 PMCID: PMC9813843 DOI: 10.4254/wjh.v14.i12.1985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/24/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
Among the most common cancers, hepatocellular carcinoma (HCC) has a high rate of tumor recurrence, tumor dormancy, and drug resistance after initial successful chemotherapy or radiotherapy. A small subset of cancer cells, cancer stem cells (CSCs), exhibit stem cell characteristics and are present in various cancers, including HCC. The dysregulation of microRNAs (miRNAs) often accompanies the occurrence and development of HCC. miRNAs can influence tumorigenesis, progression, recurrence, and drug resistance by regulating CSCs properties, which supports their clinical utility in managing and treating HCC. This review summarizes the regulatory effects of miRNAs on CSCs in HCC with a special focus on their impact on HCC recurrence.
Collapse
Affiliation(s)
- Lei Li
- Department of Pathology, University of Otago, Dunedin 9016, New Zealand
| | - Chen Xun
- Department of Hepatobiliary Surgery, Zhuzhou Central Hospital, Zhuzhou 412000, Hunan Province, China
| | - Chun-Hong Yu
- School of Engineering Medicine, Beihang University, Beijing 100191, China.
| |
Collapse
|
|
14
|
Exosome-Associated circRNAs as Key Regulators of EMT in Cancer. Cells 2022; 11:cells11101716. [PMID: 35626752 PMCID: PMC9140110 DOI: 10.3390/cells11101716] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 12/12/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a dynamic program of cell plasticity aberrantly reactivated in cancer. The crosstalk between tumor cells and the tumoral microenvironment (TME) has a pivotal importance for the induction of the EMT and the progression toward a malignant phenotype. Notably, exosomes are key mediators of this crosstalk as vehicles of specific molecular signals that include the class of circular RNAs (circRNAs). This review specifically focuses on the role of exosome-associated circRNAs as key regulators of EMT in cancer. The relevance of these molecules in regulating the intercellular communication in TME and tumor progression is highlighted. Moreover, the here-presented evidence indicates that exosome-associated circRNA modulation should be taken in account for cancer diagnostic and therapeutic approaches.
Collapse
|
|
15
|
Fan Q, Yu Y, Zhou Y, Zhang S, Wu C. An emerging role of radiation‑induced exosomes in hepatocellular carcinoma progression and radioresistance (Review). Int J Oncol 2022; 60:46. [PMID: 35266016 PMCID: PMC8923655 DOI: 10.3892/ijo.2022.5336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/01/2022] [Indexed: 11/20/2022] Open
Abstract
The incidence rates of hepatocellular carcinoma (HCC) worldwide are increasing, and the role of radiotherapy is currently under discussion. Radioresistance is one of the most important challenges in the therapy of HCC compared with other local advanced, recurrent and metastatic cancers. The mechanisms of radioresistance are complex and remain to be fully understood; however, extracellular vesicles have been investigated in recent studies. Exosomes, which are 40- to 150-nm extracellular vesicles released by cancer cells, contain multiple pathogenic components, including proteins, nucleic acids and lipids, and play critical functions in cancer progression. Emerging data indicate a diagnosis potential for exosomes in HCC, since radiation-derived exosomes promote radioresistance. Radiation-based therapy alters the contents and components of exosomes, suggesting that exosomes and their components may serve as prognostic and predictive biomarkers to monitor radiation response. Therefore, understanding the roles and mechanisms of exosomes in HCC progression and radiation response during HCC therapy may increase our knowledge concerning the roles of exosomes in radioresistance, and may lead to novel approaches for HCC prognosis and treatment. The current review summarizes recent studies on exosome involvement in HCC and the molecular changes in exosome components during HCC progression. It also discusses the functions of exosomes in HCC therapy, and highlights the importance of exosomes in HCC progression and resistance for the development of novel therapies.
Collapse
Affiliation(s)
- Qing Fan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Yue Yu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Yueling Zhou
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Sheng Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Chunli Wu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| |
Collapse
|
|
16
|
Shan Q, Takabatake K, Kawai H, Oo MW, Inada Y, Sukegawa S, Fushimi S, Nakano K, Nagatsuka H. Significance of cancer stroma for bone destruction in oral squamous cell carcinoma using different cancer stroma subtypes. Oncol Rep 2022; 47:81. [PMID: 35211756 PMCID: PMC8892615 DOI: 10.3892/or.2022.8292] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 02/07/2022] [Indexed: 11/30/2022] Open
Abstract
Stromal cells in the tumor microenvironment (TME) can regulate the progression of numerous types of cancer; however, the bone invasion of oral squamous cell carcinoma (OSCC) has been poorly investigated. In the present study, the effect of verrucous SCC-associated stromal cells (VSCC-SCs), SCC-associated stromal cells (SCC-SCs) and human dermal fibroblasts on bone resorption and the activation of HSC-3 osteoclasts in vivo were examined by hematoxylin and eosin, AE1/3 (pan-cytokeratin) and tartrate-resistant acid phosphatase staining. In addition, the expression levels of matrix metalloproteinase (MMP)9, membrane-type 1 MMP (MT1-MMP), Snail, receptor activator of NF-κB ligand (RANKL) and parathyroid hormone-related peptide (PTHrP) in the bone invasion regions of HSC-3 cells were examined by immunohistochemistry. The results suggested that both SCC-SCs and VSCC-SCs promoted bone resorption, the activation of osteoclasts, and the expression levels of MMP9, MT1-MMP, Snail, RANKL and PTHrP. However, SCC-SCs had a more prominent effect compared with VSCC-SCs. Finally, microarray data were used to predict potential genes underlying the differential effects of VSCC-SCs and SCC-SCs on bone invasion in OSCC. The results revealed that IL1B, ICAM1, FOS, CXCL12, INS and NGF may underlie these differential effects. In conclusion, both VSCC-SCs and SCC-SCs may promote bone invasion in OSCC by enhancing the expression levels of RANKL in cancer and stromal cells mediated by PTHrP; however, SCC-SCs had a more prominent effect. These findings may represent a potential regulatory mechanism underlying the bone invasion of OSCC.
Collapse
Affiliation(s)
- Qiusheng Shan
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Hotaka Kawai
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - May Wathone Oo
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Yasunori Inada
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Shintaro Sukegawa
- Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760‑8557, Japan
| | - Shigeko Fushimi
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Keisuke Nakano
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8525, Japan
| |
Collapse
|
|
17
|
Huang G, Zhong X, Yao L, Ma Q, Liao H, Xu L, Zou J, Sun R, Wang D, Guo X. MicroRNA-449a inhibits cell proliferation and migration by regulating mutant p53 in MDA-MB-468 cells. Exp Ther Med 2021; 22:1020. [PMID: 34373706 PMCID: PMC8343910 DOI: 10.3892/etm.2021.10452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 01/18/2021] [Indexed: 12/15/2022] Open
Abstract
The present study aimed to investigate the role of microRNA (miR)-449a in the proliferation, migration and apoptosis of MDA-MB-468 breast cancer cells and examine the association between miR-449a and mutant p53 in these cells. Cell proliferation, migration and invasion were examined using a crystal violet staining assay, wound healing scratch assay and Transwell assay, respectively. The expression level of miR-449a and p53 was detected by reverse transcription-quantitative PCR or western blotting. The results indicated that knockdown of mutant p53 suppressed the proliferation and migration of MDA-MB-468 cells by inhibiting the PI3K/AKT/mTOR signaling pathway. In addition, miR-449a suppressed proliferation and migration via downregulation of mutant p53 expression in MDA-MB-468 cells. Therefore, miR-449a may function as a tumor suppressor by regulating p53 expression in breast cancer cells, which may have potential implications in the treatment of patients with triple-negative breast cancer carrying mutant p53.
Collapse
Affiliation(s)
- Guangcheng Huang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xiaowu Zhong
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Lihua Yao
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Qiang Ma
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Hebin Liao
- Translational Medicine Research Center, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Lei Xu
- Translational Medicine Research Center, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Jiang Zou
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Ru Sun
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Dongsheng Wang
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Xiaolan Guo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China.,Translational Medicine Research Center, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China.,Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| |
Collapse
|
|
18
|
Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9593254. [PMID: 33299889 PMCID: PMC7707949 DOI: 10.1155/2020/9593254] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/13/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma is the fifth most common cancer worldwide and the second most lethal, following lung cancer. Currently applied therapeutic practices rely on surgical resection, chemotherapy and radiotherapy, or a combination thereof. These treatment options are associated with extreme adversities, and risk/benefit ratios do not always work in patients' favor. Anomalies of the epigenome lie at the epicenter of aberrant molecular mechanisms by which the disease develops and progresses. Modulation of these anomalous events poses a promising prospect for alternative treatment options, with an abundance of felicitous results reported in recent years. Herein, the most recent epigenetic modulators in hepatocellular carcinoma are recapitulated on.
Collapse
|
|
19
|
Rajappa A, Banerjee S, Sharma V, Khandelia P. Circular RNAs: Emerging Role in Cancer Diagnostics and Therapeutics. Front Mol Biosci 2020; 7:577938. [PMID: 33195421 PMCID: PMC7655967 DOI: 10.3389/fmolb.2020.577938] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/26/2020] [Indexed: 12/17/2022] Open
Abstract
Circular RNAs (circRNAs) are rapidly coming to the fore as major regulators of gene expression and cellular functions. They elicit their influence via a plethora of diverse molecular mechanisms. It is not surprising that aberrant circRNA expression is common in cancers and they have been implicated in multiple aspects of cancer pathophysiology such as apoptosis, invasion, migration, and proliferation. We summarize the emerging role of circRNAs as biomarkers and therapeutic targets in cancer.
Collapse
Affiliation(s)
| | | | - Vivek Sharma
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Hyderabad, India
| | - Piyush Khandelia
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Hyderabad, India
| |
Collapse
|
|
20
|
Alemohammad H, Asadzadeh Z, Motafakker Azad R, Hemmat N, Najafzadeh B, Vasefifar P, Najafi S, Baradaran B. Signaling pathways and microRNAs, the orchestrators of NANOG activity during cancer induction. Life Sci 2020; 260:118337. [PMID: 32841661 DOI: 10.1016/j.lfs.2020.118337] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/18/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are a small part of cancer cells inside the tumor that have similar characteristics to normal stem cells. CSCs stimulate tumor initiation and progression in a variety of cancers. Several transcription factors such as NANOG, SOX2, and OCT4 maintain the characteristics of CSCs and their upregulation is seen in many malignancies resulting in increased metastasis, invasion, and recurrence. Among these factors, NANOG plays an important role in regulating the self-renewal and pluripotency of CSCs and the clinical significance of NANOG has been suggested as a marker of CSCs in many cancers. The up and down-regulation of NANOG is associated with several important signaling pathways, including JAK/STAT, Wnt/β-catenin, Notch, TGF-β, Hedgehog, and several microRNAs (miRNAs). In this review, we will investigate the function of NANOG in CSCs and the molecular mechanism of its regulation by signaling pathways and miRNAs. We will also investigate targeting NANOG with different techniques, which is a promising treatment strategy for cancer treatment.
Collapse
Affiliation(s)
- Hajar Alemohammad
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Basira Najafzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Parisa Vasefifar
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
21
|
Soghli N, Qujeq D, Yousefi T, Soghli N. The regulatory functions of circular RNAs in osteosarcoma. Genomics 2020; 112:2845-2856. [DOI: 10.1016/j.ygeno.2020.03.024] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/21/2020] [Accepted: 03/23/2020] [Indexed: 02/06/2023]
|
|
22
|
Mong EF, Yang Y, Akat KM, Canfield J, VanWye J, Lockhart J, Tsibris JCM, Schatz F, Lockwood CJ, Tuschl T, Kayisli UA, Totary-Jain H. Chromosome 19 microRNA cluster enhances cell reprogramming by inhibiting epithelial-to-mesenchymal transition. Sci Rep 2020; 10:3029. [PMID: 32080251 PMCID: PMC7033247 DOI: 10.1038/s41598-020-59812-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 02/04/2020] [Indexed: 02/08/2023] Open
Abstract
During implantation, cytotrophoblasts undergo epithelial-to-mesenchymal transition (EMT) as they differentiate into invasive extravillous trophoblasts (EVTs). The primate-specific microRNA cluster on chromosome 19 (C19MC) is exclusively expressed in the placenta, embryonic stem cells and certain cancers however, its role in EMT gene regulation is unknown. In situ hybridization for miR-517a/c, a C19MC cistron microRNA, in first trimester human placentas displayed strong expression in villous trophoblasts and a gradual decrease from proximal to distal cell columns as cytotrophoblasts differentiate into invasive EVTs. To investigate the role of C19MC in the regulation of EMT genes, we employed the CRISPR/dCas9 Synergistic Activation Mediator (SAM) system, which induced robust transcriptional activation of the entire C19MC cistron and resulted in suppression of EMT associated genes. Exposure of human iPSCs to hypoxia or differentiation of iPSCs into either cytotrophoblast-stem-like cells or EVT-like cells under hypoxia reduced C19MC expression and increased EMT genes. Furthermore, transcriptional activation of the C19MC cistron induced the expression of OCT4 and FGF4 and accelerated cellular reprogramming. This study establishes the CRISPR/dCas9 SAM as a powerful tool that enables activation of the entire C19MC cistron and uncovers its novel role in suppressing EMT genes critical for maintaining the epithelial cytotrophoblasts stem cell phenotype.
Collapse
Affiliation(s)
- Ezinne F Mong
- Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Ying Yang
- Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Kemal M Akat
- Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, New York, New York, USA
| | - John Canfield
- Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Jeffrey VanWye
- Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - John Lockhart
- Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - John C M Tsibris
- Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Frederick Schatz
- Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Charles J Lockwood
- Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Thomas Tuschl
- Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, New York, New York, USA
| | - Umit A Kayisli
- Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Hana Totary-Jain
- Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA.
| |
Collapse
|
|
23
|
Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genomics Proteomics 2020; 17:1-21. [PMID: 31882547 PMCID: PMC6937123 DOI: 10.21873/cgp.20163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasis-promoting miRs (miR-29a, -219-5p, -331-3p, 425-5p, -487a and -1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101, -129-3p, -137, -149, -503, and -630) correlate with a worse clinical prognosis. We discuss the corresponding metastasis-related targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs -29a, -219-5p and -425-5p and down-regulated miRs -129-3p and -630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey.
Collapse
Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Daniela Schmid
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| |
Collapse
|
|
24
|
Han B, Huang J, Yang Z, Zhang J, Wang X, Xu N, Meng H, Wu J, Huang Q, Yang X, Shen R, Sun C. miR-449a Is Related to Short-Term Recurrence of Hepatocellular Carcinoma and Inhibits Migration and Invasion by Targeting Notch1. Onco Targets Ther 2019; 12:10975-10987. [PMID: 31853185 PMCID: PMC6916688 DOI: 10.2147/ott.s216997] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 11/19/2019] [Indexed: 12/23/2022] Open
Abstract
PURPOSE To explore the effect of miR-449a inhibits migration and invasion by targeting Notch1 and regulating epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), and further study on the molecular mechanism. PATIENTS AND METHODS The expression of miR-449a and Notch1 in HCC cells and tissues was detected by qRT-PCR. The HCC cell line HCCLM3 and SMMC-7721 were transfected with miR-449a. The invasion and migration of HCC cell lines were detected by transwell assay and wound healing assay. The Notch pathway and EMT related protein were detected with Western Blotting. The specific binding site of mir-449a on notch1 gene was detected by luciferase assay. RESULTS We found the expression of miR-449a was related to short-term recurrence of hepatocellular carcinoma after hepatectomy and acted as independent risk factors of DFS and OS. The expression of miR-449a decreased in tumor tissues and HCC cell lines, but the expression of Notch1 increased. The overexpressed miR-449a promoted the invasiveness in vitro by regulating EMT via Notch pathway. Mechanically, miR-449a inhibited the translation of Notch1 protein by binding to 3' UTR of its mRNA directly. CONCLUSION miR-449a is short-term recurrence-related miRNA and inhibits the invasion and metastasis ability of HCC cells by regulating EMT via Notch pathway. miR-449a may be a new effective therapeutic target for HCC.
Collapse
Affiliation(s)
- Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao City266003, Shandong Province, People’s Republic of China
- Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Jiawei Huang
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Zhenjie Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao City266003, Shandong Province, People’s Republic of China
| | - Jiaqi Zhang
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Xiaomin Wang
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Ning Xu
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Haining Meng
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Junyu Wu
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Qiao Huang
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Xi Yang
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Ruowu Shen
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao City266021, Shandong Province, People’s Republic of China
| | - Chuandong Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao City266003, Shandong Province, People’s Republic of China
| |
Collapse
|
|
25
|
Gurzu S, Kobori L, Fodor D, Jung I. Epithelial Mesenchymal and Endothelial Mesenchymal Transitions in Hepatocellular Carcinoma: A Review. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2962580. [PMID: 31781608 PMCID: PMC6855070 DOI: 10.1155/2019/2962580] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/30/2019] [Accepted: 09/11/2019] [Indexed: 02/05/2023]
Abstract
PURPOSE To present a comprehensive review of the literature data, published between 2000 and 2019 on the PubMed and Web of Science databases, in the field of the tumor microenvironment in hepatocellular carcinoma (HCC). All the data were combined with the personal experiences of the authors. DESIGN From 1002 representative papers, we selected 86 representative publications which included data on epithelial-to-mesenchymal transition (EMT), angiogenesis, cancer stem-like cells (CSCs), and molecular background of chemoresistance or resistance to radiotherapy. RESULTS Although the central event concerns activation of the Wnt/β-catenin pathway, other signal pathways, such as c-Met/HGF/Snail, Notch-1/NF-κB, TGF-β/SMAD, and basic fibroblast growth factor-related signaling, play a role in the EMT of HCC cells. This pathway is targeted by specific miRNAs and long noncoding RNAs, as explored in this paper. A central player in the tumor microenvironment proved to be the CSCs which can be marked by CD133, CD44, CD90, EpCAM, and CD105. CSCs can induce resistance to cytotoxic therapy or, alternatively, can be synthesized, de novo, after chemo- or radiotherapy, especially after transarterial chemoembolization- or radiofrequency ablation-induced hypoxia. The circulating tumor cells proved to have epithelial, intermediate, or mesenchymal features; their properties have a critical prognostic role. CONCLUSION The metastatic pathway of HCC seems to be related to the Wnt- or, rather, TGFβ1-mediated inflammation-angiogenesis-EMT-CSCs crosstalk link. Molecular therapy should target this molecular axis controlling the HCC microenvironment.
Collapse
Affiliation(s)
- Simona Gurzu
- Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania
- Advanced Medical and Pharmaceutical Research Center (CCAMF), University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania
- Department of Pathology, Clinical County Emergency Hospital, Targu Mures, Romania
| | - Laszlo Kobori
- Department of Transplantation and Surgery, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Decebal Fodor
- Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania
- Department of Transplantation and Surgery, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
- Department of Anatomy and Embryology, University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania
| | - Ioan Jung
- Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania
| |
Collapse
|
|
26
|
Wu X, Han Y, Liu F, Ruan L. Downregulations of miR-449a and miR-145-5p Act as Prognostic Biomarkers for Endometrial Cancer. J Comput Biol 2019; 27:834-844. [PMID: 31513434 DOI: 10.1089/cmb.2019.0215] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
This investigation aimed to explore the underlying prognosis-associated microRNA (miRNA) biomarkers in endometrial cancer. Homo sapiens miRNA data set GSE35794 and miRNA data in TGGA database were downloaded and applied to screen the differentially expressed miRNAs (DE-miRNAs) using unpaired t-test in limma package in R. Basing on Venn analysis, the overlapped DE-miRNAs were screened and their potential targets were predicted according to miRWalk followed by target functional enrichment analyses and protein-protein interaction network visualized using Cytoscape. Finally, according to the information provided by the The Cancer Genome Atlas (TCGA) database, correlations between miRNAs or targets and patient prognosis were analyzed by survival package in R. A total of 24 overlapped DE-miRNAs were identified between endometrioid endometrial cancer samples and normal samples. Then, the miRNA-target regulatory network was constructed, including 11 upregulated miRNAs (e.g., miR-200a, miR-200b, and miR-200c) and five downregulated miRNAs (e.g., miR-449a, miR-145-5p, and miR-145-3p). Lymphocyte enhancer factor-1 (LEF1) was predicted to be a target of miR-449a and SOX11 was a target of miR-145-5p. Functional enrichment analyses of these targets were significantly related to the biological process of "negative regulation of transcription from RNA polymerase II promoter" and "positive regulation of transcription from RNA polymerase II promoter" (e.g., NOTCH1, LEF1, and SOX11). In addition, survival analysis showed that miR-449a, miR-145-5p, and LEF1 were approximately correlated with the overall survival prognosis of endometrial cancer patients. Downregulations of miR-449a and miR-145-5p might be involved in the pathogenesis of endometrial cancer and could act as prognostic biomarkers for endometrial cancer patients.
Collapse
Affiliation(s)
- Xihai Wu
- Department of Gynecology and Obstetrics, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Yunhui Han
- Department of Gynecology and Obstetrics, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Fangmei Liu
- Department of Gynecology and Obstetrics, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Lihong Ruan
- Department of Gynecology and Obstetrics, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| |
Collapse
|
|
27
|
Poddar S, Kesharwani D, Datta M. miR-449a regulates insulin signalling by targeting the Notch ligand, Jag1 in skeletal muscle cells. Cell Commun Signal 2019; 17:84. [PMID: 31345231 PMCID: PMC6659245 DOI: 10.1186/s12964-019-0394-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 07/15/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND miR-449a, an intronic miRNA, is highly down-regulated in the skeletal muscle during diabetes. Its levels are epigenetically regulated by altered acetylation/deacetylation on the promoter that it shares with its host gene, Cdc20b. However, the cellular role of this epigenetically regulated miRNA in the muscle during diabetes is not well understood. Here, we sought to unravel the crosstalk between altered miR-449a expression and impaired skeletal muscle metabolism. METHODS Predicted targets of miR-449a were extracted using online available target prediction tools. Differentiated C2C12 cells were transfected with the miR-449a mimic and/or its inhibitor and the levels of the target mRNA and protein was evaluated by qRT-PCR and Western Blot analysis. This was validated by luciferase wild type and mutated constructs of the target 3'UTR. Inhibition of Notch signalling was assessed by evaluating the transcript levels of Notch target genes, Hes1 and Hey1 and the status of NICD (Notch Intracellular domain) by immunofluoresence microscopy. Effect of miR-449a on insulin signalling was evaluated by monitoring insulin induced PI3K and AKT phosphorylation and glucose uptake. RESULTS Our data demonstrate that in C2C12 skeletal muscle cells, miR-449a binds to the 3'UTR of Jag1, an important Notch ligand, and down-regulates, both its transcript and protein levels. This was, however, prevented in the presence of the miR-449a inhibitor that suggests the specificity of the miRNA effect. This was validated in human primary skeletal muscle cells where miR-449a decreased Jag1 protein levels and this was prevented in the presence of the miR-449a inhibitor. This miR-449a-Jag1 interaction subsequently affects the Notch signalling pathway as was evident by the fact that miR-449a decreased the levels of NICD and consequently, the levels of Notch target genes, Hes1 and Hey1 were significantly inhibited. miR-449a and Notch pathway inhibition using DAPT, significantly increased insulin stimulated PI3K and AKT phosphorylation and these were prevented in the presence of the miR-449a inhibitor. CONCLUSION Our results indicate towards a critical role for miR-449a and its target, Jag1 in regulating Notch signalling and insulin signalling in the skeletal muscle and imply that targeting this axis might hold therapeutic potential for impaired skeletal muscle metabolism during diabetes.
Collapse
Affiliation(s)
- Shagun Poddar
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110 007, India.,Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
| | - Devesh Kesharwani
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110 007, India.,Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
| | - Malabika Datta
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110 007, India. .,Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India.
| |
Collapse
|
|
28
|
Liu J, Yu F, Wang S, Zhao X, Jiang F, Xie J, Deng M. circGFRA1 Promotes Ovarian Cancer Progression By Sponging miR-449a. J Cancer 2019; 10:3908-3913. [PMID: 31417634 PMCID: PMC6692615 DOI: 10.7150/jca.31615] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 04/26/2019] [Indexed: 02/06/2023] Open
Abstract
Backgroud: Increasing studies show that circular RNAs (circRNAs) play important roles in tumor progression. However, the function of circRNAs in ovarian cancer is mostly unclear. Methods: We detected the expression of circGFRA1 by quantitative real-time PCR (qRT-PCR) in 50 pairs of ovarian cancer tissues and adjacent normal tissues. Then, we explored the function of circGFRA1 in ovarian cancer progression, such as cell proliferation, apoptosis and invasion. Moreover, we performed luciferase reporter and RNA immunoprecipitation (RIP) assay to study the competing endogenous RNA (ceRNA) function of circGFRA1 in ovarian cancer progression. Results: qRT-PCR showed that circGFRA1 was overexpressed in ovarian cancer tissues. Inhibition of circGFRA1 suppressed cell proliferation and invasion, but induced cell apoptosis in ovarian cancer. Luciferase reporter and RIP assay revealed that circGFRA1 could regulate the expression of GFRA1 by sponging miR-449a. Conclusions: In summary, circGFRA1 regulated GFRA1 expression and ovarian cancer progression by sponging miR-449a. circGFRA1 could be a potential diagnostic biomarker and therapeutic target for ovarian cancer.
Collapse
Affiliation(s)
- Jie Liu
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of University of South China, Hengyang, Hunan
| | - Furong Yu
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of University of South China, Hengyang, Hunan
| | - Shufen Wang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of University of South China, Hengyang, Hunan
| | - Xia Zhao
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of University of South China, Hengyang, Hunan
| | - Feng Jiang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of University of South China, Hengyang, Hunan
| | - Jing Xie
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of University of South China, Hengyang, Hunan
| | - Min Deng
- Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, Guangdong
| |
Collapse
|
|
29
|
Wu AY, Hu Y, Cang W, Li D, Wang WJ, Tian Q, Gu LY, Zhang N, Ji F, Qiu LH. Suppressive effect of microRNA-449a on the NDRG1/PTEN/AKT axis regulates endometrial cancer growth and metastasis. Exp Cell Res 2019; 382:111468. [PMID: 31201812 DOI: 10.1016/j.yexcr.2019.06.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023]
Abstract
Database screening indicated that microRNAs (miRNAs) are involved in pathogenesis of endometrial cancer. Among these miRNAs, miR-449a might be involved in tumorigenesis and lower expression of miR-449a was associated with poor prognosis. However, the role of miR-449a and its underlying molecular mechanism in endometrial cancer (EC) has not been investigated. In this study, our analysis found that miR-449a expression is inversely correlated with the stage of EC. Downregulation of miR-449a was correlated with tumor progression and poor prognosis in the EC patients. Results of functional analyses revealed that overexpression of miR-449a in human EC cells alleviated cell proliferation, invasion and metastasis. Conversely, loss of miR-449a in EC cancer cells facilitated all these cellular activities. Moreover, we identified N-myc downstream-regulated gene 1 (NDRG1) as a direct and functional target gene of miR-449a in EC cells, and the expression of NDRG1 in 87 EC specimens were inversely correlated with that of miR-449a. Additionally, further studies show that the down-regulation of NDRG1 expression inhibited proliferation and metastasis of EC cells through the PTEN/AKT pathway. Therefore, these results suggest that miR-449a suppresses the growth and metastasis of EC by directly targeting the NDRG1 gene and that the activation of miR-449a may represent an effective therapeutic strategy in EC.
Collapse
Affiliation(s)
- An-Yue Wu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Yuan Hu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Wei Cang
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Dong Li
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Wen-Jing Wang
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Qi Tian
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Li-Ying Gu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Ning Zhang
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Fang Ji
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| | - Li-Hua Qiu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200127, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, China.
| |
Collapse
|
|
30
|
Integrative Network Analysis Reveals a MicroRNA-Based Signature for Prognosis Prediction of Epithelial Ovarian Cancer. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1056431. [PMID: 31275959 PMCID: PMC6582839 DOI: 10.1155/2019/1056431] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 04/18/2019] [Indexed: 01/08/2023]
Abstract
Background Epithelial ovarian cancer (EOC) is a heterogeneous disease, which has been recently classified into four molecular subtypes, of which the mesenchymal subtype exhibited the worst prognosis. We aimed to identify a microRNA- (miRNA-) based signature by incorporating the molecular modalities involved in the mesenchymal subtype for risk stratification, which would allow the identification of patients who might benefit from more rigorous treatments. Method We characterized the regulatory mechanisms underlying the mesenchymal subtype using network analyses integrating gene and miRNA expression profiles from The Cancer Genome Atlas (TCGA) cohort to identify a miRNA signature for prognosis prediction. Results We identified four miRNAs as the master regulators of the mesenchymal subtype and developed a risk score model. The 4-miRNA signature significantly predicted overall survival (OS) and progression-free survival (PFS) in discovery (p=0.004 and p=0.04) and two independent public datasets (GSE73582: OS, HR: 2.26 (1.26-4.05), p=0.005, PFS, HR: 2.03 (1.34-3.09), p<0.001; GSE25204: OS, HR: 3.07 (1.73-5.46), p<0.001, PFS, HR: 2.59 (1.72-3.88), p<0.001). Moreover, in multivariate analyses, the miRNA signature maintained as an independent prognostic predictor and achieved superior efficiency compared to the currently used clinical factors. Conclusions In conclusion, our network analysis identified a 4-miRNA signature which has prognostic value superior to currently reported clinical covariates. This signature warrants further testing and validation for use in clinical practice.
Collapse
|
|
31
|
Tormo E, Ballester S, Adam-Artigues A, Burgués O, Alonso E, Bermejo B, Menéndez S, Zazo S, Madoz-Gúrpide J, Rovira A, Albanell J, Rojo F, Lluch A, Eroles P. The miRNA-449 family mediates doxorubicin resistance in triple-negative breast cancer by regulating cell cycle factors. Sci Rep 2019; 9:5316. [PMID: 30926829 PMCID: PMC6441107 DOI: 10.1038/s41598-019-41472-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 03/11/2019] [Indexed: 12/17/2022] Open
Abstract
The mechanisms of chemotherapy resistance in triple negative breast cancer remain unclear, and so, new molecules which might mediate this resistance could optimize treatment response. Here we analyzed the involvement of the miRNA-449 family in the response to doxorubicin. The cell viability, cell-cycle phases, and the expression of in silico target genes and proteins of sensitive/resistant triple negative breast cancer cell lines were evaluated in response to doxorubicin treatment and after gain/loss of miRNAs-449 function achieved by transient transfection. Triple negative breast cancer patients were selected for ex vivo experiments and to evaluate gene and miRNAs expression changes after treatment, as well as survival analysis by Kaplan-Meier. Doxorubicin treatment upregulated miRNAs-449 and DNA-damage responder factors E2F1 and E2F3 in triple negative breast cancer sensitive breast cancer cells, while expression remained unaltered in resistant ones. In vitro overexpression of miRNAs-449 sensitized cells to the treatment and significantly reduced the resistance to doxorubicin. These changes showed also a strong effect on cell cycle regulation. Finally, elevated levels of miRNA-449a associated significantly with better survival in chemotherapy-treated triple negative breast cancer patients. These results reveal for the first time the involvement of the miRNA-449 family in doxorubicin resistance and their predictive and prognostic value in triple negative breast cancer patients.
Collapse
Affiliation(s)
- Eduardo Tormo
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain
| | | | | | - Octavio Burgués
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain.,Pathology Department, Hospital Clínico Universitario, Valencia, Spain
| | - Elisa Alonso
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain.,Pathology Department, Hospital Clínico Universitario, Valencia, Spain
| | - Begoña Bermejo
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain
| | - Silvia Menéndez
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain
| | - Sandra Zazo
- Pathology Department, IIS- Fundación Jiménez Díaz- CIBERONC, Madrid, Spain
| | - Juan Madoz-Gúrpide
- Pathology Department, IIS- Fundación Jiménez Díaz- CIBERONC, Madrid, Spain
| | - Ana Rovira
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.,Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain
| | - Joan Albanell
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.,Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.,Universitat Pompeu Fabra, Barcelona, Spain
| | - Federico Rojo
- Pathology Department, IIS- Fundación Jiménez Díaz- CIBERONC, Madrid, Spain
| | - Ana Lluch
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain.,Universidad de Valencia, Valencia, Spain
| | - Pilar Eroles
- INCLIVA Biomedical Research Institute, Valencia, Spain. .,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain. .,COST action CA15204, Brussels, Belgium.
| |
Collapse
|
|
32
|
Wang G, Liu W, Zou Y, Wang G, Deng Y, Luo J, Zhang Y, Li H, Zhang Q, Yang Y, Chen G. Three isoforms of exosomal circPTGR1 promote hepatocellular carcinoma metastasis via the miR449a-MET pathway. EBioMedicine 2019; 40:432-445. [PMID: 30630697 PMCID: PMC6412851 DOI: 10.1016/j.ebiom.2018.12.062] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/27/2018] [Accepted: 12/30/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The role of exosomal circular RNAs (circRNAs) in Hepatocellular carcinoma (HCC) cells with high metastatic potential has been little studied. METHODS Exosomal circRNA from cells with non-metastatic (HepG2), low metastatic (97L), and high metastatic (LM3) potential were sequencing. Metastatic-related circRNAs in serum from HCC patients were measured and their association with clinical prognosis was evaluated. Furthermore, candidate functional circRNAs in LM3-derived exosomes was assessed. FINDINGS LM3 exosomes enhanced the cell migration and invasion potential of HepG2 and 97 L cells. CircPTGR1, a circRNA with three isoforms, was specifically expressed in exosomes from 97 L and LM3 cells, upregulated in serum exosomes from HCC patients and was associated with the clinical stage and prognosis. Knockdown of circPTGR1 expression suppressed the migration and invasion of HepG2 and 97L cells induced by co-culturing with LM3 exosomes. Bioinformatics, co-expression analysis, and a luciferase assay indicated that circPTGR1 competed with MET to target miR449a. INTERPRETATION Higher metastatic HCC cells can confer this potential on those with lower or no metastatic potential via exosomes with circPTGR1, resulting in increased migratory and invasive abilities in those cells. FUND: National Natural Science Foundation of China (No. 81470870, 81670601, 81570593), Guangdong Natural Science Foundation (No. 2015A030312013, 2015A030313038), Sci-tech Research Development Program of Guangdong Province (2014B020228003), Sci-tech Research Development Program of Guangzhou City (No. 201508020262, 201400000001-3, 201604020001, 201607010024), Innovative Funds for Small and Medium-Sized Enterprises of Guangdong Province (2016A010119103), Pearl River S&T Nova Program of Guangzhou (201710010178), and National 13th Five-Year Science and Technology Plan Major Projects of China (No. 2017ZX10203205-006-001).
Collapse
Affiliation(s)
- Guoying Wang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Wei Liu
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yong Zou
- Department of Blood Transfusion, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Genshu Wang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Organ Transplantation Institute of Sun Yat-sen University, Guangzhou 510630, China
| | - Yinan Deng
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jingyan Luo
- Forevergen Biosciences Centre, Guangzhou International Biotech Island, Guangzhou, 510300, China
| | - Yingcai Zhang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Hua Li
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Qi Zhang
- Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of SunYat-Sen University, Guangzhou 510630, China.
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
| | - Guihua Chen
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Organ Transplantation Institute of Sun Yat-sen University, Guangzhou 510630, China.
| |
Collapse
|
|
33
|
Cheng J, Wu LM, Deng XS, Wu J, Lv Z, Zhao HF, Yang Z, Ni Y. MicroRNA-449a suppresses hepatocellular carcinoma cell growth via G1 phase arrest and the HGF/MET c-Met pathway. Hepatobiliary Pancreat Dis Int 2018; 17:336-344. [PMID: 30108016 DOI: 10.1016/j.hbpd.2018.07.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 07/16/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Accumulating evidence demonstrates that microRNAs (miRNAs) play essential roles in tumorigenesis and cancer progression of hepatocellular carcinoma (HCC). Average targets of a miRNA were more than 100. And one miRNA may act in tumor via regulating several targets. The present study aimed to explore more potential targets of miR-449a by proteomics technology and further uncover the role of miR-449a in HCC tumorigenesis. METHODS Technologies such as iTRAQ-based quantitative proteomic were used to investigate the effect of miR-449a on HCC. The expression of c-Met and miR-449a was detected by qRT-PCR in HCC samples. Gain- and loss-of-function experiments were performed to identify the function and potential target of miR-449a in HCC cells. RESULTS In HCC, miR-449a was significantly downregulated, while c-Met was upregulated concurrently. Quantitative proteomics and luciferase reporter assay identified c-Met as a direct target of miR-449a. Moreover, miR-449a inhibited HCC growth not only by targeting CDK6 but also by suppressing c-Met/Ras/Raf/ERK signaling pathway. Furthermore, the inhibition of c-Met expression with a specific siRNA significantly inhibited cells growth and deregulated the ERK pathway in HCC. CONCLUSION The tumor suppressor miR-449a suppresses HCC tumorigenesis by repressing the c-Met/ERK pathway.
Collapse
Affiliation(s)
- Jun Cheng
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
| | - Li-Ming Wu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Xue-Song Deng
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
| | - Jian Wu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Zhen Lv
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Hang-Fen Zhao
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
| | - Zhang Yang
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; School of Life Science, Fudan University, Shanghai 200433, China
| | - Yong Ni
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China.
| |
Collapse
|
|
34
|
Li N, Zhang Y, Sidlauskas K, Ellis M, Evans I, Frankel P, Lau J, El-Hassan T, Guglielmi L, Broni J, Richard-Loendt A, Brandner S. Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades. Oncogene 2018; 37:4313-4333. [PMID: 29720725 PMCID: PMC6072706 DOI: 10.1038/s41388-018-0277-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 03/22/2018] [Accepted: 03/28/2018] [Indexed: 12/19/2022]
Abstract
To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.
Collapse
Affiliation(s)
- Ningning Li
- Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.
- The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.
| | - Ying Zhang
- Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Kastytis Sidlauskas
- Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Matthew Ellis
- Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Ian Evans
- Division of Medicine, University College London, University Street, London, WC1E 6JF, UK
| | - Paul Frankel
- Division of Medicine, University College London, University Street, London, WC1E 6JF, UK
| | - Joanne Lau
- Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Tedani El-Hassan
- Division of Neuropathology, the National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust Queen Square, London, WC1N 3BG, UK
| | - Loredana Guglielmi
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK
| | - Jessica Broni
- Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
- UCL IQPath laboratory, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Angela Richard-Loendt
- Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
- UCL IQPath laboratory, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Sebastian Brandner
- Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.
- Division of Neuropathology, the National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust Queen Square, London, WC1N 3BG, UK.
| |
Collapse
|
|
35
|
Chen Q, Yang Z, Pan G, Ding H, Jiang D, Huang J, Liu W. Tumor suppressor miR-449a inhibits the development of gastric cancer via down-regulation of SGPL1. RSC Adv 2018; 8:26020-26028. [PMID: 35541941 PMCID: PMC9082876 DOI: 10.1039/c8ra02722f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 06/23/2018] [Indexed: 12/02/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that are known to participate in the regulation of many physiological and pathological processes, which can indirectly influence the development of malignant behaviors. Numerous studies have demonstrated that miR-449a plays important roles in human carcinogenesis. However, its precise functional and regulatory roles remain unclear. In this study, we mainly explored the functional role of miR-449a in gastric cancer (GC). The expression levels of miR-449a in 98 cases of GC tissues and cell lines were determined by qRT-PCR. The possible mechanisms of miR-449a in GC cells were explored by fluorescence reporter assay. miR-449a expression was significantly lower in GC tissues compared to matched para-carcinoma tissues and was associated with tumor differentiation. Furthermore, in vitro knockdown of miR-449a by siRNA significantly inhibited MKN-28 cell proliferation, migration and invasion as well as tumorigenesis via inducing G0/G1 arrest of GC cells. In addition, we identified SGPL1 as a target of miR-449a and demonstrated that miR-449a regulated SGPL1 expression via binding its 3′-UTR region. The experiments indicated that miR-449a functions as a novel tumor suppressor in GC and its anti-oncogenic activity may involve its inhibition of the target gene SGPL1. These findings suggested that miR-449a may be a promising candidate for the development of antitumor drugs targeting GC. MicroRNAs (miRNAs) are small noncoding RNAs that are known to participate in the regulation of many physiological and pathological processes, which can indirectly influence the development of malignant behaviors.![]()
Collapse
Affiliation(s)
- Qian Chen
- Department of General Surgery, Minhang Hospital, Fudan University No. 170, Xinsong Road, Minhang District Shanghai 201199 China
| | - Zhen Yang
- Department of General Surgery, Minhang Hospital, Fudan University No. 170, Xinsong Road, Minhang District Shanghai 201199 China
| | - Gaofeng Pan
- Department of General Surgery, Minhang Hospital, Fudan University No. 170, Xinsong Road, Minhang District Shanghai 201199 China
| | - Hongjian Ding
- Department of General Surgery, Minhang Hospital, Fudan University No. 170, Xinsong Road, Minhang District Shanghai 201199 China
| | - Daowen Jiang
- Department of General Surgery, Minhang Hospital, Fudan University No. 170, Xinsong Road, Minhang District Shanghai 201199 China
| | - Jianfang Huang
- Department of Infection Diseases, The Fifth People's Hospital Affiliated to Fudan University Shanghai 201199 China
| | - Weiyan Liu
- Department of General Surgery, Minhang Hospital, Fudan University No. 170, Xinsong Road, Minhang District Shanghai 201199 China
| |
Collapse
|
|
36
|
Li F, Liang J, Bai L. MicroRNA-449a functions as a tumor suppressor in pancreatic cancer by the epigenetic regulation of ATDC expression. Biomed Pharmacother 2018; 103:782-789. [DOI: 10.1016/j.biopha.2018.04.101] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/13/2018] [Accepted: 04/13/2018] [Indexed: 02/06/2023] Open
|
|
37
|
Khatun A, Shimozawa M, Kito H, Kawaguchi M, Fujimoto M, Ri M, Kajikuri J, Niwa S, Fujii M, Ohya S. Transcriptional Repression and Protein Degradation of the Ca 2+-Activated K + Channel K Ca1.1 by Androgen Receptor Inhibition in Human Breast Cancer Cells. Front Physiol 2018; 9:312. [PMID: 29713287 PMCID: PMC5911984 DOI: 10.3389/fphys.2018.00312] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 03/14/2018] [Indexed: 01/14/2023] Open
Abstract
The large-conductance Ca2+-activated K+ channel KCa1.1 plays an important role in the promotion of breast cancer cell proliferation and metastasis. The androgen receptor (AR) is proposed as a therapeutic target for AR-positive advanced triple-negative breast cancer. We herein investigated the effects of a treatment with antiandrogens on the functional activity, activation kinetics, transcriptional expression, and protein degradation of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, voltage-sensitive dye imaging, and whole-cell patch clamp recording. A treatment with the antiandrogen bicalutamide or enzalutamide for 48 h significantly suppressed (1) depolarization responses induced by paxilline (PAX), a specific KCa1.1 blocker and (2) PAX-sensitive outward currents induced by the depolarizing voltage step. The expression levels of KCa1.1 transcripts and proteins were significantly decreased in MDA-MB-453 cells, and the protein degradation of KCa1.1 mainly contributed to reductions in KCa1.1 activity. Among the eight regulatory β and γ subunits, LRRC26 alone was expressed at high levels in MDA-MB-453 cells and primary and metastatic breast cancer tissues, whereas no significant changes were observed in the expression levels of LRRC26 and activation kinetics of PAX-sensitive outward currents in MDA-MB-453 cells by the treatment with antiandrogens. The treatment with antiandrogens up-regulated the expression of the ubiquitin E3 ligases, FBW7, MDM2, and MDM4 in MDA-MB-453 cells, and the protein degradation of KCa1.1 was significantly inhibited by the respective siRNA-mediated blockade of FBW7 and MDM2. Based on these results, we concluded that KCa1.1 is an androgen-responsive gene in AR-positive breast cancer cells, and its down-regulation through enhancements in its protein degradation by FBW7 and/or MDM2 may contribute, at least in part, to the antiproliferative and antimetastatic effects of antiandrogens in breast cancer cells.
Collapse
Affiliation(s)
- Anowara Khatun
- Division of Pathological Sciences, Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Motoki Shimozawa
- Division of Pathological Sciences, Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Hiroaki Kito
- Division of Pathological Sciences, Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Mayu Kawaguchi
- Division of Pathological Sciences, Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Mayu Fujimoto
- Division of Pathological Sciences, Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Moe Ri
- Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Junko Kajikuri
- Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Satomi Niwa
- Division of Pathological Sciences, Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Masanori Fujii
- Division of Pathological Sciences, Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Susumu Ohya
- Division of Pathological Sciences, Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan.,Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| |
Collapse
|
|
38
|
Su Z, Zhang M, Xu M, Li X, Tan J, Xu Y, Pan X, Chen N, Chen X, Zhou Q. MicroRNA181c inhibits prostate cancer cell growth and invasion by targeting multiple ERK signaling pathway components. Prostate 2018; 78:343-352. [PMID: 29341215 DOI: 10.1002/pros.23478] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 12/13/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND The ERK signaling pathway is frequently deregulated in tumorigenesis, mostly by classical mechanisms such as gene mutation of its components (eg, RAS and RAF). However, whether and how multiple key components of ERK pathway are regulated by microRNAs are not clear. METHODS We firstly predicted post-transcriptional regulation of multiple key components of the ERK signaling pathway by miR181c through bioinformatics analysis, and then confirmed the post-transcriptional regulation by dual luciferase reporter gene assays and Western blot analysis. The biological effects of miR181c on prostate cancer cell proliferation, apoptosis, migration, and invasion were measured by CCK-8 assay, flow cytometry, wound scratch assay, transwell cell migration, and invasion assays. RESULTS miR181c post-transcriptionally regulated multiple key members of the ERK signaling pathway, including extracellular signal-regulated kinase 2 (ERK2), ribosomal S6 kinase 2 (RSK2), serum response factor (SRF), and FBJ murine osteosarcoma viral oncogene homolog (c-Fos). Ectopic expression of miR181c mimics effectively suppressed prostate cancer cell proliferation, migration, and invasion, but promoted cell apoptosis. Furthermore, miR181c treatment combined with the multi-kinase inhibitor sorafenib significantly enhanced these anti-tumor effects. CONCLUSIONS Downregulation of miR181c results in deregulated ERK signaling and promotes prostate cancer cell growth and metastasis.
Collapse
Affiliation(s)
- Zhengzheng Su
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Mengni Zhang
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Miao Xu
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xinglan Li
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Junya Tan
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yunyi Xu
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xiuyi Pan
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ni Chen
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xueqin Chen
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Qiao Zhou
- Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| |
Collapse
|
|
39
|
Huang M, Li G, Pan T, Cheng Y, Ren W, Jia W, Ma J, Xu G. A novel multi-target RNAi adenovirus inhibits hepatoma cell proliferation, migration, and induction of angiogenesis. Oncotarget 2018; 7:57705-57713. [PMID: 27221035 PMCID: PMC5295383 DOI: 10.18632/oncotarget.9531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 05/04/2016] [Indexed: 12/16/2022] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multi-step process involving many genes. Consequently, single gene targeting therapy has limited efficacy, making combination therapy targeting multiple genes a necessity. Based on our previous findings, we constructed a single vector mediating simultaneous expression of multiple short hairpin RNAs (shRNAs) against human vascular endothelial growth factor receptor 2 (VEGFR2), chemokine C-C motif receptor 1 (CCR1), and epithelial cell adhesion molecule (EpCAM), three genes closely related to HCC progression that act through separate pathways. The shRNA vector efficiently downregulated the mRNA and protein of all three molecules in Huh7 hepatoma cells. The vector also inhibited cell proliferation and migration and reduced angiogenesis. Furthermore, this shRNA vector can be recombined into adenovirus, a gene therapy vector, for better in vivo application. It thus offers a potentially effective future gene therapy approach to treating human liver cancer.
Collapse
Affiliation(s)
- Mei Huang
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Guangyao Li
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Tingting Pan
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Ya Cheng
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Weihua Ren
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Weidong Jia
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China.,Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230001, China
| | - Jinliang Ma
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China.,Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230001, China
| | - Geliang Xu
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China.,Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230001, China
| |
Collapse
|
|
40
|
Yang X, Wang HL, Liang HW, Liang L, Wen DY, Zhang R, Chen G, Wei DM. Clinical significance of microRNA-449a in hepatocellular carcinoma with microarray data mining together with initial bioinformatics analysis. Exp Ther Med 2018; 15:3247-3258. [PMID: 29545842 PMCID: PMC5841030 DOI: 10.3892/etm.2018.5836] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Accepted: 01/03/2018] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence has demonstrated that microRNA (miR)-449a expression is reduced in various types of tumors and that it serves as a tumor suppressor. However, the molecular mechanism of miR-449a in hepatocellular carcinoma (HCC) has not been thoroughly elucidated and is disputed. Therefore, the aim of the present work was to systematically review the current literature and to utilize the public Gene Expression Omnibus database to determine the role of miR-449a and its significance in HCC. A total of eight original papers and seven microarrays were included in the present study. Based on the evidence, miR-449a was reduced in HCC. miR-449a is likely involved in various signaling pathways and is targeted to multiple mRNA as part of its function in HCC. In addition, a preliminary bioinformatic analysis was conducted for miR-449a to investigate the novel potential pathways that miR-449a may participate in regarding HCC.
Collapse
Affiliation(s)
- Xia Yang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Han-Lin Wang
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hai-Wei Liang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Liang Liang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, P.R. China
| | - Dong-Yue Wen
- Department of Ultrasonography, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Rui Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Dan-Ming Wei
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| |
Collapse
|
|
41
|
Wang H, Xiao Y, Wu L, Ma D. Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-000911/miR-449a pathway in breast carcinogenesis. Int J Oncol 2018; 52:743-754. [PMID: 29431182 PMCID: PMC5807038 DOI: 10.3892/ijo.2018.4265] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 01/25/2018] [Indexed: 12/17/2022] Open
Abstract
Circular RNAs (circRNAs) are key regulators in the development and progression of human cancers; however their roles in breast tumorigenesis are not yet well understood. Thus, the present study aimed to investigate the expression profiles and potential modulatory effects of circRNAs on breast carcinogenesis. A human circRNA microarray analysis was performed to screen for abnormally expressed circRNAs in breast cancer tissue and circRNA-000911 was identified as a circRNA which was significantly downregulated in breast cancer cells. Mechanistic investigations suggested that the enhanced expression of circRNA-000911 suppressed cell proliferation, migration and invasion, and promoted the apoptosis of breast cancer cells. By using a biotin-labeled circRNA-000911 probe to perform RNA precipitation in breast cancer cells, we identified miR‑449a as the circRNA‑000911-associated microRNA. Gain- and loss-of-function assays indicated that miR‑449a antagonized circRNA-000911 to regulate breast cancer progression. Subsequently, Notch1 was identified as the functional target of miR‑449a, and the overexpression of circRNA-000911 in breast cancer elevated Notch1 expression. Furthermore, Cignal Signal Transduction Reporter Array and western blot analysis identified nuclear factor-κB (NF-κB) signaling as a functional target of the circRNA-000911/miR‑449a pathway. On the whole, our findings indicate that circRNA-000911 plays an anti-oncogenic role in breast cancer and may thus serve as a promising therapeutic target for patients with breast cancer. Therefore, the overexpression of circRNA-000911 may provide a future direction which may aid in the development of a novel treatment strategy for breast cancer.
Collapse
Affiliation(s)
- Honglei Wang
- Galactophore Department, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yi Xiao
- Galactophore Department, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Li Wu
- Galactophore Department, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Dachang Ma
- Galactophore Department, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| |
Collapse
|
|
42
|
MiR-449a suppresses cell migration and invasion by targeting PLAGL2 in breast cancer. Pathol Res Pract 2018; 214:790-795. [PMID: 29653747 DOI: 10.1016/j.prp.2017.12.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/12/2017] [Accepted: 12/28/2017] [Indexed: 11/21/2022]
Abstract
BACKGROUND Breast cancer is one of the most common malignancies worldwide. However, the detailed molecular mechanisms underlying breast cancer metastasis are still incompletely clear. MicroRNAs (miRNAs) play a crucial role in cancer metastasis. In this study, we aimed to analyze the expression and function of miR-449a in breast cancer. MATERIAL AND METHODS A total of 15 human primary breast cancer tissues and adjacent non-cancerous tissues (10 pairs) were obtained. MiR-449a was examined in tumor tissues and adjacent nontumorous tissues of breast cancer patients and cell lines by real-time PCR. The protein expression levels were analyzed by western blot and immunohistochemistry staining. Luciferase reporter assays was used to validate the target of miR-449a. The effect of miR-449a on breast cancer cell migration and invasion were studied in vitro and in vivo. RESULTS The expression levels of miR-449a were significantly decreased in breast cancer tissues and cell lines. Overexpression of miR-449a suppressed breast cancer cell proliferation, clone formation, migration, invasion and metastasis in vitro and in vivo. Pleomorphic adenoma gene like-2 (PLAGL2) was identified as a major target of miR-449a. Both overexpression of miR-449a inhibited the expression of PLAGL2 significantly and the knockdown of PLAGL2 expression inhibited the breast cancer cell proliferation and metastasis. CONCLUSION We demonstrate the miR-449a tumor suppressor role in breast cancer cell migration and invasion via targeting PLAGL2. These findings suggesting that miR-449a/PLAGL2 could serve as a therapeutic strategy for targeting breast cancer.
Collapse
|
|
43
|
Abstract
MicroRNAs (miRNAs) have been reported to be associated with cancer progression and carcinogenesis. They are small, highly conserved, noncoding RNA molecules consisting of 19-25 nucleotides. By binding to complementary binding sites within the 3'-untranslated region of target mRNAs, miRNAs inhibit the translation of mRNAs or promote their degradation. miRNAs play critical roles in cancer initiation and development by functioning either as oncogenes or as tumor suppressors. Similarly, several studies have shown that miRNAs are involved in regulating various biological processes, including apoptosis, proliferation, cellular differentiation, signal transduction, and carcinogenesis. Among miRNAs, one that may be of particular interest in cancer biology is miR-449a, which has been reported to inhibit tumor growth, invasion, and metastasis, and to promote apoptosis and differentiation through the transforming growth factor-β activated kinase 1, NOTCH, nuclear factor-κB/P65/vascular endothelial growth factor, retinoblastoma-E2F, mitogen-activated protein kinase signaling pathways, WNT-β-catenin signaling, tumor protein P53, and androgen receptor signaling pathways. The miR-449 cluster is located in the second intron of CDC20B on chromosome 5q11.2, a region that has been identified as a susceptibility locus in cancer, and the abnormal expression of miR-449a may be related to the occurrence and development of tumors. As one example, miR-449a has been reported to be involved in the development of carcinoma and may be a potential prognostic indicator. On the basis of the putative pathogenetic relationships between cancer and miR-449a, we consider that miR-449a has the potential to serve as a therapeutic agent for the treatment of some types of cancer. In this review, the role of miR-449a in tumorigenesis and its mechanism of action are explored. Furthermore, its potential as a therapeutic agent in cancer treatment is considered.
Collapse
|
|
44
|
Deng N, Li L, Gao J, Zhou J, Wang Y, Wang C, Liu Y. Hsa_circ_0009910 promotes carcinogenesis by promoting the expression of miR-449a target IL6R in osteosarcoma. Biochem Biophys Res Commun 2018; 495:189-196. [DOI: 10.1016/j.bbrc.2017.11.028] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Accepted: 11/04/2017] [Indexed: 01/22/2023]
|
|
45
|
Loss of miR-449a in ERG-associated prostate cancer promotes the invasive phenotype by inducing SIRT1. Oncotarget 2017; 7:22791-806. [PMID: 26988912 PMCID: PMC5008401 DOI: 10.18632/oncotarget.8061] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 02/25/2016] [Indexed: 11/25/2022] Open
Abstract
Epigenetic regulation by SIRT1, a multifaceted NAD+-dependent protein deacetylase, is one of the most common factors modulating cellular processes in a broad range of diseases, including prostate cancer (CaP). SIRT1 is over-expressed in CaP cells, however the associated mechanism is not well understood. To identify whether specific microRNAs might mediate this linkage, we have screened a miRNA library for differential expression in ERG-associated CaP tissues. Of 20 differentially and significantly expressed miRNAs that distinguish ERG-positive tumors from ERG-negative tumors, we find miR-449a is highly suppressed in ERG-positive tumors. We establish that SIRT1 is a direct target of miR-449a and is also induced by ERG in ERG-associated CaP. Our data suggest that attenuation of miR-449a promotes the invasive phenotype of the ERG-positive CaP in part by inducing the expression of SIRT1 in prostate cancer cells. Furthermore, we also find that suppression of SIRT1 results in a significant reduction in ERG expression in ERG-positive CaP cells, indicating a feed-back regulatory loop associated with ERG, miR-449a and SIRT1. We also report that ERG suppresses p53 acetylation perhaps through miR-449a-SIRT1 axis in CaP cells. Our findings provide new insight into the function of miRNAs in regulating ERG-associated CaP. Thus, miR-449a activation or SIRT1 suppression may represent new therapeutic opportunity for ERG-associated CaP.
Collapse
|
|
46
|
Gui Y, Khan MGM, Bobbala D, Dubois C, Ramanathan S, Saucier C, Ilangumaran S. Attenuation of MET-mediated migration and invasion in hepatocellular carcinoma cells by SOCS1. World J Gastroenterol 2017; 23:6639-6649. [PMID: 29085209 PMCID: PMC5643285 DOI: 10.3748/wjg.v23.i36.6639] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/07/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of suppressor of cytokine signaling 1 (SOCS1) in regulating MET-mediated invasive potential of hepatocellular carcinoma (HCC) cells.
METHODS Stable derivatives of mouse (Hepa1-6) and human (hep3B, HepG2) HCC cell lines expressing SOCS1 or control vector were evaluated for their ability to migrate towards hepatocyte growth factor (HGF) in the transwell migration assay, invade extracellular matrix in response to HGF stimulation in a 3-D invasion assay by confocal microscopy, and to undergo anchorage-independent proliferation in semisolid agar. Following intravenous and intrasplenic inoculation into NOD.scid.gamma mice, the ability of Hepa cells to form othotopic tumors was evaluated. Following HGF stimulation of Hepa and Hep3B cells, expression of proteins implicated in epithelial-to-mesenchymal transition was evaluated by western blot and qRT-PCR.
RESULTS SOCS1 expression in mouse and human HCC cells inhibited HGF-induced migration through matrigel. In the 3-D invasion assay, HGF stimulation induced invasion of HCC cells across type-I collagen matrix, and SOCS1 expression significantly reduced the depth of invasion. SOCS1 expression also reduced the number and size of colonies formed by anchorage-independent growth in semisolid agar. Following intravenous inoculation, control Hepa cell formed large tumor nodules that obliterated the liver whereas the SOCS1-expressing Hepa cells formed significantly smaller nodules. Tumors formed by SOCS1-expressing cells showed reduced phosphorylation of STAT3 and ERK that was accompanied by reduced levels of MET protein expression. HGF stimulated Hepa cells expressing SOCS1 showed increased expression of E-cadherin and decreased expression of EGR1, SNAI1 and ZEB1. Comparable results were obtained with Hep3B cells. SOCS1 expressing HCC cells also showed reduced levels of EGR1 and SNAI1 transcripts.
CONCLUSION Our findings indicate that loss of SOCS1-dependent control over epithelial-to-mesenchymal transition may contribute to MET-mediated migration, invasion and metastatic growth of HCC.
Collapse
Affiliation(s)
- Yirui Gui
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Md Gulam Musawwir Khan
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Diwakar Bobbala
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Claire Dubois
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Sheela Ramanathan
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Caroline Saucier
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Subburaj Ilangumaran
- Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| |
Collapse
|
|
47
|
Ni J, Bucci J, Chang L, Malouf D, Graham P, Li Y. Targeting MicroRNAs in Prostate Cancer Radiotherapy. Theranostics 2017; 7:3243-3259. [PMID: 28900507 PMCID: PMC5595129 DOI: 10.7150/thno.19934] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 05/10/2017] [Indexed: 02/06/2023] Open
Abstract
Radiotherapy is one of the most important treatment options for localized early-stage or advanced-stage prostate cancer (CaP). Radioresistance (relapse after radiotherapy) is a major challenge for the current radiotherapy. There is great interest in investigating mechanisms of radioresistance and developing novel treatment strategies to overcome radioresistance. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level, participating in numerous physiological and pathological processes including cancer invasion, progression, metastasis and therapeutic resistance. Emerging evidence indicates that miRNAs play a critical role in the modulation of key cellular pathways that mediate response to radiation, influencing the radiosensitivity of the cancer cells through interplaying with other biological processes such as cell cycle checkpoints, apoptosis, autophagy, epithelial-mesenchymal transition and cancer stem cells. Here, we summarize several important miRNAs in CaP radiation response and then discuss the regulation of the major signalling pathways and biological processes by miRNAs in CaP radiotherapy. Finally, we emphasize on microRNAs as potential predictive biomarkers and/or therapeutic targets to improve CaP radiosensitivity.
Collapse
|
|
48
|
He SJ, Xiang CQ, Zhang Y, Lu XT, Chen HW, Xiong LX. Recent progress on the effects of microRNAs and natural products on tumor epithelial-mesenchymal transition. Onco Targets Ther 2017; 10:3435-3451. [PMID: 28744148 PMCID: PMC5513877 DOI: 10.2147/ott.s139546] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a biological process of phenotypic transition of epithelial cells that can promote physiological development as well as tissue healing and repair. In recent years, cancer researchers have noted that EMT is closely related to the occurrence and development of tumors. When tumor cells undergo EMT, they can develop enhanced migration and local tissue invasion abilities, which can lead to metastatic growth. Nevertheless, two researches in NATURE deny its necessity in specific tumors and that is discussed in this review. The degree of EMT and the detection of EMT-associated marker molecules can also be used to judge the risk of metastasis and to evaluate patients’ prognosis. MicroRNAs (miRNAs) are noncoding small RNAs, which can inhibit gene expression and protein translation through specific binding with the 3′ untranslated region of mRNA. In this review, we summarize the miRNAs that are reported to influence EMT through transcription factors such as ZEB, SNAIL, and TWIST, as well as some natural products that regulate EMT in tumors. Moreover, mutual inhibition occurs between some transcription factors and miRNAs, and these effects appear to occur in a complex regulatory network. Thus, understanding the role of miRNAs in EMT and tumor growth may lead to new treatments for malignancies. Natural products can also be combined with conventional chemotherapy to enhance curative effects.
Collapse
Affiliation(s)
- Shu-Jin He
- Department of Pathophysiology, Medical College, Nanchang University.,Second Clinical Medical College, Nanchang University
| | - Chu-Qi Xiang
- Department of Pathophysiology, Medical College, Nanchang University.,First Clinical Medical College, Nanchang University
| | - Yu Zhang
- First Clinical Medical College, Nanchang University
| | - Xiang-Tong Lu
- Department of Pathophysiology, Medical College, Nanchang University
| | - Hou-Wen Chen
- Department of Pathophysiology, Medical College, Nanchang University.,Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang, People's Republic of China
| | - Li-Xia Xiong
- Department of Pathophysiology, Medical College, Nanchang University.,Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang, People's Republic of China
| |
Collapse
|
|
49
|
Chen W, Liu Y, Chen H, Ning H, Ding K. Loss of miR-449a-caused PrLZ overexpression promotes prostate cancer metastasis. Int J Oncol 2017. [PMID: 28627667 PMCID: PMC5504971 DOI: 10.3892/ijo.2017.4038] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Distant metastasis is the worst prognostic factor for PCa patients. It has been reported that miR-449a enhances radiosensitivity of prostate cancer cells, but the function of miR449a in metastasis of prostate cancer is mainly unknown. In the present study, we strove to investigate the function and diagnostic value of miR-449a in metastasis of prostate cancer. qRT-PCR was used to quantify the expression of miR449a and PrLZ in PCa cell lines and tissues. we found that miR449a expression was decreased in PCa cell lines. Moreover, miR‑449a was downregulated in PCa tissues, especially in primary lesion tissues of metastatic PCa patients. CCK8, FACS, transwell and tube formation assay were performed to assess growth and metastasis of PCa cells in vitro. Lentivirus mediated miR-449a overexpression suppressed proliferation of LNcap and PC-3, and miR-449a also significantly inhibited invasion and angiogenesis ability of LNcap and PC-3. IHC showed that PrLZ was upregulated in PCa tissues. Luciferase assay and western blotting verified that miR-449a targeted PrLZ expression. Moreover, PrLZ shRNA also significantly suppressed proliferation and metastasis of LNcap and PC-3. In addition, western blotting revealed that miR-449a overexpression and PrLZ shRNA all remarkably inhibited the stemness features in LNcap and PC-3. Furthermore, BALB/c nude mouse subcutaneous xenograft model was uesd to verify the function of miR-449a and PrLZ. Our results showed that miR-449a and PrLZ shRNA significantly suppressed PC-3 tumorigenesis and metastasis in vivo. Our studies suggested that miR-449a decreased in malignant process of PCa and was accompanied by excess expression of PrLZ. The loss of miR-449a caused PrLZ overexpression regulated prostate cancer progression and metastasis via regulating the stemness features of prostate cancer cells. The diagnostic value of miR-449a as a distant metastasis predictor of PCa needs further investigation.
Collapse
Affiliation(s)
- Wei Chen
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Yi Liu
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Hongde Chen
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Hao Ning
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Kejia Ding
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| |
Collapse
|
|
50
|
Sandbothe M, Buurman R, Reich N, Greiwe L, Vajen B, Gürlevik E, Schäffer V, Eilers M, Kühnel F, Vaquero A, Longerich T, Roessler S, Schirmacher P, Manns MP, Illig T, Schlegelberger B, Skawran B. The microRNA-449 family inhibits TGF-β-mediated liver cancer cell migration by targeting SOX4. J Hepatol 2017; 66:1012-1021. [PMID: 28088579 DOI: 10.1016/j.jhep.2017.01.004] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 12/22/2016] [Accepted: 01/03/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS Modulation of microRNA expression is a potential treatment for hepatocellular carcinoma (HCC). Therefore, the epigenetically regulated microRNA-449 family (miR-449a, miR-449b, miR-449c) was characterized with regards to its functional effects and target genes in HCC. METHODS After transfection of miR-449a, miR-449b, and/or miR-449c, tumor-relevant functional effects were analyzed using in vitro assays and a xenograft mouse model. Binding specificities, target genes, and regulated pathways of each miRNA were identified by microarray analyses. Target genes were validated by luciferase reporter assays and expression analyses in vitro. Furthermore, target gene expression was analyzed in 61 primary human HCCs compared to normal liver tissue. RESULTS Tumor suppressive effects, binding specificities, target genes, and regulated pathways of miR-449a and miR-449b differed from those of miR-449c. Transfection of miR-449a, miR-449b, and/or miR-449c inhibited cell proliferation and migration, induced apoptosis, and reduced tumor growth to different extents. Importantly, miR-449a, miR-449b, and, to a lesser degree, miR-449c directly targeted SOX4, which codes for a transcription factor involved in epithelial-mesenchymal transition and HCC metastasis, and thereby inhibited TGF-β-mediated cell migration. CONCLUSIONS This study provides detailed insights into the regulatory network of the epigenetically regulated miRNA-449 family and, for the first time, describes distinct tumor suppressive effects and target specificities of miR-449a, miR-449b, and miR-449c. Our results indicate that particularly miR-449a and miR-449b may be considered for miRNA replacement therapy to prevent HCC progression and metastasis. LAY SUMMARY In this study, we demonstrated that the microRNA-449 family acts as a tumor suppressor in liver cancer by causing cell death and inhibiting cell migration. These effects are caused by downregulation of the oncogene SOX4, which is frequently overexpressed in liver cancer. We conclude that the microRNA-449 family may be a target for liver cancer therapy.
Collapse
Affiliation(s)
- Maria Sandbothe
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Reena Buurman
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Nicole Reich
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Luisa Greiwe
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Beate Vajen
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Engin Gürlevik
- Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Vera Schäffer
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Marlies Eilers
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Florian Kühnel
- Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Alejandro Vaquero
- Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program, Institut d'Investigació Biomèdica de Bellvitge, Barcelona, Spain
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital RWTH Aachen, Heidelberg, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Michael P Manns
- Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas Illig
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | | | - Britta Skawran
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
| |
Collapse
|