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Yang C, Wang R, Hardy P. The Multifaceted Roles of MicroRNA-181 in Stem Cell Differentiation and Cancer Stem Cell Plasticity. Cells 2025; 14:132. [PMID: 39851559 PMCID: PMC11763446 DOI: 10.3390/cells14020132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/26/2025] Open
Abstract
Stem cells are undifferentiated or partially differentiated cells with an extraordinary ability to self-renew and differentiate into various cell types during growth and development. The epithelial-mesenchymal transition (EMT), a critical developmental process, enhances stem cell-like properties in cells, and is associated with both normal stem cell function and the formation of cancer stem cells. Cell stemness and the EMT often coexist and are interconnected in various contexts. Cancer stem cells are a critical tumor cell population that drives tumorigenesis, cancer progression, drug resistance, and metastasis. Stem cell differentiation and the generation of cancer stem cells are regulated by numerous molecules, including microRNAs (miRNAs). These miRNAs, particularly through the modulation of EMT-associated factors, play major roles in controlling the stemness of cancer stem cells. This review presents an up-to-date summary of the regulatory roles of miR-181 in human stem cell differentiation and cancer cell stemness. We outline studies from the current literature and summarize the miR-181-controlled signaling pathways responsible for driving human stem cell differentiation or the emergence of cancer stem cells. Given its critical role in regulating cell stemness, miR-181 is a promising target for influencing human cell fate. Modulation of miR-181 expression has been found to be altered in cancer stem cells' biological behaviors and to significantly improve cancer treatment outcomes. Additionally, we discuss challenges in miRNA-based therapies and targeted delivery with nanotechnology-based systems.
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Affiliation(s)
- Chun Yang
- CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC H3T 1C5, Canada;
| | - Rui Wang
- Departments of Pharmacology and Physiology, Université de Montréal, Montreal, QC H3T 1C5, Canada;
| | - Pierre Hardy
- CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC H3T 1C5, Canada;
- Departments of Pharmacology and Physiology, Université de Montréal, Montreal, QC H3T 1C5, Canada;
- Departments of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1C5, Canada
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McIntyre G, Jackson Z, Colina J, Sekhar S, DiFeo A. miR-181a: regulatory roles, cancer-associated signaling pathway disruptions, and therapeutic potential. Expert Opin Ther Targets 2024; 28:1061-1091. [PMID: 39648331 DOI: 10.1080/14728222.2024.2433687] [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: 08/01/2024] [Accepted: 11/20/2024] [Indexed: 12/10/2024]
Abstract
INTRODUCTION microRNA-181a (miR-181a) is a crucial post-transcriptional regulator of many mRNA transcripts and noncoding-RNAs, influencing cell proliferation, cancer cell stemness, apoptosis, and immune responses. Its abnormal expression is well-characterized in numerous cancers, establishing it as a significant genomic vulnerability and biomarker in cancer research. AREAS COVERED Here, we summarize miR-181a's correlation with poor patient outcomes across numerous cancers and the mechanisms governing miR-181a's activity and processing. We comprehensively describe miR-181a's involvement in multiple regulatory cancer signaling pathways, cellular processes, and the tumor microenvironment. We also discuss current therapeutic approaches to targeting miR-181a, highlighting their limitations and future potential. EXPERT OPINION miR-181a is a clinically relevant pan-cancer biomarker with potential as a therapeutic target. Its regulatory control of tumorigenic signaling pathways and immune responses positions it as a promising candidate for personalized treatments. The success of miR-181a as a target relies on the development of specific therapeutics platforms. Future research on miR-181a's role in the tumor microenvironment and the RNA binding proteins that regulate its stability will help uncover new techniques to targeting miR-181a. Further research into miR-181a serum levels in patients undergoing therapy will help to better stratify patients and enhance therapeutic success.
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Affiliation(s)
- Grace McIntyre
- Department of Pathology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Zoe Jackson
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Jose Colina
- Department of Pathology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Sreeja Sekhar
- Department of Pathology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Analisa DiFeo
- Department of Pathology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
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3
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Jasim SA, Salahdin OD, Malathi H, Sharma N, Rab SO, Aminov Z, Pramanik A, Mohammed IH, Jawad MA, Gabel BC. Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA). Cell Biochem Biophys 2024; 82:3031-3051. [PMID: 39060914 DOI: 10.1007/s12013-024-01423-5] [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] [Accepted: 07/10/2024] [Indexed: 07/28/2024]
Abstract
Tumor recurrence after curative therapy and hepatocellular carcinoma (HCC) cells' resistance to conventional therapies is the reasons for the worse clinical results of HCC patients. A tiny population of cancer cells with a strong potential for self-renewal, differentiation, and tumorigenesis has been identified as cancer stem cells (CSCs). The discovery of CSC surface markers and the separation of CSC subpopulations from HCC cells have been made possible by recent developments in the study of hepatic (liver) CSCs. Hepatic CSC surface markers include epithelial cell adhesion molecules (EpCAM), CD133, CD90, CD13, CD44, OV-6, ALDH, and K19. CSCs have a significant influence on the development of cancer, invasiveness, self-renewal, metastasis, and drug resistance in HCC, and thus provide a therapeutic chance to treat HCC and avoid its recurrence. Therefore, it is essential to develop treatment approaches that specifically and effectively target hepatic stem cells. Given this, one potential treatment approach is to use particular small interfering RNA (siRNA) to target CSC, disrupting their behavior and microenvironment as well as changing their epigenetic state. The characteristics of CSCs in HCC are outlined in this study, along with new treatment approaches based on siRNA that may be used to target hepatic CSCs and overcome HCC resistance to traditional therapies.
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Affiliation(s)
| | | | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University, Bangalore, Karnataka, India
| | - Neha Sharma
- Chandigarh Pharmacy College, Chandigarh group of Colleges, Jhanjeri, 140307, Mohali, Punjab, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Zafar Aminov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Israa Hussein Mohammed
- College of nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Benien C Gabel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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4
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Hongfang G, Khan R, El-Mansi AA. Bioinformatics Analysis of miR-181a and Its Role in Adipogenesis, Obesity, and Lipid Metabolism Through Review of Literature. Mol Biotechnol 2024; 66:2710-2724. [PMID: 37773313 DOI: 10.1007/s12033-023-00894-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 09/04/2023] [Indexed: 10/01/2023]
Abstract
The miRNAs regulate various biological processes in the mammalian body system. The role of miR-181a in the development, progression, and expansion of cancers is well-documented. However, the role of miR-181a in adipogenesis; lipid metabolism; obesity; and obesity-related issues such as diabetes mellitus needs to be explored. Therefore, in the present study, the literature was searched and bioinformatics tools were applied to explore the role of miR-181a in adipogenesis. The list of adipogenic and lipogenic target genes validated through different publications were extracted and compiled. The network and functional analysis of these target genes was performed through in-silico analysis. The mature sequence of miR-181a of different species were extracted from and were found highly conserved among the curated species. Additionally, we also used various bioinformatics tools such as target gene extraction from Targetscan, miRWalk, and miRDB, and the list of the target genes from these different databases was compared, and common target genes were predicted. These common target genes were further subjected to the enrichment score and KEGG pathways analysis. The enrichment score of the vital KEGG pathways of the target genes is the key regulator of adipogenesis, lipogenesis, obesity, and obesity-related syndromes in adipose tissues. Therefore, the information presented in the current review will explore the regulatory roles of miR-181a in fat tissues and its associated functions and manifestations.
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Affiliation(s)
- Guo Hongfang
- Medical College of Xuchang University, No.1389, Xufan Road, Xuchang City, 461000, Henan Province, People's Republic of China
| | - Rajwali Khan
- Department of Livestock Management, Breeding and Genetics, The University of Agriculture, Peshawar, 25130, Pakistan.
| | - Ahmed A El-Mansi
- Biology Department, Faculty of Science, King Khalid University, Abha, Saudi Arabia
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5
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Chen J, Liu K, Vadas MA, Gamble JR, McCaughan GW. The Role of the MiR-181 Family in Hepatocellular Carcinoma. Cells 2024; 13:1289. [PMID: 39120319 PMCID: PMC11311592 DOI: 10.3390/cells13151289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/28/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues-this up-regulation induced epithelial-mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC.
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Affiliation(s)
- Jinbiao Chen
- Liver Injury and Cancer Program, Cancer Innovations Centre, Centenary Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
| | - Ken Liu
- Liver Injury and Cancer Program, Cancer Innovations Centre, Centenary Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
| | - Mathew A. Vadas
- Vascular Biology Program, Healthy Ageing Centre, Centenary Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (M.A.V.); (J.R.G.)
| | - Jennifer R. Gamble
- Vascular Biology Program, Healthy Ageing Centre, Centenary Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (M.A.V.); (J.R.G.)
| | - Geoffrey W. McCaughan
- Liver Injury and Cancer Program, Cancer Innovations Centre, Centenary Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
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6
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Baysal İ, Örsten S, Cengiz G, Ünal E, Doğrul AB, Çiftçi T, Çiftçi SY, Akinci D, Akhan O. Assessing the Potential Apoptotic Effects of Different Hydatid Cyst Fluids on Human Healthy Hepatocytes and Hepatocellular Carcinoma Cells. Acta Parasitol 2024; 69:700-709. [PMID: 38372909 PMCID: PMC11001659 DOI: 10.1007/s11686-024-00797-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 01/09/2024] [Indexed: 02/20/2024]
Abstract
Cystic Echinococcosis (CE) is a zoonotic infection caused by the larval form of Echinococcus granulosus in humans. Emerging evidence suggests an intriguing inverse association between E. granulosus infection and the occurrence of cancer. This study aimed to investigate the influence of diverse host-derived hydatid cyst fluids (HCF) with distinct genotypes on human liver hepatocytes (HC) and hepatocellular carcinoma cells (HepG2). Specifically, we examined their effects on cell proliferation, apoptosis sensitivity (BAX/BCL-2), apoptosis-related p53 expression, and the expression of cancer-related microRNA (hsa-miR-181b-3p). Cell proliferation assays, real-time PCR, and ELISA studies were conducted to evaluate potential anti-cancer properties. The findings revealed that animal-origin HCF (G1(A)) induced direct cell death by augmenting the susceptibility of HepG2 cells to apoptosis. Treatment with both G1(A) and G1(H) HCF sensitized HepG2 and HC cell lines to apoptosis by modulating the BAX/BCL-2 ratio, accompanied by upregulation of the p53 gene. Additionally, G1(A) HCF and human-derived HCFs (G1(H), G7(H)) reduced the expression of miR-181b-3p in HepG2 cells. Consequently, this study demonstrates the potential anti-cancer effect of HCF in HepG2 cells and provides the first comparative assessment of HCFs from human and animal sources with diverse genotypes, offering novel insights into this field.
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Affiliation(s)
- İpek Baysal
- Vocational School of Health Services, Hacettepe University, 06100, Ankara, Turkey.
| | - Serra Örsten
- Vocational School of Health Services, Hacettepe University, 06100, Ankara, Turkey
| | - Görkem Cengiz
- Vocational School of Health Services, Yüksek İhtisas University, 06291, Ankara, Turkey
| | - Emre Ünal
- Faculty of Medicine, Department of Radiology, Hacettepe University, 06100, Ankara, Turkey
| | - Ahmet Bülent Doğrul
- Faculty of Medicine, Department of General Surgery, Hacettepe University, 06100, Ankara, Turkey
| | - Türkmen Çiftçi
- Faculty of Medicine, Department of Radiology, Hacettepe University, 06100, Ankara, Turkey
| | - Samiye Yabanoğlu Çiftçi
- Faculty of Pharmacy, Department of Biochemistry, Hacettepe University, 06100, Ankara, Turkey
| | - Devrim Akinci
- Faculty of Medicine, Department of Radiology, Hacettepe University, 06100, Ankara, Turkey
| | - Okan Akhan
- Faculty of Medicine, Department of Radiology, Hacettepe University, 06100, Ankara, Turkey
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Nelaturi P, Kademani SP, Nallagangula KS, Ravikumar S. Role of MicroRNAs in Alcohol-Related Liver Disease. ALCOHOLISM TREATMENT QUARTERLY 2024; 42:115-137. [DOI: 10.1080/07347324.2023.2256756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Affiliation(s)
- Prabhudas Nelaturi
- Multi-Disciplinary Centre for Biomedical Research, Aarupadai Veedu Medical College and Hospital, Vinayaka Mission’s Research Foundation (Deemed to be University), Puducherry, India
| | - Sangeetha P Kademani
- Multi-Disciplinary Centre for Biomedical Research, Aarupadai Veedu Medical College and Hospital, Vinayaka Mission’s Research Foundation (Deemed to be University), Puducherry, India
| | | | - Sambandam Ravikumar
- Multi-Disciplinary Centre for Biomedical Research, Aarupadai Veedu Medical College and Hospital, Vinayaka Mission’s Research Foundation (Deemed to be University), Puducherry, India
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Gupta J, Suliman M, Ali R, Margiana R, Hjazi A, Alsaab HO, Qasim MT, Hussien BM, Ahmed M. Double-edged sword role of miRNA-633 and miRNA-181 in human cancers. Pathol Res Pract 2023; 248:154701. [PMID: 37542859 DOI: 10.1016/j.prp.2023.154701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/16/2023] [Accepted: 07/18/2023] [Indexed: 08/07/2023]
Abstract
Understanding the function and mode of operation of microRNAs (miRNAs) in cancer is of growing interest. The short non-coding RNAs known as miRNAs, which target mRNA in multicellular organisms, are described as controlling essential cellular processes. The miR-181 family and miR-633 are well-known miRNAs that play a key role in the development and metastasis of tumor cells. They may facilitate either tumor-suppressive or oncogenic function in malignant cells, according to mounting evidence. Metastatic cells that are closely linked to cancer cell migration, invasion, and angiogenesis can be identified by abnormal levels of miR-181 and miR-633. Numerous studies have demonstrated their capacity to control drug resistance, cell growth, apoptosis, and the epithelial-mesenchymal transition (EMT) and metastasis process. Interestingly, the levels of miR-181 and miR-633 and their potential target genes in the basic cellular process can vary depending on the type of cancer cells and their gene expression profile. Such miRNAs' interactions with other non-coding RNAs such as long non-coding RNAs and circular RNAs can influence tumor behaviors. Herein, we concentrated on the multifaceted roles of miR-181 and miR-633 and potential targets in human tumorigenesis, ranging from cell growth and metastasis to drug resistance.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, U. P., India.
| | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Rida Ali
- Rawalpindi Medical University, Rawalpindi, Pakistan
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Beneen M Hussien
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Muhja Ahmed
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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Rahmani F, Hashemian P, Tabrizi AT, Ghorbani Z, Ziaeemehr A, Alijannejad S, Ferns GA, Avan A, Shahidsales S. Regulatory role of miRNAs on Wnt/β-catenin signaling in tumorigenesis of glioblastoma. Indian J Cancer 2023; 60:295-302. [PMID: 37787188 DOI: 10.4103/ijc.ijc_251_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
Glioblastoma (GBM) is one of the most aggressive tumors in the brain with high mortality worldwide. Despite recent advances in therapeutic strategies, the survival rate remains low in patients with GBM. The pathogenesis of GBM is a very complicated process involving various genetic mutations affecting several oncogenic signaling pathways like Wnt/β-catenin axis. Overactivation of the Wnt/β-catenin signaling pathway is associated with decreased survival and poor prognosis in patients with GBM. MicroRNAs (miRNAs) were shown to play important roles in the regulation of cell proliferation, differentiation, apoptosis, and tumorigenesis by modulating the expression of their target genes. Aberrant expression of miRNAs were reported in various human malignancies including GBM, breast, colorectal, liver, and prostate cancers, but little is known about their cellular mechanisms. Therefore, recognition of the expression profile and regulatory effects of miRNAs on the Wnt/β-catenin pathway may offer a novel approach for the classification, diagnosis, prognosis, and treatment of patients with GBM. This review summarizes previous data on the modulatory role of miRNAs on the Wnt/β-catenin pathway implicated in tumorigenesis of GBM.
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Affiliation(s)
- Farzad Rahmani
- Metabolic Syndrome Research Center; Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Pedram Hashemian
- Department of Pathology, Jahad Daneshgahi Institute, Mashhad Branch, Mashhad, Iran
| | | | - Zeynab Ghorbani
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Aghigh Ziaeemehr
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajede Alijannejad
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University of Mashhad, Mashhad, Iran
| | - Gordon A Ferns
- Brighton and Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Verma S, Sahu BD, Mugale MN. Role of lncRNAs in hepatocellular carcinoma. Life Sci 2023; 325:121751. [PMID: 37169145 DOI: 10.1016/j.lfs.2023.121751] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/21/2023] [Accepted: 04/29/2023] [Indexed: 05/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is among the deadliest cancer in human malignancies. It is the most common and severe type of primary liver cancer. However, the molecular mechanisms underlying HCC pathogenesis remain poorly understood. Long non-coding RNAs (lncRNAs), a new kind of RNA and epigenetic factors, play a crucial role in tumorigenesis and the progression of HCC. LncRNAs are capable of promoting the autophagy, proliferation, and migration of tumor cells by targeting and modulating the expression of downstream genes in signaling pathways related to cancer; these transcripts modify the activity and expression of various tumor suppressors and oncogenes. LncRNAs could act as biomarkers for treatment approaches such as immunotherapy, chemotherapy, and surgery to effectively treat HCC patients. Improved knowledge regarding the aetiology of HCC may result from an advanced understanding of lncRNAs. Enhanced oxidative stress in the mitochondrial and Endoplasmic reticulum leads to the activation of unfolded protein response pathway that plays a crucial role in the pathophysiology of hepatocellular carcinoma. The mutual regulation between LncRNAs and Endoplasmic reticulum (ER) stress in cancer and simultaneous activation of the unfolded protein response (UPR) pathway determines the fate of tumor cells in HCC. Mitochondria-associated lncRNAs work as essential components of several gene regulatory networks; abnormal regulation of mitochondria-associated lncRNAs may lead to oncogenesis, which provides further insight into the understanding of tumorigenesis and therapeutic strategies.
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Affiliation(s)
- Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Bidhya Dhar Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, 781101, Assam, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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11
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Lin D, Chen Y, Koksal AR, Dash S, Aydin Y. Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients. Cell Commun Signal 2023; 21:102. [PMID: 37158967 PMCID: PMC10165818 DOI: 10.1186/s12964-023-01081-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 02/13/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/β-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/β-catenin signaling is needed. METHODS Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection. RESULTS Both chronic HCV infection and replicon-induced Wnt/β-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3β-mediated Wnt/β-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3β-mediated Wnt/β-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection. CONCLUSION Targeting ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/β-catenin signaling by DAA treatment. Video Abstract.
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Affiliation(s)
- Dong Lin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
| | - Yijia Chen
- The College of Liberal Arts and Sciences, Arizona State University, Tempe, AZ, 85281, USA
| | - Ali Riza Koksal
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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12
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Zhao X, Zhuang Y, Wang B, Yuan B, Du S, Zeng Z. The miR-34a-5p-c-MYC-CHK1/CHK2 Axis Counteracts Cancer Stem Cell-Like Properties and Enhances Radiosensitivity in Hepatocellular Cancer Through Repression of the DNA Damage Response. Radiat Res 2023; 199:48-60. [PMID: 36445955 DOI: 10.1667/rade-22-00098.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/14/2022] [Indexed: 11/30/2022]
Abstract
Radiotherapy has become an increasingly widespread modality for treating hepatocellular cancer (HCC); however, the development of radioresistance significantly limits its effectiveness and invariably leads to tumor recurrence. Cancer stem cell (CSC) theory offers a potential explanation for tumor relapse and radioresistance, but the underlying mechanism remains unknown. Herein we investigate the role of miRNA in molecular regulation of stemness and radioresistance in HCC. Two HCC radiation-resistant cell lines (Huh7-RR and SMMC-7721-RR) were established by selecting the radioresistant subpopulation from HCC cells via clonogenic survival assays. MiRNA Sequencing was used to identify potential radiosensitivity involved miRNA in HCC-RR cells. Xenograft tumor mouse model was established for in vivo study. CSC properties were assessed using sphere formation assay and side population (SP) cells analysis. We found that miR-34a-5p was significantly downregulated in HCC-RR cells. Overexpression of miR-34a-5p counteracts CSC properties and enhances radiosensitivity in HCC. Mechanistic investigation revealed that c-MYC is the direct target of miR-34a-5p. Overexpression of miR-34a-5p reversed c-MYC-induced radioresistance. Moreover, we found that the specific molecular mechanism was that c-MYC activated CHK1 and CHK2, which are two key DNA damage checkpoint kinases, and facilitated the DNA damage response to radiation. Repression of the miR-34a-5p-cMYC-CHK1/CHK2 axis contributes to the acquisition of radioresistance in HCC cells. In summary, the miR-34a-5p-c-MYC-CHK1/CHK2 axis counteracts cancer stem cell-like properties and enhances radiosensitivity in hepatocellular cancer through repression of the DNA damage response.
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Affiliation(s)
- Xiaomei Zhao
- Departments of Radiation Oncology Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuan Zhuang
- Departments of Radiation Oncology Zhongshan Hospital, Fudan University, Shanghai, China
| | - Biao Wang
- Departments of Radiation Oncology Zhongshan Hospital, Fudan University, Shanghai, China
| | - Baoying Yuan
- Departments of Radiation Oncology Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shisuo Du
- Departments of Radiation Oncology Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaochong Zeng
- Departments of Radiation Oncology Zhongshan Hospital, Fudan University, Shanghai, China
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13
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In Silico and In Vivo Evaluation of microRNA-181c-5p's Role in Hepatocellular Carcinoma. Genes (Basel) 2022; 13:genes13122343. [PMID: 36553610 PMCID: PMC9777864 DOI: 10.3390/genes13122343] [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: 10/29/2022] [Revised: 11/30/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a fatal disease, accounting for 75-85% of primary liver cancers. The conclusive research on miR-181c-5p's role in hepatocarcinogenesis, whether it has oncogenic effects or acts as a tumor repressor, is limited and fluctuating. Therefore, the current study aimed to elucidate the role of miR-181c-5p in HCC in silico and in vivo. The bioinformatics analysis of miR-181c-5p expression data in HCC using several databases strongly shed light on its involvement in HCC development, but also confirmed the fluctuating data around its role. miR-181c-5p was proven here to have an oncogenic role by increasing HepG2 cells' viability as confirmed by MTT analysis. In addition, miR-181c-5p was upregulated in the HCC positive control group and progressed the HCC development and malignant features by its forced expression in an HCC mouse model by targeted delivery using a LA-PAMAM polyplex. This is indicated by the cancerous gross and histological features, and the significant increase in liver function biomarkers. The functional enrichment bioinformatics analyses of miR-181c-5p-downregulated targets in HCC indicated that miR-181c-5p targets were significantly enriched in multiple pathways and biological processes involved in HCC development. Fbxl3, an example for miR-181c-5p potential targets, downregulation and its correlation with miR-181c-5p were validated by qPCR. In conclusion, miR-181c-5p is upregulated in HCC and has an oncogenic role enhancing HCC progression.
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14
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Panoramic view of microRNAs in regulating cancer stem cells. Essays Biochem 2022; 66:345-358. [PMID: 35996948 DOI: 10.1042/ebc20220007] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) are a subgroup of tumor cells, possessing the abilities of self-renewal and generation of heterogeneous tumor cell lineages. They are believed to be responsible for tumor initiation, metastasis, as well as chemoresistance in human malignancies. MicroRNAs (miRNAs) are small noncoding RNAs that play essential roles in various cellular activities including CSC initiation and CSC-related properties. Mature miRNAs with ∼22 nucleotides in length are generated from primary miRNAs via its precursors by miRNA-processing machinery. Extensive studies have demonstrated that mature miRNAs modulate CSC initiation and stemness features by regulating multiple pathways and targeting stemness-related factors. Meanwhile, both miRNA precursors and miRNA-processing machinery can also affect CSC properties, unveiling a new insight into miRNA function. The present review summarizes the roles of mature miRNAs, miRNA precursors, and miRNA-processing machinery in regulating CSC properties with a specific focus on the related molecular mechanisms, and also outlines the potential application of miRNAs in cancer diagnosis, predicting prognosis, as well as clinical therapy.
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15
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Chen J, Zhao Y, Zhang F, Li J, Boland JA, Cheng NC, Liu K, Tiffen JC, Bertolino P, Bowen DG, Krueger A, Lisowski L, Alexander IE, Vadas MA, El-Omar E, Gamble JR, McCaughan GW. Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7. Cell Mol Life Sci 2022; 79:443. [PMID: 35867177 PMCID: PMC9307539 DOI: 10.1007/s00018-022-04452-6] [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: 03/24/2022] [Revised: 06/23/2022] [Accepted: 06/26/2022] [Indexed: 11/30/2022]
Abstract
MiR-181 expression levels increased in hepatocellular carcinoma (HCC) compared to non-cancerous tissues. MiR-181 has been widely reported as a possible driver of tumourigenesis but also acts as a tumour suppressor. In addition, the miR-181 family regulates the development and function of immune and vascular cells, which play vital roles in the progression of tumours. More complicatedly, many genes have been identified as miR-181 targets to mediate the effects of miR-181. However, the role of miR-181 in the development of primary tumours remains largely unexplored. We aimed to examine the function of miR-181 and its vital mediators in the progression of diethylnitrosamine-induced primary liver cancers in mice. The size of liver tumours was significantly reduced by 90% in global (GKO) or liver-specific (LKO) 181ab1 knockout mice but not in hematopoietic and endothelial lineage-specific knockout mice, compared to WT mice. In addition, the number of tumours was significantly reduced by 50% in GKO mice. Whole-genome RNA-seq analysis and immunohistochemistry showed that epithelial-mesenchymal transition was partially reversed in GKO tumours compared to WT tumours. The expression of CBX7, a confirmed miR-181 target, was up-regulated in GKO compared to WT tumours. Stable CBX7 expression was achieved with an AAV/Transposase Hybrid-Vector System and up-regulated CBX7 expression inhibited liver tumour progression in WT mice. Hepatic CBX7 deletion restored the progression of LKO liver tumours. MiR-181a expression was the lowest and CBX7 expression the highest in iClust2 and 3 subclasses of human HCC compared to iClust1. Gene expression profiles of GKO tumours overlapped with low-proliferative peri-portal-type HCCs. Liver-specific loss of miR-181ab1 inhibited primary liver tumour progression via up-regulating CBX7 expression, but tumour induction requires both hepatic and non-hepatic miR-181. Also, miR-181ab1-deficient liver tumours may resemble low-proliferative periportal-type human HCC.
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Affiliation(s)
- Jinbiao Chen
- Liver Injury and Cancer Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Yang Zhao
- Vascular Biology Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia.,School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
| | - Fan Zhang
- UNSW Microbiome Research Centre, School of Clinical Medicine, UNSW Medicine and Health, St George and Sutherland Clinical Campuses, Kogarah, NSW, 2217, Australia
| | - Jia Li
- Vascular Biology Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia.,Centre for Motor Neuron Disease, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Jade A Boland
- Liver Injury and Cancer Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Ngan Ching Cheng
- Liver Injury and Cancer Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia.,Vascular Biology Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Ken Liu
- Liver Injury and Cancer Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia.,Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, 2050, Australia
| | - Jessamy C Tiffen
- Melanoma Epigenetics Lab Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Patrick Bertolino
- Liver Immunology Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - David G Bowen
- Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, 2050, Australia.,Liver Immunology Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Andreas Krueger
- Molecular Immunology, Faculty of Biology and Chemistry, Justus Liebig University Gießen, Schubertstr 81, 35392, Giessen, Germany.,Institute for Molecular Medicine, Frankfurt Cancer Institute, Goethe-University, Frankfurt, Germany
| | - Leszek Lisowski
- Translational Vectorology Research Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, 2145, Australia.,Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland
| | - Ian E Alexander
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW, 2145, Australia
| | - Mathew A Vadas
- Vascular Biology Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Emad El-Omar
- UNSW Microbiome Research Centre, School of Clinical Medicine, UNSW Medicine and Health, St George and Sutherland Clinical Campuses, Kogarah, NSW, 2217, Australia
| | - Jennifer R Gamble
- Vascular Biology Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Geoffrey W McCaughan
- Liver Injury and Cancer Program Centenary Institute and Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia. .,Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, 2050, Australia.
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16
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Yang C, Passos Gibson V, Hardy P. The Role of MiR-181 Family Members in Endothelial Cell Dysfunction and Tumor Angiogenesis. Cells 2022; 11:1670. [PMID: 35626707 PMCID: PMC9140109 DOI: 10.3390/cells11101670] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 02/04/2023] Open
Abstract
Endothelial dysfunction plays a critical role in many human angiogenesis-related diseases, including cancer and retinopathies. Small non-coding microRNAs (miRNAs) repress gene expression at the post-transcriptional level. They are critical for endothelial cell gene expression and function and are involved in many pathophysiological processes. The miR-181 family is one of the essential angiogenic regulators. This review summarizes the current state of knowledge of the role of miR-181 family members in endothelial cell dysfunction, with emphasis on their pathophysiological roles in aberrant angiogenesis. The actions of miR-181 members are summarized concerning their targets and associated major angiogenic signaling pathways in a cancer-specific context. Elucidating the underlying functional mechanisms of miR-181 family members that are dysregulated in endothelial cells or cancer cells is invaluable for developing miRNA-based therapeutics for angiogenesis-related diseases such as retinopathies, angiogenic tumors, and cancer. Finally, potential clinical applications of miR-181 family members in anti-angiogenic tumor therapy are discussed.
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Affiliation(s)
- Chun Yang
- Research Center of CHU Sainte-Justine, University of Montréal, Quebec, QC H3T 1C5, Canada;
| | - Victor Passos Gibson
- Departments of Pharmacology and Physiology, University of Montréal, Quebec, QC H3T 1C5, Canada;
| | - Pierre Hardy
- Research Center of CHU Sainte-Justine, University of Montréal, Quebec, QC H3T 1C5, Canada;
- Departments of Pharmacology and Physiology, University of Montréal, Quebec, QC H3T 1C5, Canada;
- Departments of Pediatrics, University of Montréal, Quebec, QC H3T 1C5, Canada
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17
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Rastgar Rezaei Y, Zarezadeh R, Nikanfar S, Oghbaei H, Nazdikbin N, Bahrami-Asl Z, Zarghami N, Ahmadi Y, Fattahi A, Nouri M, Dittrich R. microRNAs in the pathogenesis of non-obstructive azoospermia: the underlying mechanisms and therapeutic potentials. Syst Biol Reprod Med 2021; 67:337-353. [PMID: 34355990 DOI: 10.1080/19396368.2021.1951890] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
miRNAs are involved in different biological processes, including proliferation, differentiation, and apoptosis. Interestingly, 38% of the X chromosome-linked miRNAs are testis-specific and have crucial roles in regulating the renewal and cell cycle of spermatogonial stem cells. Previous studies demonstrated that abnormal expression of spermatogenesis-related miRNAs could lead to nonobstructive azoospermia (NOA). Moreover, differential miRNAs expression in seminal plasma of NOA patients has been reported compared to normozoospermic men. However, the role of miRNAs in NOA pathogenesis and the underlying mechanisms have not been comprehensively studied. Therefore, the aim of this review is to mechanistically describe the role of miRNAs in the pathogenesis of NOA and discuss the possibility of using the miRNAs as therapeutic targets.Abbreviations: AMO: anti-miRNA antisense oligonucleotide; AZF: azoospermia factor region; CDK: cyclin-dependent kinase; DAZ: deleted in azoospermia; ESCs: embryonic stem cells; FSH: follicle-stimulating hormone; ICSI: intracytoplasmic sperm injection; JAK/STAT: Janus kinase/signal transducers and activators of transcription; miRNA: micro-RNA; MLH1: Human mutL homolog l; NF-κB: Nuclear factor-kappa B; NOA: nonobstructive azoospermia; OA: obstructive azoospermia; PGCs: primordial germ cells; PI3K/AKT: Phosphatidylinositol 3-kinase/protein kinase B; Rb: retinoblastoma tumor suppressor; ROS: Reactive Oxygen Species; SCOS: Sertoli cell-only syndrome; SIRT: sirtuin; SNPs: single nucleotide polymorphisms; SSCs: spermatogonial stem cells; TESE: testicular sperm extraction; TGF-β: transforming growth factor-beta.
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Affiliation(s)
- Yeganeh Rastgar Rezaei
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Zarezadeh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Nikanfar
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Oghbaei
- Department of Physiology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Zahra Bahrami-Asl
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nosratollah Zarghami
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Ahmadi
- Department of Urology, Sina Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Fattahi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ralf Dittrich
- Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
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18
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Lin D, Reddy V, Osman H, Lopez A, Koksal AR, Rhadhi SM, Dash S, Aydin Y. Additional Inhibition of Wnt/β-Catenin Signaling by Metformin in DAA Treatments as a Novel Therapeutic Strategy for HCV-Infected Patients. Cells 2021; 10:790. [PMID: 33918222 PMCID: PMC8065725 DOI: 10.3390/cells10040790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.
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Affiliation(s)
- Dong Lin
- Laboratory Medicine and Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; (V.R.); (H.O.); (A.L.); (A.R.K.); (S.M.R.); (S.D.)
| | | | | | | | | | | | | | - Yucel Aydin
- Laboratory Medicine and Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; (V.R.); (H.O.); (A.L.); (A.R.K.); (S.M.R.); (S.D.)
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19
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Im J, Nam SK, Lee HS. MicroRNA-552 expression in colorectal cancer and its clinicopathological significance. J Pathol Transl Med 2021; 55:125-131. [PMID: 33596633 PMCID: PMC7987523 DOI: 10.4132/jptm.2021.01.17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 01/17/2021] [Indexed: 12/24/2022] Open
Abstract
Background MicroRNA-552 (miR-552) has been reported to correlate with the development and progression of various cancers, including colorectal cancer (CRC). This study aimed to investigate miR-552 expression in cancer tissue samples compared to normal mucosal tissue and its role as a diagnostic or prognostic marker in CRC patients. Methods Normal mucosal tissues and primary cancer tissues from 80 surgically resected CRC specimens were used. Quantitative real-time polymerase chain reaction was performed for miR-552 and U6 small nuclear RNA to analyze miR-552 expression and its clinicopathological significance. Immunohistochemistry for p53 and phosphatase and tension homolog (PTEN) was performed to evaluate their association with miR-552 expression. Results miR-552 expression was significantly higher in primary cancer tissues compared to normal mucosal tissues (p<.001). The expression level of miR552 was inversely correlated with that of PTEN (p=.068) and p53 (p=.004). Survival analysis showed that high miR-552 expression was associated with worse prognosis but this was not statistically significant (p=.255). However, patients with CRC having high miR-552 expression and loss of PTEN expression had significantly worse prognosis than others (p=.029). Conclusions Our results suggest that high miR-552 expression might be a potential diagnostic biomarker for CRC, and its combined analysis with PTEN expression can possibly be used as a prognostic marker.
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Affiliation(s)
- Joon Im
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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20
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Potential Diagnostic and Prognostic Utility of miR-141, miR-181b1, and miR-23b in Breast Cancer. Int J Mol Sci 2020; 21:ijms21228589. [PMID: 33202602 PMCID: PMC7697480 DOI: 10.3390/ijms21228589] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/05/2020] [Accepted: 11/12/2020] [Indexed: 12/14/2022] Open
Abstract
miRNAs, a group of short noncoding RNAs, are key regulators of fundamental cellular processes and signaling pathways. Dysregulation of miRNA expression with known oncogenic or tumor suppressor functions has been associated with neoplastic transformation. Numerous studies have reported dysregulation of miRNA-141, miR-181b1, and miR-23b in a wide range of malignancies, including breast cancer. To the best of our knowledge, no previous study had demonstrated the expression of miR-141-3p, miR-181b1-5p, and miR-23b-3p in different histological grades and molecular subtypes of breast cancer. Here, we identified differential expression of these three miRNAs in breast cancer tissues compared with benign breast fibroadenomas. In addition, high expression levels of miR-141-3p and miR-181b1-5p are strongly associated with aggressive breast carcinomas. We also confirmed the clinical potential of using the three miRNAs individually or combined as diagnostic and prognostic markers in breast cancer. Using bioinformatics analyses, we identified 23 hub genes of these three miRNAs which are involved in key signaling pathways in breast cancer. Furthermore, the KM plotter online database analysis demonstrates the association between elevated expression of miR-141 and miR-181b and shorter overall survival of breast cancer patients. Together, our data suggest an oncogenic role of the studied miRNAs and highlight their molecular roles and potential clinical applications in breast cancer.
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21
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Zhuang J, Tan J, Wu C, Zhang J, Liu T, Fan C, Li J, Zhang Y. Extracellular vesicles engineered with valency-controlled DNA nanostructures deliver CRISPR/Cas9 system for gene therapy. Nucleic Acids Res 2020; 48:8870-8882. [PMID: 32810272 PMCID: PMC7498310 DOI: 10.1093/nar/gkaa683] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 07/17/2020] [Accepted: 08/05/2020] [Indexed: 12/16/2022] Open
Abstract
Extracellular vesicles (EVs) hold great promise for transporting CRISPR–Cas9 RNA-guided endonucleases (RNP) throughout the body. However, the cell-selective delivery of EVs is still a challenge. Here, we designed valency-controlled tetrahedral DNA nanostructures (TDNs) conjugated with DNA aptamer, and loaded the valency-controlled TDNs on EV surface via cholesterol anchoring for specific cell targeting. The targeting efficacy of different ratios of aptamer/cholesterol from 1:3 to 3:1 in TDNs on decorating EVs was investigated. TDNs with one aptamer and three cholesterol anchors (TDN1) efficiently facilitated the tumor-specific accumulation of the EVs in cultured HepG2 cells and human primary liver cancer-derived organoids, as well as xenograft tumor models. The intracellular delivery of RNP by TDN1-EVs successfully realized its subsequent genome editing, leading to the downregulation of GFP or WNT10B in specific cells. This system was ultimately applied to reduce the protein expression of WNT10B, which presented remarkable tumor growth inhibition in vitro, ex vivo and in vivo, and could be extended to other therapeutic targets. The present study provides a platform for the directional display of aptamer on surface labeling and the EVs-based Cas9 delivery, which provides a meaningful idea for future cell-selective gene editing.
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Affiliation(s)
- Jialang Zhuang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Jizhou Tan
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Chenglin Wu
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Jie Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Ting Liu
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Chunhai Fan
- School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Dongchuan Rd 800, Shanghai 200240, P. R. China
| | - Jiaping Li
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Yuanqing Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
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22
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Lee HY, Hong IS. Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer. Cancers (Basel) 2020; 12:cancers12102746. [PMID: 32987767 PMCID: PMC7598600 DOI: 10.3390/cancers12102746] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
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Affiliation(s)
- Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, 85 Goesan-eup, Munmu-ro, Goesan-gun, Chungcheongbuk-do 367700, Korea;
| | - In-Sun Hong
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406840, Korea
- Correspondence: ; Tel.: +82-32-899-6315; Fax: +82-32-899-6350
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23
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Yan LJ, Guo XH, Wang WP, Hu YR, Duan SF, Liu Y, Sun Z, Huang SN, Li HL. Gene Therapy and Photothermal Therapy of Layer-by-Layer Assembled AuNCs /PEI/miRNA/ HA Nanocomplexes. Curr Cancer Drug Targets 2020; 19:330-337. [PMID: 30332960 DOI: 10.2174/1568009618666181016144855] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 03/15/2018] [Accepted: 06/22/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNA (miRNA) therapy, which was widely considered to treat a series of cancer, has been confronted with numerous obstacles to being delivered into target cells because of its easy biodegradation and instability. METHODS In this research, we successfully constructed 11-mercaptoundecanoic acid modified gold nanocages (AuNCs)/polyethyleneimine (PEI)/miRNA/hyaluronic acid (HA) complexes (abbreviated as AuNCs/PEI/miRNA/HA) using a layer-by-layer method for target-specific intracellular delivery of miRNA by HA receptor mediated endocytosis. RESULTS The results of UV spectra, hydrodynamic diameter and zeta potential analyses confirmed the formation of AuNCs/PEI/ miRNA/HA complex with its average particle size of ca. 153 nm and surface charge of ca. -9.43 mV. Next, we evaluated the antitumor effect of the nanocomplex mediated by the combination of gene therapy and photothermal therapy (PTT) against hepatocellular carcinoma (HCC) in vitro. CONCLUSION Our experimental results indicated that the AuNCs/PEI/miRNA/HA complex effectively delivered miRNA to the target cells and its antitumor effect was significantly enhanced by the combination of gene therapy and photothermal therapy. In addition, anti-miR-181b could promote Bel-7402 cell arrest in S phase and improve TIMP-3 mRNA expression. All these results suggested that AuNCs/PEI/miRNA/HA gene delivery system with combination of gene therapy and photothermal therapy might be exploited for HCC treatment.
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Affiliation(s)
- Li-Juan Yan
- Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.,Key Laboratory of Key Technology of Drug Preparation, Ministry of Education, Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Xin-Hong Guo
- Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.,Key Laboratory of Key Technology of Drug Preparation, Ministry of Education, Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Wei-Ping Wang
- Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.,Key Laboratory of Key Technology of Drug Preparation, Ministry of Education, Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Yu-Rong Hu
- Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.,Key Laboratory of Key Technology of Drug Preparation, Ministry of Education, Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Shao-Feng Duan
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan 475004, China.,Henan International Joint Laboratory for Nuclear Protein Regulation, School of Medical Sciences, Henan University, N. Jinming Ave., Kaifeng, Henan 475004, China
| | - Ying Liu
- Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.,Key Laboratory of Key Technology of Drug Preparation, Ministry of Education, Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Zhi Sun
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Medical Sciences, Henan University, N. Jinming Ave., Kaifeng, Henan 475004, China
| | - Sheng-Nan Huang
- Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.,Key Laboratory of Key Technology of Drug Preparation, Ministry of Education, Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
| | - Hui-Li Li
- Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.,Key Laboratory of Key Technology of Drug Preparation, Ministry of Education, Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
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24
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Paul S, Ali A, Katare R. Molecular complexities underlying the vascular complications of diabetes mellitus - A comprehensive review. J Diabetes Complications 2020; 34:107613. [PMID: 32505477 DOI: 10.1016/j.jdiacomp.2020.107613] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/27/2020] [Accepted: 04/18/2020] [Indexed: 12/19/2022]
Abstract
Diabetes is a chronic disease, characterized by hyperglycemia, which refers to the elevated levels of glucose in the blood, due to the inability of the body to produce or use insulin effectively. Chronic hyperglycemia levels lead to macrovascular and microvascular complications. The macrovascular complications consist of peripheral artery disease (PAD), cardiovascular diseases (CVD) and cerebrovascular diseases, while the microvascular complications comprise of diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy and diabetic neuropathy. Vascular endothelial dysfunction plays a crucial role in mediating both macrovascular and microvascular complications under hyperglycemic conditions. In diabetic microvasculature, the intracellular hyperglycemia causes damage to the vascular endothelium through - (i) activation of four biochemical pathways, namely the Polyol pathway, protein kinase C (PKC) pathway, advanced glycation end products (AGE) pathway and hexosamine pathway, all of which commutes glucose and its intermediates leading to overproduction of reactive oxygen species, (ii) dysregulation of growth factors and cytokines, (iii) epigenetic changes which concern the changes in DNA as a response to intracellular changes, and (iv) abnormalities in non-coding RNAs, specifically microRNAs. This review will focus on gaining an understanding of the molecular complexities underlying the vascular complications in diabetes mellitus, to increase our understanding towards the development of new mechanistic therapeutic strategies to prevent or treat diabetes-induced vascular complications.
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Affiliation(s)
- Shalini Paul
- Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand
| | - Azam Ali
- Centre for Bioengineering and Nanomedicine (Dunedin), University of Otago, Dunedin, New Zealand
| | - Rajesh Katare
- Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand.
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25
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Expression patterns of seven key genes, including β-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a and miR-93 in gastric cancer. Sci Rep 2020; 10:12342. [PMID: 32704077 PMCID: PMC7378835 DOI: 10.1038/s41598-020-69308-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/01/2020] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer (GC) is one of the most prevalent cancers and a major cause of cancer related mortality worldwide. Incidence of GC is affected by various factors, including genetic and environmental factors. Despite extensive research has been done for molecular characterization of GC, it remains largely unknown. Therefore, further studies specially conducted among various ethnicities in different geographic locations, are required to know the precise molecular mechanisms leading to tumorigenesis and progression of GC. The expression patterns of seven candidate genes, including β-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a, and miR-93 were determined in 24 paired GC tissues and corresponding non-cancerous tissues by quantitative Real-Time PCR. The association between the expression of these genes and clinicopathologic factors were also investigated. Our results demonstrated that overall mRNA levels of GATA6 were significantly decreased in the tumor samples in comparison with the non-cancerous tissues (median fold change (FC) = 0.3143; P = 0.0003). Overall miR-93 levels were significantly increased in the tumor samples relative to the non-cancerous gastric tissues (FC = 2.441; P = 0.0002). β-catenin mRNA expression showed a strong positive correlation with miR-34a (r = 0.5784; P = 0.0031), and miR-181a (r = 0.5652; P = 0.004) expression. miR-34a and miR-181a expression showed a significant positive correlation (r = 0.4862; P = 0.016). Moreover, lower expression of Notch1 was related to distant metastasis in GC patients with a borderline statistical significance (p = 0.0549). These data may advance our understanding of the molecular biology that drives GC as well as provide potential targets for defining novel therapeutic strategies for GC treatment.
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26
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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27
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Gu Y, Zheng X, Ji J. Liver cancer stem cells as a hierarchical society: yes or no? Acta Biochim Biophys Sin (Shanghai) 2020; 52:723-735. [PMID: 32490517 DOI: 10.1093/abbs/gmaa050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) are cells possessing abilities of self-renewal, differentiation, and tumorigenicity in NOD/SCID mice. Based on this definition, multiple cell surface markers (such as CD24, CD133, CD90, and EpCAM) as well as chemical methods are discovered to enrich liver CSCs in the recent decade. Accumulated studies have revealed molecular signatures and signaling pathways involved in regulating different liver CSCs. Among liver CSCs positive for different markers, some molecular features and regulatory pathways are commonly shared, while some are only unique in certain CSC populations. These studies imply that liver CSCs exhibit diverse heterogeneity, while a functional relationship also exists. The aim of this review is to revisit the society of liver CSCs and summarize the common or unique molecular features of known liver CSCs. We hope to call for attention of researchers on the relationship of the liver CSC subgroups and to provide clues on the hierarchical structure of the liver CSC society.
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Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xin Zheng
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
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28
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Ouyang X, Wang Z, Yao L, Zhang G. Elevated CELSR3 expression is associated with hepatocarcinogenesis and poor prognosis. Oncol Lett 2020; 20:1083-1092. [PMID: 32724347 PMCID: PMC7377182 DOI: 10.3892/ol.2020.11671] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 02/04/2020] [Indexed: 02/06/2023] Open
Abstract
Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) has been reported to exhibit a cancer-specific pattern. The present study aimed to investigate the clinical value and functional role of CELSR3 in hepatocellular carcinoma (HCC), and determine the underlying molecular mechanism in patients with HCC. CELSR3 expression in tumor and paracancerous HCC tissues was obtained from The Cancer Genome Atlas. Differential expression analysis was performed using the edgeR package. Pearson correlation analysis was used to analyze the correlation between methylation and mRNA levels of CELSR3. Pathways affected by aberrant CELSR3 expression were identified through Gene Set Enrichment Analysis. The results demonstrated that CELSR3 was highly expressed in the early stage of cancer and was present throughout the entire cancer process, which suggested that CELSR3 may serve a key role in the carcinogenesis of HCC. In addition, upregulation of CELSR3 was associated with its methylation level; high CELSR3 expression indicated a shorter overall survival time. Multiple candidate genes were screened by integrating differentially expressed (DE) mRNAs and target genes of DE microRNAs (miRs). Subsequent pathway enrichment analysis demonstrated that the upregulated genes were predominantly enriched in the ‘Neuroactive ligand-receptor interaction’ and ‘Cell cycle’ pathways, whereas the downregulated genes were primarily enriched in ‘Cytokine-cytokine receptor interaction’ and ‘Metabolic pathways’. CELSR3 and its connected nodes and edges were initially removed from the miRNA-mRNA regulatory network in order to prevent bias and compared with the network containing CELSR3 alone. The frequently dysregulated miRNAs were identified as miR-181 family members, and the results suggested that miR-181 and the Wnt/β-catenin signaling pathway influenced CELSR3 expression.
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Affiliation(s)
- Xiwu Ouyang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Zhiming Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Lei Yao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Gewen Zhang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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29
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Li N, Cheng C, Wang T. MiR-181c-5p Mitigates Tumorigenesis in Cervical Squamous Cell Carcinoma via Targeting Glycogen Synthase Kinase 3β Interaction Protein (GSKIP). Onco Targets Ther 2020; 13:4495-4505. [PMID: 32547080 PMCID: PMC7247609 DOI: 10.2147/ott.s245254] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 05/06/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Cervical cancer (CC) is a highly prevalent cancer and one of the main causes of death among women worldwide. The miR-181 family has turned out to be associated with tumorigenesis in a variety of tumors by regulating the expression of tumor-related genes. However, the mechanisms and biological function of miR-181c-5p in cervical squamous cell carcinoma (SCC) have not been well elucidated. MATERIALS AND METHODS SiHa cell lines with specific gene overexpression vectors were constructed. Targetscan was used to predict the binding site of miR-181c-5p and GSKIP. MTT assay was used to detect the clone formation rate. Flow cytometry was used to detect the apoptosis rate and to separate the cell markers. The Transwell test was used to detect cell invasion. Immunohistochemistry was used to detect protein expression in tumor tissues. Western Blotting was used to detect the expression levels of related proteins. RESULTS GSKIP was predicted to be the target gene of miR-181c-5p in cervical SCC. MiR-181c-5p overexpression suppressed SiHa cells proliferation and promoted apoptosis; the protein expressions of Ki67 and PCNA were decreased, but the expressions of Caspase-3 and Bax/Bcl-2 were increased. The overexpression of miR-181c-5p inhibited the stem-like properties of SiHa cells; the expressions of SOX2, OCT4 and CD44 were decreased. Furthermore, miR-181c-5p upregulation limited the invasion of SiHa cells; the expression of E-cadherin was higher, but the expressions of N-cadherin and Vimentin were lower. MiR-181c-5p overexpression inhibited tumorigenesis in cervical SCC tissues; the expressions of Ki67, Caspase-3, CD44 and Vimentin in vivo were consistent with those in vitro. CONCLUSION Taken together, miR-181c-5p was able to mitigate the cancer cell characteristic and invasive properties of cervical SCC through targeting GSKIP gene.
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Affiliation(s)
- Niuniu Li
- Department of Gynecology and Obstetrics of Shiyan, Taihe Hospital of Hubei Province, Shiyan, Hubei442000, People’s Republic of China
| | - Chun Cheng
- Department of Pediatrics, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei435000, People’s Republic of China
| | - Tieyan Wang
- Clinical Pathology Department of Shiyan, Taihe Hospital of Hubei Province, Shiyan, Hubei442000, People’s Republic of China
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30
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Jackson KL, Gueguen C, Lim K, Eikelis N, Stevenson ER, Charchar FJ, Lambert GW, Burke SL, Paterson MR, Marques FZ, Head GA. Neural suppression of miRNA-181a in the kidney elevates renin expression and exacerbates hypertension in Schlager mice. Hypertens Res 2020; 43:1152-1164. [PMID: 32427944 DOI: 10.1038/s41440-020-0453-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/05/2020] [Accepted: 04/14/2020] [Indexed: 11/09/2022]
Abstract
BPH/2J mice are a genetic model of hypertension with overactivity of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). BPH/2J display higher renal renin mRNA and low levels of its negative regulator microRNA-181a (miR-181a). We hypothesise that high renal SNS activity may reduce miR-181a expression, which contributes to elevated RAS activity and hypertension in BPH/2J. Our aim was to determine whether in vivo administration of a renal-specific miR-181a mimic or whether renal denervation could increase renal miR-181a abundance to reduce renal renin mRNA, RAS activity and hypertension in BPH/2J mice. Blood pressure (BP) in BPH/2J and normotensive BPN/3J mice was measured via radiotelemetry probes. Mice were administered miR-181a mimic or a negative control (1-25 nmol, i.v., n = 6-10) with BP measured for 48 h after each dose or they underwent renal denervation or sham surgery (n = 7-9). Injection of 5-25 nmol miR-181a mimic reduced BP in BPH/2J mice after 36-48 h (-5.3 ± 1.8, -6.1 ± 1.9 mmHg, respectively, P < 0.016). Treatment resulted in lower renal renin and inflammatory marker (TLR4) mRNA levels in BPH/2J. The mimic abolished the hypotensive effect of blocking the RAS with enalaprilat (P < 0.01). No differences between mimic or vehicle were observed in BPN/3J mice except for a higher level of renal angiotensinogen in the mimic-treated mice. Renal miR-181a levels that were lower in sham BPH/2J mice were greater following renal denervation and were thus similar to those of BPN/3J. Our findings suggest that the reduced renal miR-181a may partially contribute to the elevated BP in BPH/2J mice, through an interaction between the renal sympathetic nerves and miR-181a regulation of the RAS.
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Affiliation(s)
- Kristy L Jackson
- Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Cindy Gueguen
- Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Kyungjoon Lim
- Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC, Australia
| | - Nina Eikelis
- Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC, Australia
| | - Emily R Stevenson
- Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Fadi J Charchar
- Faculty of Science and Technology, Federation University Australia, Ballarat, VIC, Australia
| | - Gavin W Lambert
- Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC, Australia
| | - Sandra L Burke
- Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Madeleine R Paterson
- Hypertension Research Laboratory, School of Biological Sciences, Monash University, Clayton, VIC, Australia
| | - Francine Z Marques
- Faculty of Science and Technology, Federation University Australia, Ballarat, VIC, Australia.,Hypertension Research Laboratory, School of Biological Sciences, Monash University, Clayton, VIC, Australia.,Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Geoffrey A Head
- Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. .,Department of Pharmacology, Monash University, Clayton, VIC, Australia.
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31
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Indrieri A, Carrella S, Carotenuto P, Banfi S, Franco B. The Pervasive Role of the miR-181 Family in Development, Neurodegeneration, and Cancer. Int J Mol Sci 2020; 21:ijms21062092. [PMID: 32197476 PMCID: PMC7139714 DOI: 10.3390/ijms21062092] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/13/2020] [Accepted: 03/16/2020] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs playing a fundamental role in the regulation of gene expression. Evidence accumulating in the past decades indicate that they are capable of simultaneously modulating diverse signaling pathways involved in a variety of pathophysiological processes. In the present review, we provide a comprehensive overview of the function of a highly conserved group of miRNAs, the miR-181 family, both in physiological as well as in pathological conditions. We summarize a large body of studies highlighting a role for this miRNA family in the regulation of key biological processes such as embryonic development, cell proliferation, apoptosis, autophagy, mitochondrial function, and immune response. Importantly, members of this family have been involved in many pathological processes underlying the most common neurodegenerative disorders as well as different solid tumors and hematological malignancies. The relevance of this miRNA family in the pathogenesis of these disorders and their possible influence on the severity of their manifestations will be discussed. A better understanding of the miR-181 family in pathological conditions may open new therapeutic avenues for devasting disorders such as neurodegenerative diseases and cancer.
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Affiliation(s)
- Alessia Indrieri
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy; (S.C.); (P.C.)
- Medical Genetics, Department of Translational Medical Sciences, University of Naples “Federico II”, Via Sergio Pansini 5, 80131 Naples, Italy
- Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), 20090 Milan, Italy
- Correspondence: (A.I.); (S.B.); (B.F.); Tel.: +39-081-19230655 (A.I.); +39-081-19230606 (S.B.); +39-081-19230615 (B.F.)
| | - Sabrina Carrella
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy; (S.C.); (P.C.)
- Medical Genetics, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Pietro Carotenuto
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy; (S.C.); (P.C.)
- The Institute of Cancer Research, Cancer Therapeutics Unit 15 Cotswold Road, Sutton, London SM2 5NG, UK
| | - Sandro Banfi
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy; (S.C.); (P.C.)
- Medical Genetics, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
- Correspondence: (A.I.); (S.B.); (B.F.); Tel.: +39-081-19230655 (A.I.); +39-081-19230606 (S.B.); +39-081-19230615 (B.F.)
| | - Brunella Franco
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy; (S.C.); (P.C.)
- Medical Genetics, Department of Translational Medical Sciences, University of Naples “Federico II”, Via Sergio Pansini 5, 80131 Naples, Italy
- Correspondence: (A.I.); (S.B.); (B.F.); Tel.: +39-081-19230655 (A.I.); +39-081-19230606 (S.B.); +39-081-19230615 (B.F.)
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Abstract
People living with HIV can experience accelerated aging and the development of neurological disorders. Recently, we reported that HIV-1 infection results in a dramatic loss of peroxisomes in macrophages and brain tissue. This is significant because (i) peroxisomes are important for the innate immune response and (ii) loss of peroxisome function is associated with cellular aging and neurodegeneration. Accordingly, understanding how HIV-1 infection causes peroxisome depletion may provide clues regarding how the virus establishes persistent infections and, potentially, the development of neurological disorders. Here, we show that the accessory protein Vpu is necessary and sufficient for the induction of microRNAs that target peroxisome biogenesis factors. The ability of Vpu to downregulate peroxisome formation depends on the Wnt/β-catenin pathway. Thus, in addition to revealing a novel mechanism by which HIV-1 uses intracellular signaling pathways to target antiviral signaling platforms (peroxisomes), we have uncovered a previously unknown link between the Wnt/β-catenin pathway and peroxisome homeostasis. Human immunodeficiency virus type 1 (HIV-1) establishes lifelong infections in humans, a process that relies on its ability to thwart innate and adaptive immune defenses of the host. Recently, we reported that HIV-1 infection results in a dramatic reduction of the cellular peroxisome pool. Peroxisomes are metabolic organelles that also function as signaling platforms in the innate immune response. Here, we show that the HIV-1 accessory protein Vpu is necessary and sufficient for the depletion of cellular peroxisomes during infection. Vpu induces the expression of four microRNAs that target mRNAs encoding proteins required for peroxisome formation and metabolic function. The ability of Vpu to downregulate peroxisomes was found to be dependent upon the Wnt/β-catenin signaling pathway. Given the importance of peroxisomes in innate immune signaling and central nervous system function, the roles of Vpu in dampening antiviral signaling appear to be more diverse than previously realized. Finally, our findings highlight a potential role for Wnt/β-catenin signaling in peroxisome homeostasis through modulating the production of biogenesis factors.
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Stem Cell Therapy for Hepatocellular Carcinoma: Future Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1237:97-119. [PMID: 31728916 DOI: 10.1007/5584_2019_441] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer and results in a high mortality rate worldwide. Unfortunately, most cases of HCC are diagnosed in an advanced stage, resulting in a poor prognosis and ineffective treatment. HCC is often resistant to both radiotherapy and chemotherapy, resulting in a high recurrence rate. Although the use of stem cells is evolving into a potentially effective approach for the treatment of cancer, few studies on stem cell therapy in HCC have been published. The administration of stem cells from bone marrow, adipose tissue, the amnion, and the umbilical cord to experimental animal models of HCC has not yielded consistent responses. However, it is possible to induce the apoptosis of cancer cells, repress angiogenesis, and cause tumor regression by administration of genetically modified stem cells. New alternative approaches to cancer therapy, such as the use of stem cell derivatives, exosomes or stem cell extracts, have been proposed. In this review, we highlight these experimental approaches for the use of stem cells as a vehicle for local drug delivery.
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miR-1185-1 and miR-548q Are Biomarkers of Response to Weight Loss and Regulate the Expression of GSK3B. Cells 2019; 8:cells8121548. [PMID: 31801236 PMCID: PMC6953011 DOI: 10.3390/cells8121548] [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: 11/13/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 12/12/2022] Open
Abstract
The aim of the present investigation was to identify putative miRNAs involved in the response to weight loss. Reverse-transcribed RNA isolated from white blood cells (WBCs) of a subpopulation from the Reduction of the Metabolic Syndrome in Navarra-Spain (RESMENA-S) study (low-responders (LR) and high-responders (HR)) was hybridized in a gene expression microarray. Moreover, miRNAs were sequenced by miRNA-Seq. It was found that miR-548q and miR-1185-1 were overexpressed in HR, both in the microarray and in the miRNA-Seq. A bioinformatic prediction of putative target genes of the selected miRNAs found that GSK3B, a putative target for miR-548q and miR-1185-1, was downregulated in HR. Particular 3′-UTR binding regions of GSK3B were cloned downstream of the firefly luciferase gene. HEK-293T cells were co-transfected with either 0.25 μg of empty pmiR-GLO or pmiR-GLO-548q-3′-UTR/pmiR-GLO-1185-1-3′-UTR, and 7.5 pmol of miR-548q/miR-1185-1 mimics, demonstrating that miR-1185-1 bound to the 3′-UTR region of GSK3B. THP-1 cells were transfected with either 20/40 nM of miR-548q/miR-1185-1 mimics, evidencing that miR-1185-1inhibited the expression of the gene when transfected at doses of 20/40 nM, whereas miR-548q inhibited GSK3B expression at a dose of 40 nM. As a conclusion, miR-548q and miR-1185-1 levels in WBCs are biomarkers of response to weight-loss diets and could be involved in the regulation of the proinflammatory gene GSK3B.
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miR-221-3p and miR-15b-5p promote cell proliferation and invasion by targeting Axin2 in liver cancer. Oncol Lett 2019; 18:6491-6500. [PMID: 31814849 PMCID: PMC6888111 DOI: 10.3892/ol.2019.11056] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 10/11/2019] [Indexed: 12/16/2022] Open
Abstract
Globally, liver cancer has the third highest mortality rate among all types of cancer due to the invasive and metastatic capacities of liver tumor cells. MicroRNA (miR) is a class of non-coding RNAs that participate in the development of liver cancer. The aim of the present study was to explore the molecular mechanisms by which miR-221-3p and miR-15b-5p promote the proliferation and invasion of liver cancer cells through targeting axis formation inhibitor 2 (Axin2) and to identify suitable targets for the treatment of liver cancer. The expression levels of miR-221-3p and miR-15b-5p were determined in liver cancer tissues and cells by quantitative PCR, and the association between miR-221-3p, miR-15b-5p and Axin2 expression in liver cancer cells was analyzed using cell transfection. The results demonstrated that miR-221-3p and miR-15b-5p levels were upregulated in liver cancer tissues and cell lines, and results from predictive bioinformatic analysis and identification revealed that Axin2 was the common target gene of miR-221-3p and miR-15b-5p. miR-221-3p and miR-15b-5p may be used as prognostic indicators for liver cancer. The miR-221-3p/miR-15b-5p-Axin2 axis may serve as a therapeutic target in patients with liver cancer.
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Takai A, Dang H, Oishi N, Khatib S, Martin SP, Dominguez DA, Luo J, Bagni R, Wu X, Powell K, Ye QH, Jia HL, Qin LX, Chen J, Mitchell GA, Luo X, Thorgeirsson SS, Wang XW. Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM + Hepatocellular Carcinoma. Cancer Res 2019; 79:2379-2391. [PMID: 30862714 PMCID: PMC6497533 DOI: 10.1158/0008-5472.can-18-3015] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 01/28/2019] [Accepted: 03/04/2019] [Indexed: 12/29/2022]
Abstract
Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell-like EpCAM+AFP+ HCC subtype have poor prognosis. Here, we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAM+AFP+ HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/β-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a bona fide target for EpCAM+ HCC. PMPCB blockage suppressed EpCAM expression and Wnt/β-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suppression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM+ HCC subpopulations. SIGNIFICANCE: This study identifies PMPCB as critical to mitochondrial homeostasis and a synthetic lethal candidate that selectively kills highly resistant EpCAM+ HCC tumors by inactivating the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Atsushi Takai
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Hien Dang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
- Department of Surgery, Division of Surgical Research, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Naoki Oishi
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Subreen Khatib
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Sean P Martin
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Dana A Dominguez
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Ji Luo
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Rachel Bagni
- Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Xiaolin Wu
- Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Katie Powell
- Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | | | | | | | - Jinqiu Chen
- Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Gary A Mitchell
- Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Xiaoling Luo
- Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Snorri S Thorgeirsson
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
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37
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LncRNA CASC7 inhibits the progression of glioma via regulating Wnt/β-catenin signaling pathway. Pathol Res Pract 2019; 215:564-570. [DOI: 10.1016/j.prp.2019.01.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 12/26/2018] [Accepted: 01/12/2019] [Indexed: 12/18/2022]
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38
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Aslani S, Abhari A, Sakhinia E, Sanajou D, Rajabi H, Rahimzadeh S. Interplay between microRNAs and Wnt, transforming growth factor-β, and bone morphogenic protein signaling pathways promote osteoblastic differentiation of mesenchymal stem cells. J Cell Physiol 2018; 234:8082-8093. [PMID: 30548580 DOI: 10.1002/jcp.27582] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 09/18/2018] [Indexed: 12/17/2022]
Abstract
Osteoblasts are terminally differentiated cells with mesenchymal origins, known to possess pivotal roles in sustaining bone microstructure and homeostasis. These cells are implicated in the pathophysiology of various bone disorders, especially osteoporosis. Over the last few decades, strategies to impede bone resorption, principally by bisphosphonates, have been mainstay of treatment of osteoporosis; however, in recent years more attention has been drawn on bone-forming approaches for managing osteoporosis. MicroRNAs (miRNAs) are a broad category of noncoding short sequence RNA fragments that posttranscriptionally regulate the expression of diverse functional and structural genes in a negative manner. An accumulating body of evidence signifies that miRNAs direct mesenchymal stem cells toward osteoblast differentiation and bone formation through bone morphogenic protein, transforming growth factor-β, and Wnt signaling pathways. MiRNAs are regarded as excellent future therapeutic candidates because of their small size and ease of delivery into the cells. Considering their novel therapeutic significance, this review discusses the main miRNAs contributing to the anabolic aspects of bone formation and illustrates their interactions with corresponding signaling pathways involved in osteoblastic differentiation.
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Affiliation(s)
- Somayeh Aslani
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Abhari
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ebrahim Sakhinia
- Deparment of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Davoud Sanajou
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Rajabi
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sevda Rahimzadeh
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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39
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Gu Y, Wei X, Sun Y, Gao H, Zheng X, Wong LL, Jin L, Liu N, Hernandez B, Peplowska K, Zhao X, Zhan QM, Feng XH, Tang ZY, Ji J. miR-192-5p Silencing by Genetic Aberrations Is a Key Event in Hepatocellular Carcinomas with Cancer Stem Cell Features. Cancer Res 2018; 79:941-953. [PMID: 30530815 DOI: 10.1158/0008-5472.can-18-1675] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 10/11/2018] [Accepted: 11/30/2018] [Indexed: 02/07/2023]
Abstract
Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. Through miRNA profile analysis in an HCC cohort (n = 241) for five groups of CSC+ HCC tissues, i.e., EpCAM+, CD90+, CD133+, CD44+, and CD24+ HCC, we identified a 14-miRNA signature commonly altered among these five groups of CSC+ HCC. miR-192-5p, the top-ranked CSC miRNA, was liver-abundant and -specific and markedly downregulated in all five groups of CSC+ HCC from two independent cohorts (n = 613). Suppressing miR-192-5p in HCC cells significantly increased multiple CSC populations and CSC-related features through targeting PABPC4. Both TP53 mutation and hypermethylation of the mir-192 promoter impeded transcriptional activation of miR-192-5p in HCC cell lines and primary CSC+ HCC. This study reveals the circuit from hypermethylation of the mir-192 promoter through the increase in PABPC4 as a shared genetic regulatory pathway in various groups of primary CSC+ HCC. This circuit may be the driver that steers liver cells toward hepatic CSC cells, leading to hepatic carcinogenesis. SIGNIFICANCE: miR-192-5p and its regulatory pathway is significantly abolished in multiple groups of HCC expressing high levels of CSC markers, which may represent a key event for hepatic carcinogenesis.
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Affiliation(s)
- Yuanzhuo Gu
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Xiyang Wei
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yulin Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongjun Gao
- University of Hawai'i Cancer Center, Honolulu, Hawaii.,Clinical Laboratory, China Meitan General Hospital, Beijing, China
| | | | - Linda L Wong
- University of Hawai'i Cancer Center, Honolulu, Hawaii.,Department of Surgery, John A. Burns School of Medicine, University of Hawai'i, Honolulu, Hawaii
| | - Ling Jin
- University of Hawai'i Cancer Center, Honolulu, Hawaii
| | - Niya Liu
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | | | | | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi-Min Zhan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xin-Hua Feng
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zhao-You Tang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Junfang Ji
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China.
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40
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Wang LQ, Yu P, Li B, Guo YH, Liang ZR, Zheng LL, Yang JH, Xu H, Liu S, Zheng LS, Zhou H, Qu LH. miR-372 and miR-373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways. Mol Oncol 2018; 12:1949-1964. [PMID: 30171794 PMCID: PMC6210048 DOI: 10.1002/1878-0261.12376] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 07/28/2018] [Accepted: 08/10/2018] [Indexed: 01/05/2023] Open
Abstract
miR‐372/373, a cluster of stem cell‐specific microRNAs transactivated by the Wnt pathway, has been reported to be dysregulated in various cancers, particularly colorectal cancer (CRC); however, the unique role of these microRNAs in cancer remains to be discovered. In the present study, we characterized the upregulation in expression of miR‐372/373 in CRC tissues from The Cancer Genome Atlas data, and then showed that overexpression of miR‐372/373 enhanced the stemness of CRC cells by enriching the CD26/CD24‐positive cell population and promoting self‐renewal, chemotherapy resistance and the invasive potential of CRC cells. To clarify the mechanism underlying microRNA‐induced stemness, we profiled 45 cell signaling pathways in CRC cells overexpressing miR‐372/373 and found that stemness‐related pathways, such as Nanog and Hedgehog, were upregulated. Instead, differentiation‐related pathways, such as NFκB, MAPK/Erk and VDR, were markedly repressed by miR‐372/373. Numerous new targets of miR‐372/373 were identified, including SPOP, VDR and SETD7, all of which are factors important for cell differentiation. Furthermore, in contrast to the increase in miR‐372/373 expression in CRC tissues, the expression levels of SPOP and VDR mRNA were significantly downregulated in these tissues, indicative of the poor differentiation status of CRC. Taken together, our findings suggest that miR‐372/373 enhance CRC cell stemness by repressing the expression of differentiation genes. These results provide new insights for understanding the function and mechanisms of stem cell‐specific microRNAs in the development of metastasis and drug resistance in CRC.
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Affiliation(s)
- Lu-Qin Wang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Peng Yu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Bin Li
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yan-Hua Guo
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Zi-Rui Liang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Ling-Ling Zheng
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jian-Hua Yang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Hui Xu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Shun Liu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Li-Si Zheng
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Hui Zhou
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Liang-Hu Qu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
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41
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Liu X, Peng H, Liao W, Luo A, Cai M, He J, Zhang X, Luo Z, Jiang H, Xu L. MiR-181a/b induce the growth, invasion, and metastasis of neuroblastoma cells through targeting ABI1. Mol Carcinog 2018; 57:1237-1250. [PMID: 29802737 DOI: 10.1002/mc.22839] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/26/2018] [Accepted: 05/23/2018] [Indexed: 02/05/2023]
Abstract
Neuroblastoma is a pediatric malignancy, and the clinical phenotypes range from localized tumors with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40%, despite intensive therapy. Emerging evidence suggests that aberrant miRNA regulation plays a role in neuroblastoma, but the miRNA functions and mechanisms remain unknown. miR-181 family members were detected in 32 neuroblastoma patients, and the effects of miR-181a/b on cell viability, invasion, and migration were evaluated in vitro and in vivo. A parallel global mRNA expression profile was obtained for neuroblastoma cells overexpressing miR-181a. The potential targets of miR-181a/b were validated. miR-181a/b expression levels were positively associated with MYCN amplification and neuroblastoma aggressiveness. Moreover, ectopic miR-181a/b expression significantly induced the growth and invasion of neuroblastoma cells in vitro and in vivo. Microarray analysis revealed that mRNAs were consistently downregulated after miR-181a overexpression, leading to cell migration. In addition, the expression of ABI1 was suppressed by miR-181a/b, and ABI1 was validated as a direct target of miR-181a/b. We concluded that miR-181a/b were significantly upregulated in aggressive neuroblastoma, which enhanced its tumorigenesis and progression by suppressing the expression of ABI1.
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Affiliation(s)
- Xiaodan Liu
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Hongxia Peng
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wang Liao
- Department of Pediatrics, Foshan Maternal and Child Health Care Hospital, Foshan, China
| | - Ailing Luo
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Mansi Cai
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xiaohong Zhang
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ziyan Luo
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Hua Jiang
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ling Xu
- Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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42
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Immunohistochemical Coexpression of Epithelial Cell Adhesion Molecule and Alpha-Fetoprotein in Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2018; 2018:5970852. [PMID: 30112355 PMCID: PMC6077358 DOI: 10.1155/2018/5970852] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 07/05/2018] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND AND AIM The epithelial cell adhesion molecule (EpCAM) has been proposed as a marker for cancer stem cells in human hepatocellular carcinoma (HCC) as well as in the development of novel target therapies. This study aimed to investigate the immunohistochemical expression of EpCAM and alpha-fetoprotein (AFP) in HCC patients and their association with clinicopathological characteristics. METHODS This study included Child-Pugh A HCC patients undergoing curative surgical resection. RESULTS A significant difference was observed in the ratio between the different phenotypes (p = 0.002), identifying 12 (29.3%) EPCAM positive tumors and 29 (70.7%) negative tumors. EpCAM+ expression was associated with AFP + (OR = 12.5, 95% CI, 1.9-84.1, p<0.001). In univariate analysis, a significant association was observed between AFP+ and EPCAM+ and the serum AFP level. A diameter of ≤ 5 cm was associated with EPCAM+, while angiolymphatic invasion was associated with APF+. In a multivariate analysis, only tumors of ≤ 5 cm were significantly associated with EpCAM+ (OR = 8.7; 95%CI, 1.27-100.0; p = 0.022). The overall survival rate was 74.9%, 69.4%, 69.4%, and 53.5% at 12, 24, 36, and 48 months, respectively. CONCLUSION A considerable number of patients with EpCAM+ HCC would benefit from a specific target therapy.
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43
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Nie X, Liu Y, Chen WD, Wang YD. Interplay of miRNAs and Canonical Wnt Signaling Pathway in Hepatocellular Carcinoma. Front Pharmacol 2018; 9:657. [PMID: 29977206 PMCID: PMC6021530 DOI: 10.3389/fphar.2018.00657] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/01/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma is one of the leading causes of cancer death worldwide and the activation of canonical Wnt signaling pathway is universal in hepatocellular carcinoma patients. MicroRNAs are found to participate in the pathogenesis of hepatocellular carcinoma by activating or inhibiting components in the canonical Wnt signaling pathway. Meanwhile, transcriptional activation of microRNAs by canonical Wnt signaling pathway also contributes to the occurrence and progression of hepatocellular carcinoma. Pharmacological inhibition of hepatocellular carcinoma pathogenesis and other cancers by microRNAs are now in clinical trials despite the challenges of identifying efficient microRNAs candidates and safe delivery vehicles. The focus of this review is on the interplay mechanisms between microRNAs and canonical Wnt signaling pathway in hepatocellular carcinoma, and a deep understanding of the crosstalk will promote to develop a better management of this disease.
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Affiliation(s)
- Xiaobo Nie
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China
| | - Yiran Liu
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China.,Department of Pathology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
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44
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Sun Y, Ji F, Kumar MR, Zheng X, Xiao Y, Liu N, Shi J, Wong L, Forgues M, Qin LX, Tang ZY, Zhao X, Wang XW, Ji J. Transcriptome integration analysis in hepatocellular carcinoma reveals discordant intronic miRNA-host gene pairs in expression. Int J Biol Sci 2017; 13:1438-1449. [PMID: 29209147 PMCID: PMC5715526 DOI: 10.7150/ijbs.20836] [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: 05/02/2017] [Accepted: 09/21/2017] [Indexed: 12/13/2022] Open
Abstract
Intronic miRNAs, residing in intronic regions of host genes, are thought to be co-transcribed from their host genes and present consistent expression patterns with host genes. Recent studies reported a few intronic miRNAs with discordant expression with their host genes. We therefore aimed to understand the expression pattern of intronic miRNAs and their host genes in hepatocellular carcinoma (HCC) and reveal possible associated molecular mechanisms. Our genome wide integration analysis of miRNA and mRNA transcriptomes, in three dataset from 550 patients with HCC, found that a large amount of miRNA-host gene pairs were discordantly expressed. Consistent results were also revealed in 775 breast cancer patients. Further, most of HCC-related intronic miRNAs were predicted to have distinct upstream regulators and independent proximal promoter signals from host genes. The discordant expression of representative pairs, miR-26s/CTDSPs, was validated experimentally. We have also identified the independent transcriptional start site, promoter signal, and transcriptional factor of miR-26b from its host gene. Collectively, discordant expression of intronic miRNAs and their host genes was relatively ubiquitous and the intronic miRNA “independent transcription” may partially contribute to such a phenotype.
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Affiliation(s)
- Yulin Sun
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.,University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA.,State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fubo Ji
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Mia R Kumar
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Xin Zheng
- Sinowell Beijing Tech Ltd, Beijing, 100045, China
| | - Yi Xiao
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Niya Liu
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Jiong Shi
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA.,Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, 200433
| | - Linda Wong
- University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA.,Department of Surgery, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI, 96813, USA
| | - Marshonna Forgues
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Lun-Xiu Qin
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, 200433
| | - Zhao-You Tang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, 200433
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xin Wei Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Junfang Ji
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
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Livingstone MC, Johnson NM, Roebuck BD, Kensler TW, Groopman JD. Profound changes in miRNA expression during cancer initiation by aflatoxin B 1 and their abrogation by the chemopreventive triterpenoid CDDO-Im. Mol Carcinog 2017; 56:2382-2390. [PMID: 28218475 DOI: 10.1002/mc.22635] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/01/2017] [Accepted: 02/16/2017] [Indexed: 12/17/2022]
Abstract
Aflatoxin B1 (AFB1 ) is a potent human and animal hepatocarcinogen. To investigate the effects of aflatoxin on miRNA expression during the initiation phase of carcinogenesis, next-generation sequencing was used to analyze liver tissues from F344 rats exposed to 200 μg/kg per day AFB1 for 4 week. A panel of miRNAs was identified that was upregulated with AFB1 treatment compared to controls: rno-miR-434-3p, rno-miR-411-5p, rno-miR-221-3p, rno-miR-127-3p, rno-miR-205, rno-miR-429, rno-miR-34a-5p, rno-miR-181c-3p, rno-miR-200b-3p, and rno-miR-541-5p. Analysis of rat livers exposed to AFB1 plus the chemopreventive triterpenoid CDDO-Im revealed a striking abrogation of this upregulation. These changes were validated by real-time PCR. We also explored the temporal variation in expression of the candidate miRNAs during the 4-week dosing period. Most of the candidate miRNAs were upregulated at week 1 and increased for the duration of AFB1 dosing over the 4-week period. Treatment with CDDO-Im ameliorated these effects at all time points. All candidate miRNAs were detectable in serum from aflatoxin treated animals; however, there was no significant difference in expression for 7 of the 11 miRNAs examined. Exposure to AFB1 upregulated miR-122-5p (fivefold), 34a-5p (13-fold), and 181c-3p (170-fold) compared with controls. The findings from this study give insight into epigenetic changes induced by aflatoxin taking place during the initial step of carcinogenesis.
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Affiliation(s)
| | | | - Bill D Roebuck
- Dartmouth College School of Medicine, Hanover, New Hampshire
| | - Thomas W Kensler
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - John D Groopman
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Markopoulos GS, Roupakia E, Tokamani M, Chavdoula E, Hatziapostolou M, Polytarchou C, Marcu KB, Papavassiliou AG, Sandaltzopoulos R, Kolettas E. A step-by-step microRNA guide to cancer development and metastasis. Cell Oncol (Dordr) 2017; 40:303-339. [DOI: 10.1007/s13402-017-0341-9] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2017] [Indexed: 01/17/2023] Open
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Carotenuto P, Fassan M, Pandolfo R, Lampis A, Vicentini C, Cascione L, Paulus-Hock V, Boulter L, Guest R, Quagliata L, Hahne JC, Ridgway R, Jamieson T, Athineos D, Veronese A, Visone R, Murgia C, Ferrari G, Guzzardo V, Evans TRJ, MacLeod M, Feng GJ, Dale T, Negrini M, Forbes SJ, Terracciano L, Scarpa A, Patel T, Valeri N, Workman P, Sansom O, Braconi C. Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut 2017; 66:1268-1277. [PMID: 27618837 PMCID: PMC5530482 DOI: 10.1136/gutjnl-2016-312278] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/05/2016] [Accepted: 08/17/2016] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/β-catenin pathway in liver cancer. DESIGN Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/β-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation. RESULTS Overexpression of the T-UCR uc.158- could differentiate Wnt/β-catenin dependent HCC from normal liver and from β-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158- was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of β-catenin altered uc.158- expression in human malignant hepatocytes. uc.158- expression was increased in CTNNB1-mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of β-catenin. uc.158- was increased in TAA rat CCA and reduced after treatment with Wnt/β-catenin inhibitors. uc.158- expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158- reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158- sequence. Modulation of uc.158- changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158- inhibitor and anti-miR-193b rescued the effect of uc.158- inhibition on cell viability. CONCLUSIONS We showed that uc.158- is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics.
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Affiliation(s)
| | - Matteo Fassan
- Department of Medicine, University of Padua, Padua, Italy
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | | | | | | | | | | | - Luke Boulter
- MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK
| | - Rachel Guest
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Luca Quagliata
- Molecular Pathology Division, Institute of Pathology, University of Basel, Basel, Switzerland
| | | | - Rachel Ridgway
- Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK
| | - Tam Jamieson
- Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK
| | - Dimitris Athineos
- Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK
| | - Angelo Veronese
- Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy
| | - Rosa Visone
- Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy
| | - Claudio Murgia
- Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK
| | | | | | | | - Martin MacLeod
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Gui Ji Feng
- School of Biosciences, Cardiff University, Cardiff, UK
| | - Trevor Dale
- School of Biosciences, Cardiff University, Cardiff, UK
| | | | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Luigi Terracciano
- Molecular Pathology Division, Institute of Pathology, University of Basel, Basel, Switzerland
| | - Aldo Scarpa
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | | | - Nicola Valeri
- The Institute of Cancer Research, London, UK
- The Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | | | - Owen Sansom
- Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK
| | - Chiara Braconi
- The Institute of Cancer Research, London, UK
- The Royal Marsden NHS Foundation Trust, London and Surrey, UK
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Santiago L, Daniels G, Wang D, Deng FM, Lee P. Wnt signaling pathway protein LEF1 in cancer, as a biomarker for prognosis and a target for treatment. Am J Cancer Res 2017; 7:1389-1406. [PMID: 28670499 PMCID: PMC5489786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 04/08/2017] [Indexed: 06/07/2023] Open
Abstract
Transcription factors are regulatory proteins that either activate or repress the transcription of genes via binding to DNA regulatory sequences and regulating recruitment of transcriptional complexes. Lymphoid enhancer-binding factor 1 (LEF1), a member of the T-cell Factor (TCF)/LEF1 family of high-mobility group transcription factors, is a downstream mediator of the Wnt/β-catenin signaling pathway, but can also modulate gene transcription independently. LEF1 is essential in stem cell maintenance and organ development, especially in its role in epithelial-mesenchymal transition (EMT) by activating the transcription of hallmark EMT effectors including N-Cadherin, Vimentin, and Snail. Aberrant expression of LEF1 is implicated in tumorigenesis and cancer cell proliferation, migration, and invasion. LEF1's activity in particular cancer cell types, such as chronic lymphocytic leukemia (CLL), Burkitt lymphoma (BL), acute lymphoblastic leukemia (ALL), oral squamous cell carcinoma (OSCC), and colorectal cancer (CRC), makes it a valuable biomarker in predicting patient prognosis. Additionally, due to aberrant LEF1 activity resulting in cancer progression, knockdown and inhibition treatments designed to target LEF1 have proven effective in alleviating cancer growth, migration, and invasion in CLL, CRC, glioblastoma multiforme (GBM), and renal cell carcinoma (RCC). In prostate cancer cells, LEF1 promotes androgen receptor expression and activity in an androgen-independent manner, ultimately increasing prostate cancer growth regardless of androgen ablation therapy. In this review, we review LEF1 regulation, its role in tumorigenesis in several cancer types, and its clinical value as a biomarker for predicting prognoses and as a target for treatment.
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Affiliation(s)
- Larion Santiago
- Department of Pathology, School of Medicine, New York UniversityNew York, American
| | - Garrett Daniels
- Department of Pathology, School of Medicine, New York UniversityNew York, American
| | - Dongwen Wang
- Department of Urology, First Hospital of Shanxi Medical UniversityTaiyuan, Shanxi, China
| | - Fang-Ming Deng
- Department of Pathology, School of Medicine, New York UniversityNew York, American
- Association of Chinese American PhysiciansFlushing, New York, American
| | - Peng Lee
- Department of Pathology, School of Medicine, New York UniversityNew York, American
- Department of Urology, School of Medicine, New York UniversityNew York, American
- Department of NYU Cancer Institute, School of Medicine, New York UniversityNew York, American
- Department of New York Harbor Healthcare System, School of Medicine, New York UniversityNew York, American
- Association of Chinese American PhysiciansFlushing, New York, American
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Yang CM, Ji S, Li Y, Fu LY, Jiang T, Meng FD. β-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma. Onco Targets Ther 2017; 10:711-724. [PMID: 28260916 PMCID: PMC5328321 DOI: 10.2147/ott.s117933] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
β-Catenin (CTNNB1 gene coding protein) is a component of the Wnt signaling pathway that has been shown to play an important role in the formation of certain cancers. Abnormal accumulation of CTNNB1 contributes to most cancers. This research studied the involvement of β-catenin in renal cell carcinoma (RCC) cell proliferation, apoptosis, migration, and invasion. Proliferation, cell cycle, and apoptosis were analyzed by using Cell Counting Kit-8 and by flow cytometry. Migration and invasion assays were measured by transwell analysis. Real-time polymerase chain reaction and Western blot analysis were used to detect the expression of CTNNB1, ICAM-1, VCAM-1, CXCR4, and CCL18 in RCC cell lines. It was found that CTNNB1 knockdown inhibited cell proliferation, migration, and invasion and induced apoptosis of A-498 cells. CTNNB1 overexpression promoted cell proliferation, migration, and invasion and inhibited apoptosis of 786-O cells. Moreover, knockdown of CTNNB1 decreased the levels of ICAM-1, VCAM-1, CXCR4, and CCL18 expression, but CTNNB1 overexpression increased the expression of ICAM-1, VCAM-1, CXCR4, and CCL18. Further in vivo tumor formation study in nude mice indicated that inhibition of CTNNB1 delayed the progress of tumor formation through inhibiting PCNA and Ki67 expression. These results indicate that CTNNB1 could act as an oncogene and may serve as a promising therapeutic strategy for RCC.
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Affiliation(s)
- Chun-ming Yang
- Department of Urology, The First Affiliated Hospital, China Medical University
| | - Shan Ji
- Department of Endocrinology, The Fifth People’s Hospital of Shenyang
| | - Yan Li
- Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Li-ye Fu
- Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Tao Jiang
- Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Fan-dong Meng
- Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital, China Medical University, Shenyang, China
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50
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Stem cell, biomaterials and growth factors therapy for hepatocellular carcinoma. Biomed Pharmacother 2017; 88:1046-1053. [PMID: 28192881 DOI: 10.1016/j.biopha.2017.01.154] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 01/26/2017] [Accepted: 01/26/2017] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma is an antecedent of liver illnesses, including viral hepatitis, alcohol abuse, or metabolic disease. Transforming growth factor-Beta (TGF-b) plays an important role in creating a favorable microenvironment for tumor cell growth via two major mechanisms: an intrinsic activity as an autocrine growth factor and an extrinsic activity by inducing microenvironment changes. Recently stem cell therapy as also been a promising and potential treatment for liver cancer and in addition signaling pathways like GF/GFR systems, SDF-1α/CXC4 ligand receptor interaction and PI3K/Akt signaling, and cytokines has been identified to regulate cell fate decisions, and can be utilized to positively influence cell therapy outcomes. Thus stem cell-based therapy, together with signaling pathways can become a practical option in regenerative processes for replacing dead hepatocytes cells. Targeted drug delivery systems (TDDS) via biomaterials are presently been explored for cancer therapeutics especially liver cancer as it allows the enhancement of drug concentration in the liver and decrease the dosage and side effects. This review is intended to give a comprehensive summary of available liver cancer therapy using stem cells, growth factor and biomaterials.
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