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Song Z, Zhang Y, Luo W, Sun C, Lv C, Wang S, He Q, Xu R, Bai Z, Chang X, Yang Y. HAND2-AS1 Promotes Ferroptosis to Reverse Lenvatinib Resistance in Hepatocellular Carcinoma by TLR4/NOX2/DUOX2 Axis. Curr Cancer Drug Targets 2025; 25:144-158. [PMID: 38465433 DOI: 10.2174/0115680096279597240219055135] [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: 09/14/2023] [Revised: 01/11/2024] [Accepted: 01/23/2024] [Indexed: 03/12/2024]
Abstract
INTRODUCTION Lenvatinib resistance causes less than 40% of the objective response rate. Therefore, it is urgent to explore new therapeutic targets to reverse the lenvatinib resistance for HCC. HAND2-AS1 is a critical tumor suppressor gene in various cancers. METHODS Here, we investigated the role of HAND2-AS1 in the molecular mechanism of lenvatinib resistance in HCC. It was found that HAND2-AS1 was lowly expressed in the HepG2 lenvatinib resistance (HepG2-LR) cells and HCC tissues and associated with progression-free intervals via TCGA. Overexpression of HAND2-AS1 (OE-HAND2-AS1) decreased the IC50 of lenvatinib in HepG2-LR cells to reverse lenvatinib resistance. Moreover, OE-HAND2-AS1 induced intracellular concentrations of malondialdehyde (MDA) and lipid ROS and decreased the ratio of glutathione to glutathione disulfide (GSH/GSSG) to promote ferroptosis. RESULTS A xenograft model in which nude mice were injected with OE-HAND2-AS1 HepG2-LR cells confirmed that OE-HAND2-AS1 could reverse lenvatinib resistance and decrease tumor formation in vivo. HAND2-AS1 promoted the expression of ferroptosis-related genes (TLR4, NOX2, and DUOX2) and promoted ferroptosis to reverse lenvatinib resistance by increasing TLR4/ NOX2/DUOX2 via competing endogenous miR-219a-1-3p in HCC cells. Besides, patients with a low HAND2-AS1 level had early recurrence after resection. CONCLUSION HAND2-AS1 promotes ferroptosis in HCC cells and reverses lenvatinib resistance by regulating TLR4/NOX2/DUOX2 axis. It suggested that HAND2-AS1 may be a potential therapeutic target and an indicator of early recurrence for HCC.
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Affiliation(s)
- Zheng Song
- Peking University 302 Clinical Medical School, Beijing, China
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Yu Zhang
- Peking University 302 Clinical Medical School, Beijing, China
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Wei Luo
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Chao Sun
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
| | - Caihong Lv
- Peking University 302 Clinical Medical School, Beijing, China
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Sihao Wang
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
| | - Quanwei He
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
| | - Ran Xu
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China
| | - Zhaofang Bai
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Xiujuan Chang
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Yongping Yang
- Peking University 302 Clinical Medical School, Beijing, China
- Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
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Zou Q, Wang HW, Di XL, Li Y, Gao H. Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis. World J Gastrointest Oncol 2024; 16:1547-1563. [PMID: 38660652 PMCID: PMC11037064 DOI: 10.4251/wjgo.v16.i4.1547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/08/2024] [Accepted: 02/07/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Increasing data indicated that long noncoding RNAs (lncRNAs) were directly or indirectly involved in the occurrence and development of tumors, including hepatocellular carcinoma (HCC). Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues, but its role in HCC progression is unclear. Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes. AIM To study the role of ultrasound microbubbles (UTMBs) mediated HAND2-AS1 in the progression of HCC, in order to provide a new reference for the treatment of HCC. METHODS In vitro, we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs, and detected cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) by cell counting kit-8 assay, flow cytometry, Transwell invasion assay and Western blotting, respectively. In addition, we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior. Next, the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2 (TIMP2) overexpression vector, and we detected cell proliferation, apoptosis, invasion and EMT. In vivo, we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability. RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation, invasion, and EMT, encouraged apoptosis, and HAND2-AS1 silencing eliminated the effect of UTMBs. Additionally, miR-873-5p targets the gene HAND2-AS1, which also targets the 3'UTR of TIMP2. And miR-873-5p mimic counteracted the impact of HAND2-AS1. Further, miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs. We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase (MMP) 2/MMP9. In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice. CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.
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Affiliation(s)
- Qiang Zou
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Hao-Wen Wang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, Heilongjiang Province, China
| | - Xi-Liang Di
- Department of Hematology and Oncology, Linyi People’s Hospital, Linyi 251500, Shandong Province, China
| | - Yuan Li
- Department of Hematology and Oncology, Linyi People’s Hospital, Linyi 251500, Shandong Province, China
| | - Hui Gao
- Department of Comprehensive Oncology, Baotou Cancer Hospital, Baotou 014030, Inner Mongolia Autonomous Region, China
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Shafi O, Siddiqui G, Jaffry HA. The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review. BMC Cancer 2023; 23:1245. [PMID: 38110859 PMCID: PMC10726542 DOI: 10.1186/s12885-023-11723-3] [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: 08/08/2023] [Accepted: 12/05/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Cardiac Myxoma is a primary tumor of heart. Its origins, rarity of the occurrence of primary cardiac tumors and how it may be related to limited cardiac regenerative potential, are not yet entirely known. This study investigates the key cardiac genes/ transcription factors (TFs) and signaling pathways to understand these important questions. METHODS Databases including PubMed, MEDLINE, and Google Scholar were searched for published articles without any date restrictions, involving cardiac myxoma, cardiac genes/TFs/signaling pathways and their roles in cardiogenesis, proliferation, differentiation, key interactions and tumorigenesis, with focus on cardiomyocytes. RESULTS The cardiac genetic landscape is governed by a very tight control between proliferation and differentiation-related genes/TFs/pathways. Cardiac myxoma originates possibly as a consequence of dysregulations in the gene expression of differentiation regulators including Tbx5, GATA4, HAND1/2, MYOCD, HOPX, BMPs. Such dysregulations switch the expression of cardiomyocytes into progenitor-like state in cardiac myxoma development by dysregulating Isl1, Baf60 complex, Wnt, FGF, Notch, Mef2c and others. The Nkx2-5 and MSX2 contribute predominantly to both proliferation and differentiation of Cardiac Progenitor Cells (CPCs), may possibly serve roles based on the microenvironment and the direction of cell circuitry in cardiac tumorigenesis. The Nkx2-5 in cardiac myxoma may serve to limit progression of tumorigenesis as it has massive control over the proliferation of CPCs. The cardiac cell type-specific genetic programming plays governing role in controlling the tumorigenesis and regenerative potential. CONCLUSION The cardiomyocytes have very limited proliferative and regenerative potential. They survive for long periods of time and tightly maintain the gene expression of differentiation genes such as Tbx5, GATA4 that interact with tumor suppressors (TS) and exert TS like effect. The total effect such gene expression exerts is responsible for the rare occurrence and benign nature of primary cardiac tumors. This prevents the progression of tumorigenesis. But this also limits the regenerative and proliferative potential of cardiomyocytes. Cardiac Myxoma develops as a consequence of dysregulations in these key genes which revert the cells towards progenitor-like state, hallmark of CM. The CM development in carney complex also signifies the role of TS in cardiac cells.
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Affiliation(s)
- Ovais Shafi
- Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan.
| | - Ghazia Siddiqui
- Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan
| | - Hassam A Jaffry
- Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan
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Vazana-Netzarim R, Elmalem Y, Sofer S, Bruck H, Danino N, Sarig U. Distinct HAND2/HAND2-AS1 Expression Levels May Fine-Tune Mesenchymal and Epithelial Cell Plasticity of Human Mesenchymal Stem Cells. Int J Mol Sci 2023; 24:16546. [PMID: 38003736 PMCID: PMC10672054 DOI: 10.3390/ijms242216546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/09/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
We previously developed several successful decellularization strategies that yielded porcine cardiac extracellular matrices (pcECMs) exhibiting tissue-specific bioactivity and bioinductive capacity when cultured with various pluripotent and multipotent stem cells. Here, we study the tissue-specific effects of the pcECM on seeded human mesenchymal stem cell (hMSC) phenotypes using reverse transcribed quantitative polymerase chain reaction (RT-qPCR) arrays for cardiovascular related gene expression. We further corroborated interesting findings at the protein level (flow cytometry and immunological stains) as well as bioinformatically using several mRNA sequencing and protein databases of normal and pathologic adult and embryonic (organogenesis stage) tissue expression. We discovered that upon the seeding of hMSCs on the pcECM, they displayed a partial mesenchymal-to-epithelial transition (MET) toward endothelial phenotypes (CD31+) and morphologies, which were preceded by an early spike (~Day 3 onward after seeding) in HAND2 expression at both the mRNA and protein levels compared to that in plate controls. The CRISPR-Cas9 knockout (KO) of HAND2 and its associated antisense long non-coding RNA (HAND2-AS1) regulatory region resulted in proliferation arrest, hypertrophy, and senescent-like morphology. Bioinformatic analyses revealed that HAND2 and HAND2-AS1 are highly correlated in expression and are expressed in many different tissue types albeit at distinct yet tightly regulated expression levels. Deviation (downregulation or upregulation) from these basal tissue expression levels is associated with a long list of pathologies. We thus suggest that HAND2 expression levels may possibly fine-tune hMSCs' plasticity through affecting senescence and mesenchymal-to-epithelial transition states, through yet unknown mechanisms. Targeting this pathway may open up a promising new therapeutic approach for a wide range of diseases, including cancer, degenerative disorders, and aging. Nevertheless, further investigation is required to validate these findings and better understand the molecular players involved, potential inducers and inhibitors of this pathway, and eventually potential therapeutic applications.
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Affiliation(s)
- Rachel Vazana-Netzarim
- The Dr. Miriam and Sheldon Adelson School of Medicine, Department of Morphological Sciences and Teratology, Ariel University, Ariel 4070000, Israel; (R.V.-N.); (N.D.)
| | - Yishay Elmalem
- Department of Chemical Engineering, Faculty of Engineering, Ariel University, Ariel 4070000, Israel (S.S.); (H.B.)
| | - Shachar Sofer
- Department of Chemical Engineering, Faculty of Engineering, Ariel University, Ariel 4070000, Israel (S.S.); (H.B.)
| | - Hod Bruck
- Department of Chemical Engineering, Faculty of Engineering, Ariel University, Ariel 4070000, Israel (S.S.); (H.B.)
| | - Naama Danino
- The Dr. Miriam and Sheldon Adelson School of Medicine, Department of Morphological Sciences and Teratology, Ariel University, Ariel 4070000, Israel; (R.V.-N.); (N.D.)
| | - Udi Sarig
- The Dr. Miriam and Sheldon Adelson School of Medicine, Department of Morphological Sciences and Teratology, Ariel University, Ariel 4070000, Israel; (R.V.-N.); (N.D.)
- Department of Chemical Engineering, Faculty of Engineering, Ariel University, Ariel 4070000, Israel (S.S.); (H.B.)
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Ghafouri-Fard S, Hussen BM, Abdullah SR, Dadyar M, Taheri M, Kiani A. A review on the role of HAND2-AS1 in cancer. Clin Exp Med 2023; 23:3179-3188. [PMID: 37204522 PMCID: PMC10618356 DOI: 10.1007/s10238-023-01092-3] [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: 12/07/2022] [Accepted: 05/11/2023] [Indexed: 05/20/2023]
Abstract
HAND2 antisense RNA 1 (HAND2-AS1) is a newly recognized lncRNA encoded by a gene on 4q34.1. This lncRNA has 10 exons and is predicted to have a positive effect on expression of certain genes. HAND2-AS1 is mainly considered as a tumor suppressive lncRNA in different tissues. Moreover, HAND2-AS1 has been shown to regulate expression of several targets with possible roles in the carcinogenesis through serving as a sponge for miRNAs. This lncRNA can also influence activity of BMP, TGF-β1, JAK/STAT and PI3K/Akt pathways. Down-regulation of HAND2-AS1 in tumor tissues has been associated with larger tumor size, higher tumor grade, higher chance of metastasis and poor clinical outcome. The present study aims at summarization of the impact of HAND2-AS1 in the carcinogenesis and its potential in cancer diagnosis or prediction of cancer prognosis.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Tehran Lung Research and Developmental Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq
- Tehran Lung Research and Developmental Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Snur Rasool Abdullah
- Department of Medical Laboratory Science, Lebanese French University, Erbil, Kurdistan Region, Iraq
- Tehran Lung Research and Developmental Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Dadyar
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Tehran Lung Research and Developmental Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Arda Kiani
- Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Tehran Lung Research and Developmental Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Krajnović M, Kožik B, Božović A, Jovanović-Ćupić S. Multiple Roles of the RUNX Gene Family in Hepatocellular Carcinoma and Their Potential Clinical Implications. Cells 2023; 12:2303. [PMID: 37759525 PMCID: PMC10527445 DOI: 10.3390/cells12182303] [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: 07/26/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent cancers in humans, characterised by a high resistance to conventional chemotherapy, late diagnosis, and a high mortality rate. It is necessary to elucidate the molecular mechanisms involved in hepatocarcinogenesis to improve diagnosis and treatment outcomes. The Runt-related (RUNX) family of transcription factors (RUNX1, RUNX2, and RUNX3) participates in cardinal biological processes and plays paramount roles in the pathogenesis of numerous human malignancies. Their role is often controversial as they can act as oncogenes or tumour suppressors and depends on cellular context. Evidence shows that deregulated RUNX genes may be involved in hepatocarcinogenesis from the earliest to the latest stages. In this review, we summarise the topical evidence on the roles of RUNX gene family members in HCC. We discuss their possible application as non-invasive molecular markers for early diagnosis, prognosis, and development of novel treatment strategies in HCC patients.
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Affiliation(s)
| | - Bojana Kožik
- Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, Vinča, 11351 Belgrade, Serbia; (M.K.); (A.B.); (S.J.-Ć.)
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Wu X, Xu Q, Li T, Wei Y, Zeng R, Lin R, Xu L, Ye L, Liu Z. Bladder Cancer Progression Is Suppressed Through the Heart and Neural Crest Derivatives Expressed 2-Antisense RNA 1/microRNA-93-5p/Defective in Cullin Neddylation 1 Domain Containing 3 Axis. Appl Biochem Biotechnol 2023; 195:4116-4133. [PMID: 36656536 DOI: 10.1007/s12010-022-04295-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2022] [Indexed: 01/20/2023]
Abstract
MicroRNAs (miRNAs) are critical in progression of bladder cancer (BCa). miRNA-93-5p is increased in cancers and is positively correlated with an unfavorable prognosis. But its effects on BCa remain rarely understood. This investigation aimed to dig out miRNA-93-5p affecting biological behaviors of BCa. In this research, mRNA and protein expression in cancer cells were assessed via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell Counting Kit-8 (CCK-8), colony formation, scratch healing, and transwell assays were utilized to analyze cancer cell viability, colony-forming, migration, and invasion, respectively. Bioinformatics analysis predicted upstream regulatory genes and downstream target genes of miRNA-93-5p, with the targeting relationship being verified through a dual-luciferase assay. The BCa xenograft model in nude mice further investigated the effect of miRNA-93-5p and AND2-AS1 on tumor size and quality, and validated the relationship between HAND2-AS1/miRNA-93-5p/DCUN1D3. Our results displayed that miRNA-93-5p was increased in BCa cell lines. Knockdown miRNA-93-5p constrained BCa cell malignant phenotypes. HAND2-AS1 targeted miRNA-93-5p, thus restraining malignant progression of BCa cells. DCUN1D3 was found downstream of miRNA-93-5p. miRNA-93-5p modulated proliferation, migration, and invasion of BCa cells by targeting DCUN1D3. In vivo experiments disclosed that forced expression of lncRNA HAND2-AS1, and inhibited miRNA-93-5p regressed tumor growth. Meanwhile, the same as the results of cell experiments, the expression of miRNA-93-5p was downregulated, and DCUN1D3 expression was advanced in tumor tissues. To conclude, lncRNA HAND2-AS1 exerted anti-tumor effects and regulated BCa cell proliferation, invasion, and migration by targeting miRNA-93-5p/DCUN1D3.
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Affiliation(s)
- Xiang Wu
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
- Department of Urology, Fujian Provincial Hospital, No. 516 Jinrong South Road, Cangshan District, Fuzhou, 350001, China
| | - Qingjiang Xu
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
- Department of Urology, Fujian Provincial Hospital, No. 516 Jinrong South Road, Cangshan District, Fuzhou, 350001, China
| | - Tao Li
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
- Department of Urology, Fujian Provincial Hospital, No. 516 Jinrong South Road, Cangshan District, Fuzhou, 350001, China
| | - Yongbao Wei
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
- Department of Urology, Fujian Provincial Hospital, No. 516 Jinrong South Road, Cangshan District, Fuzhou, 350001, China
| | - Rong Zeng
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
- Department of Urology, Fujian Provincial Hospital, No. 516 Jinrong South Road, Cangshan District, Fuzhou, 350001, China
| | - Rongcheng Lin
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
- Department of Urology, Fujian Provincial Hospital, No. 516 Jinrong South Road, Cangshan District, Fuzhou, 350001, China
| | - Lina Xu
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
- Department of Urology, South Branch of Fujian Provincial Hospital, Fuzhou, 350001, China
| | - Liefu Ye
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China.
- Department of Urology, Fujian Provincial Hospital, No. 516 Jinrong South Road, Cangshan District, Fuzhou, 350001, China.
| | - Zhihua Liu
- Provincial Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China.
- Department of Urology, South Branch of Fujian Provincial Hospital, Fuzhou, 350001, China.
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Xue J, Zhao H, Fu Y, Liu X, Wu X. Integrated analysis of multiple transcriptomic data identifies ST8SIA6‑AS1 and LINC01093 as potential biomarkers in HBV‑associated liver cancer. Oncol Lett 2023; 25:185. [PMID: 37065781 PMCID: PMC10091192 DOI: 10.3892/ol.2023.13771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 12/02/2022] [Indexed: 04/18/2023] Open
Abstract
The mechanisms of long-non-coding RNAs (lncRNAs) in hepatitis B virus (HBV) infection-associated liver cancer remain largely unclear. Therefore, the aim of the present study was to investigate the regulatory mechanisms of lncRNAs in this disease. HBV-liver cancer related transcriptome expression profile data (GSE121248 and GSE55092) from the Gene Expression Omnibus database and survival prognosis information from The Cancer Genome Atlas (TCGA) database were obtained for analysis. The limma package was used to identify the overlapped differentially expressed RNAs (DERs), including DElncRNAs and DEmRNAs, in the GSE121248 and GSE55092 datasets. The screened optimized lncRNA signatures were used to develop a nomogram model based on the GSE121248 dataset, which was validated using the GSE55092 and TCGA datasets. A competitive endogenous RNA (ceRNA) network was constructed based on the screened prognosis-associated lncRNA signatures from TCGA dataset. In addition, the levels of specific lncRNAs were evaluated in HBV-infected human liver cancer tissues and cells, and Cell Counting Kit-8, ELISA and Transwell assays were performed to evaluate the effects of the lncRNAs in HBV-expressing liver cancer cells. A total of 535 overlapped DERs, including 30 DElncRNAs and 505 DEmRNAs, were identified in the GSE121248 and GSE55092 datasets. An optimized DElncRNA signature comprising 10 lncRNAs was used to establish a nomogram. ST8SIA6-AS1 and LINC01093 were identified as lncRNAs associated with HBV-liver cancer prognosis in TCGA dataset, and were applied to construct a ceRNA network. Reverse transcription-quantitative PCR analysis showed that ST8SIA6-AS1 was upregulated and LINC01093 was downregulated in HBV-infected human liver cancer tissues and HBV-expressing liver cancer cells compared with non-HBV-infected controls. ST8SIA6-AS1 knockdown and LINC01093 overexpression independently reduced the number of copies of HBV DNA, the levels of hepatitis B surface antigen and hepatitis B e antigen, as well as cell proliferation, migration and invasion. In summary, the present study identified ST8SIA6-AS1 and LINC01093 as two potential biomarkers that may be effective therapeutic targets for HBV-associated liver cancer.
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Affiliation(s)
- Jianhua Xue
- Department of Infectious Diseases, Hospital for Infectious Diseases of Pudong District, Shanghai 201318, P.R. China
| | - Hui Zhao
- Department of Infectious Diseases, Hospital for Infectious Diseases of Pudong District, Shanghai 201318, P.R. China
| | - Yifei Fu
- Department of Infectious Diseases, Hospital for Infectious Diseases of Pudong District, Shanghai 201318, P.R. China
| | - Xu Liu
- Department of Infectious Diseases, Hospital for Infectious Diseases of Pudong District, Shanghai 201318, P.R. China
| | - Xiangxiang Wu
- Department of Traditional Chinese Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
- Correspondence to: Dr Xiangxiang Wu, Department of Traditional Chinese Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou, Shanghai 200437, P.R. China, E-mail:
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Wang P, Zhang J, Zhang H, Zhang F. The role of MACF1 on acute myeloid leukemia cell proliferation is involved in Runx2-targeted PI3K/Akt signaling. Mol Cell Biochem 2023; 478:433-441. [PMID: 35857251 DOI: 10.1007/s11010-022-04517-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 06/24/2022] [Indexed: 11/25/2022]
Abstract
Acute myeloid leukemia (AML) is a type of hematologic diseases, which is related to abnormal genes. The aberrant microtubule actin cross-linking factor 1 (MACF1) is associated with progression of multiple tumors by initiating cell proliferation. Nevertheless, the function and action mechanism of MACF1 in AML cell proliferation remain mostly unknown. Our study aimed to explore the influence of MACF1 on AML cell proliferation by CCK-8 and EdU staining assays. Moreover, we aimed to explore the effect of MACF1 on downstream Runx2 and the PI3K/Akt signaling. MACF1 expression in AML patients was predicted by bioinformatics analysis. Cells were transfected with si-con, si-MACF1 or Runx2 using Lipofectamine 2000. Upregulated MACF1 was found in AML patients and predicted worse overall survival. MACF1 expression was upregulated in AML cells compared with that in hematopoietic stem and progenitor cells. MACF1 silencing reduced AML cell proliferation. Runx2 level was increased in AML cells, and decreased by silencing MACF1. Runx2 upregulation rescued MACF1 silencing-mediated inhibition of proliferation. MACF1 downregulation inhibited activation of the PI3K/Akt pathway by decreasing Runx2. Activation of the PI3K/Akt pathway abrogated the suppressive role of MACF1 downregulation in AML cell proliferation. In conclusion, MACF1 knockdown decreased AML cell proliferation by reducing Runx2 and inactivating the PI3K/Akt signaling.
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Affiliation(s)
- Ping Wang
- Department of Hematology, People's Hospital of Chongqing Banan District (Banan Hospital of Chongqing Medical University), No.659, Yu'nan Avenue, Chongqing, 401320, People's Republic of China.
| | - Jiajia Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, 454000, Henan, People's Republic of China
| | - Hui Zhang
- Department of Endocrinology, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, 454000, Henan, People's Republic of China
| | - Fang Zhang
- Department of Neurology, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, 454000, Henan, People's Republic of China
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Huang Z, Wang Z, Xia H, Ge Z, Yu L, Li J, Bao H, Liang Z, Cui Y, Xu Y. Long noncoding RNA HAND2-AS1: A crucial regulator of malignancy. Clin Chim Acta 2023; 539:162-169. [PMID: 36528049 DOI: 10.1016/j.cca.2022.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/12/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Long non-coding RNAs (LncRNAs) are single-stranded RNAs over 200 nucleotides in length that have no protein-coding function and have long been considered non-functional by-products of transcription. Recent studies have shown that dysregulation of lncRNAs may be involved in the malignant biological behavior of tumors. Targeted regulation of lncRNAs has become a research focus of anti-tumor treatment. LncRNAs heart and neural crest derivatives expressed 2 antisense RNA 1 (HAND2-AS1) was down-regulated in various tumors and can be used as a critical tumor regulator to modulate tumor cells proliferation, apoptosis, metastasis, invasion, metabolism and drug resistance. Additionally, aberrantly expressed HAND2-AS1 was closely related to the clinical pathological characteristics of cancer patients and serve as a promising tumor diagnostic and prognostic biomarker. This article aims to review the roles of HAND2-AS1 in tumorigenesis and development, as well as the underlying molecular mechanisms and clinical significance.
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Affiliation(s)
- Ziyue Huang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Zhensheng Wang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Haoming Xia
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Ziqiang Ge
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Liang Yu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China; The key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin 150086, Heilongjiang, China; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 999077, Hong Kong
| | - Jiehan Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Haolin Bao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Zixin Liang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China; The key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin 150086, Heilongjiang, China; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 999077, Hong Kong.
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11
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Mesenchymal stem cell-derived exosomes and non-coding RNAs: Regulatory and therapeutic role in liver diseases. Biomed Pharmacother 2023; 157:114040. [PMID: 36423545 DOI: 10.1016/j.biopha.2022.114040] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/22/2022] Open
Abstract
Liver disease has become a major health problem worldwide due to its high morbidity and mortality. In recent years, a large body of literature has shown that mesenchymal stem cell-derived exosomes (MSC-Exo) are able to play similar physiological roles as mesenchymal stem cells (MSCs). More importantly, there is no immune rejection caused by transplanted cells and the risk of tumor formation, which has become a new strategy for the treatment of various liver diseases. Moreover, accumulating evidence suggests that non-coding RNAs (ncRNAs) are the main effectors by which they exert hepatoprotective effects. Therefore, by searching the databases of Web of Science, PubMed, ScienceDirect, Google Scholar and CNKI, this review comprehensively reviewed the therapeutic effects of MSC-Exo and ncRNAs in liver diseases, including liver injury, liver fibrosis, and hepatocellular carcinoma. According to the data, the therapeutic effects of MSC-Exo and ncRNAs on liver diseases are closely related to a variety of molecular mechanisms, including inhibition of inflammatory response, alleviation of liver oxidative stress, inhibition of apoptosis of hepatocytes and endothelial cells, promotion of angiogenesis, blocking the cell cycle of hepatocellular carcinoma, and inhibition of activation and proliferation of hepatic stellate cells. These important findings will provide a direction and basis for us to explore the potential of MSC-Exo and ncRNAs in the clinical treatment of liver diseases in the future.
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12
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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13
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Recalde M, Gárate-Rascón M, Herranz JM, Elizalde M, Azkona M, Unfried JP, Boix L, Reig M, Sangro B, Fernández-Barrena MG, Fortes P, Ávila MA, Berasain C, Arechederra M. DNA Methylation Regulates a Set of Long Non-Coding RNAs Compromising Hepatic Identity during Hepatocarcinogenesis. Cancers (Basel) 2022; 14:cancers14092048. [PMID: 35565178 PMCID: PMC9102946 DOI: 10.3390/cancers14092048] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/13/2022] [Accepted: 04/17/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Hepatocarcinogenesis is a long process which implies the loss of hepatic functions. Our effort is to understand the mechanisms implicated in this pathological process in order to contribute to the development of new diagnostic markers and therapeutic targets. In this study we have identified a set of lncRNAs significantly downregulated in hepatocellular carcinoma (HCC) in correlation with the grade of tumor dedifferentiation and patients’ worse prognosis. Mechanistically, our results show that they are related with hepatic differentiation and at least a subset of those lncRNAs are essential to ensure the expression of other hepato-specific genes required for liver function. Moreover, we demonstrate that the expression of these lncRNAs in HCC is silenced by DNA methylation. All in all, we uncover connected epigenetic alterations involved in the progression of liver cancer and identify potential new biomarkers. Abstract Background: Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis. Methods and Results: The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis. Conclusions: Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients’ prognosis.
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Affiliation(s)
- Miriam Recalde
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
| | - María Gárate-Rascón
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
| | - José María Herranz
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
| | - María Elizalde
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
| | - María Azkona
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
| | - Juan P. Unfried
- Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain;
| | - Loreto Boix
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain
| | - María Reig
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain
| | - Bruno Sangro
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
- Hepatology Unit, Navarra University Clinic, 31008 Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Puri Fortes
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
- Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain;
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Matías A. Ávila
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Carmen Berasain
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- Correspondence: (C.B.); (M.A.); Tel.: +34-948194700 (C.B. & M.A.)
| | - María Arechederra
- Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.R.); (M.G.-R.); (J.M.H.); (M.E.); (M.A.); (M.G.F.-B.); (M.A.Á.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain; (L.B.); (M.R.); (B.S.); (P.F.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- Correspondence: (C.B.); (M.A.); Tel.: +34-948194700 (C.B. & M.A.)
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Circulating Long Non-Coding RNAs as Novel Potential Biomarkers for Osteogenic Sarcoma. Cancers (Basel) 2021; 13:cancers13164214. [PMID: 34439367 PMCID: PMC8392488 DOI: 10.3390/cancers13164214] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 12/11/2022] Open
Abstract
Circulating cell-free nucleic acids recently became attractive targets to develop non-invasive diagnostic tools for cancer detection. Along with DNA and mRNAs, transcripts lacking coding potential (non-coding RNAs, ncRNAs) directly involved in the process of tumor pathogenesis have been recently detected in liquid biopsies. Interestingly, circulating ncRNAs exhibit specific expression patterns associated with cancer and suggest their role as novel biomarkers. However, the potential of circulating long ncRNAs (c-lncRNAs) to be markers in osteosarcoma (OS) is still elusive. In this study we performed a systematic review to identify thirteen c-lncRNAs whose altered expression in blood associate with OS. We herein discuss the potential impact that these c-lncRNAs may have on clinical decision-making in the management of OS. Overall, we aimed to provide novel insights that can contribute to the development of future precision medicine in oncology.
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15
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Ni L, Yuan C. The Pathogenic Potential of RUNX2. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2021; 000:000-000. [DOI: 10.14218/erhm.2021.00028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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