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Li A, Li P, Mu C, Li D, Chen K, Liang Z. UPF1 Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating SMURF2-Mediated Ubiquitination Degradation of FOXA2. Korean Circ J 2025; 55:305-321. [PMID: 39962965 PMCID: PMC12046306 DOI: 10.4070/kcj.2024.0190] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/12/2024] [Accepted: 10/30/2024] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Myocardial ischemia/reperfusion injury (MIRI) is an important factor affecting therapeutic effect and prognosis of acute myocardial infarction. Here, the effects of up-frameshift 1 (UPF1) on cardiomyocyte apoptosis in MIRI were evaluated. METHODS H9C2 cells were cultured under hypoxia/reoxygenation (H/R) condition. The expression of UPF1, SMAD-specific E3 ubiquitin ligase 2 (SMURF2), forkhead box A2 (FOXA2), protease-activated receptor 4 (PAR4), Bax, and Cleaved caspase-3 was assessed utilizing reverse transcription quantitative polymerase chain reaction and western blot. Cell viability and apoptosis were measured by Cell Counting Kit-8 and flow cytometry. Infarct area was examined by tetrazolium chloride staining in myocardial ischemia/reperfusion (I/R) rat model. HE and immunohistochemistry staining evaluated myocardial injury and UPF1 expression, respectively. Terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling staining tested apoptosis. RNA immunoprecipitation, chromatin immunoprecipitation and dual luciferase assay verified molecular interactions. FOXA2 ubiquitination was detected by immunoprecipitation assay. SMURF2 mRNA stability was tested by actinomycin D treatment. RESULTS FOXA2 effectively suppressed cardiomyocyte apoptosis induced by H/R by inhibiting PAR4 at transcriptional level. Degradation of FOXA2 was facilitated through SMURF2-mediated ubiquitination. Increased expression of UPF1 resulted in a reduction of H/R-induced cardiomyocyte apoptosis, and improved myocardial dysfunction caused by I/R in vivo. UPF1 influenced the decay of SMURF2 mRNA, leading to a decrease in its expression. Through SMURF2/FOXA2/PAR4 axis, UPF1 effectively suppressed cardiomyocyte apoptosis triggered by H/R. CONCLUSIONS By suppressing SMURF2 mRNA stability, UPF1 upregulated FOXA2 expression to inhibit PAR4, leading to inhibition of apoptosis during MIRI, which provides new therapeutic targets for MIRI treatment.
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Affiliation(s)
- Aixin Li
- The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Medical Intensive Care Unit, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Peng Li
- Department of Neurology, Jiamusi Central Hospital, Jiamusi, China
| | - Chunling Mu
- Department of Cardiovascular Medicine, Harbin Fourth Hospital, Harbin, China
| | - Dong Li
- Department of Pharmacy, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Keyan Chen
- Department of Endocrinology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Zhaoguang Liang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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2
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Alsaab HO, Almalki Y. The Association between the NLRP3 Inflammasome and Specific Long-Non Coding RNAs (lncRNAs) in Cancer; New Perspective and Summary of Recent Studies. Cell Biochem Biophys 2025; 83:147-158. [PMID: 39285156 DOI: 10.1007/s12013-024-01494-4] [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: 08/21/2024] [Indexed: 03/03/2025]
Abstract
In response to cellular perturbations, a multimeric cytosolic protein complex known as the NLRP3 inflammasome assembles. As a result of this assembly, caspase-1 is activated, which encourages inflammatory cell death (pyroptosis) as well as the maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Tumor etiology involves dysregulation of NLRP3 inflammasome activation, but because of conflicting results, its significance in the onset and spread of cancer is still up for debate. New research indicates that long-non coding RNAs (lncRNAs) play a crucial part in controlling the activity of the NLRP3 inflammasome in a number of disorders. Non-coding RNAs longer than 200 nucleotides are known as lncRNAs. Cancer development has been connected to its deregulation in the development of illnesses. Growing data suggests that controlling lncRNAs on the NLRP3 inflammasome plays a crucial role in the emergence and progression of cancer-related challenges. Here, we discuss over how lncRNAs control the NLRP3 inflammasome and how it functions in different types of cancer cells, offering new perspectives on creating new cancer treatment strategies in the future.
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Affiliation(s)
- Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif 21944, Saudi Arabia.
| | - Yahya Almalki
- Department of Pediatrics, College of Medicine, Qassim University, Buraydah, Saudi Arabia
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Zeng M, Chen Z, Wang Y, Yang Z, Xiang J, Wang X, Wang X. LncRNA MALAT1 to Enhance Pyroptosis in Viral Myocarditis Through UPF1-Mediated SIRT6 mRNA Decay and Wnt-β-Catenin Signal Pathway. Cardiovasc Toxicol 2024; 24:1439-1454. [PMID: 39367210 DOI: 10.1007/s12012-024-09922-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/14/2024] [Indexed: 10/06/2024]
Abstract
Viral myocarditis (VMC) is an inflammatory disease of the myocardium caused by cardioviral infection, especially coxsackievirus B3 (CVB3), and is a major contributor to acute heart failure and sudden cardiac death in children and adolescents. LncRNA MALAT1 knockdown reportedly inhibits the differentiation of Th17 cells to attenuate CVB3-induced VMC in mice. Moreover, long non-coding RNAs (lncRNAs) interact with RNA-binding proteins (RBPs) to regulate UPF1-mediated mRNA decay. However, it remains unclear whether MALAT1 can bind to UPF1 to mediate the mRNA decay of its target genes in VMC. Herein, we aimed to explore the effect of lncRNA MALAT1 on UPF1-mediated SIRT6 mRNA decay in VMC using in vivo and in vitro experiments. CVB3-infected BABL/C mice were used as VMC models, and MALAT1 interfering adenovirus was injected to achieve MALAT1 knockdown. The heart function of the VMC mice was assessed using echocardiography. Pathological changes in myocardial tissues were assessed after hematoxylin-eosin staining. Myocardial injury and inflammation were evaluated by measuring creatine kinase isoenzyme B, cardiac troponin T, interleukin (IL)-1β, and IL-18. TUNEL staining was performed to assess apoptosis in myocardial tissues. In vitro experiments were performed using H9c2 cells after transfection and CVB3 infection. The lactic dehydrogenase release, caspase-1 activity, and IL-1β and IL-18 levels in the cellular supernatant were detected. Western blotting was performed to determine the expression of pyroptosis-related proteins (GSDMD-N, NLRP3, ASC, and Cleaved-Caspase-1) and Wnt/β-catenin signal pathway-related proteins (Wnt1, β-catenin, and p-GSK-3β). RNA immunoprecipitation and RNA stability assays assessed the relationship between MALAT1, UPF1, and SIRT6. CVB3-infected mice and H9c2 cells exhibited elevated MALAT1 and reduced SIRT6 expression. MALAT1 knockdown or SIRT6 overexpression suppressed inflammation and pyroptosis and inhibited the activation of the Wnt/β-catenin signal pathway in myocardial tissues and cells. MALAT1 enhanced the enrichment of SIRT6 mRNA by UPF1 and disturbed the stability of SIRT6 mRNA to promote the development of VMC. MALAT1 can bind UPF1 to mediate SIRT6 mRNA decay and activate the Wnt/β-catenin signal pathway in VMC.
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Affiliation(s)
- Min Zeng
- Department of Cardiology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), No. 86 Ziyuan Road, Yuhua District, Changsha, Hunan, 410007, People's Republic of China.
| | - Zhi Chen
- Department of Cardiology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), No. 86 Ziyuan Road, Yuhua District, Changsha, Hunan, 410007, People's Republic of China
| | - Yefeng Wang
- Department of Cardiology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), No. 86 Ziyuan Road, Yuhua District, Changsha, Hunan, 410007, People's Republic of China
| | - Zhou Yang
- Department of Cardiology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), No. 86 Ziyuan Road, Yuhua District, Changsha, Hunan, 410007, People's Republic of China
| | - Jinxing Xiang
- Department of Cardiology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), No. 86 Ziyuan Road, Yuhua District, Changsha, Hunan, 410007, People's Republic of China
| | - Xiang Wang
- Department of Cardiology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), No. 86 Ziyuan Road, Yuhua District, Changsha, Hunan, 410007, People's Republic of China
| | - Xun Wang
- Department of Cardiology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), No. 86 Ziyuan Road, Yuhua District, Changsha, Hunan, 410007, People's Republic of China
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Abikar A, Mustafa MMS, Athalye RR, Nadig N, Tamboli N, Babu V, Keshavamurthy R, Ranganathan P. Comparative transcriptome of normal and cancer-associated fibroblasts. BMC Cancer 2024; 24:1231. [PMID: 39369238 PMCID: PMC11456241 DOI: 10.1186/s12885-024-13006-x] [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: 06/12/2024] [Accepted: 09/27/2024] [Indexed: 10/07/2024] Open
Abstract
BACKGROUND The characteristics of a tumor are largely determined by its interaction with the surrounding micro-environment (TME). TME consists of both cellular and non-cellular components. Cancer-associated fibroblasts (CAFs) are a major component of the TME. They are a source of many secreted factors that influence the survival and progression of tumors as well as their response to drugs. Identification of markers either overexpressed in CAFs or unique to CAFs would pave the way for novel therapeutic strategies that in combination with conventional chemotherapy are likely to have better patient outcome. METHODS Fibroblasts have been derived from Benign Prostatic Hyperplasia (BPH) and prostate cancer. RNA from these has been used to perform a transcriptome analysis in order to get a comparative profile of normal and cancer-associated fibroblasts. RESULTS The study has identified 818 differentially expressed mRNAs and 17 lincRNAs between normal and cancer-associated fibroblasts. Also, 15 potential lincRNA-miRNA-mRNA combinations have been identified which may be potential biomarkers. CONCLUSIONS This study identified differentially expressed markers between normal and cancer-associated fibroblasts that would help in targeted therapy against CAFs/derived factors, in combination with conventional therapy. However, this would in future need more experimental validation.
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Affiliation(s)
- Apoorva Abikar
- Centre for Human Genetics, Bengaluru, India
- Manipal Academy of Higher Education, Manipal, India
| | | | | | | | | | - Vinod Babu
- Institute of Nephro-Urology, Bengaluru, India
| | | | - Prathibha Ranganathan
- Centre for Human Genetics, Bengaluru, India.
- Manipal Academy of Higher Education, Manipal, India.
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Behera A, Panigrahi GK, Sahoo A. Nonsense-Mediated mRNA Decay in Human Health and Diseases: Current Understanding, Regulatory Mechanisms and Future Perspectives. Mol Biotechnol 2024:10.1007/s12033-024-01267-7. [PMID: 39264527 DOI: 10.1007/s12033-024-01267-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 08/24/2024] [Indexed: 09/13/2024]
Abstract
Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that is conserved across all eukaryotes ensuring the quality of transcripts by targeting messenger RNA (mRNA) harbouring premature stop codons. It regulates the gene expression by targeting aberrant mRNA carrying pre-termination codons (PTCs) and eliminates C-terminal truncated proteins. NMD distinguishes aberrant and non-aberrant transcript by looking after long 3' UTRs and exon-junction complex (EJC) downstream of stop codon that indicate the presence of PTC. Therefore, NMD modulates cellular surveillance and eliminates the truncated proteins but if the PTC escapes the surveillance pathway it can lead to potential negative phenotype resulting in genetic diseases. The alternative splicing also contributes in formation of NMD-sensitive isoforms by introducing PTC. NMD plays a complex role in cancer, it can either aggravate or downregulates the tumour. Some tumours agitate NMD to deteriorate mRNAs encoding tumour suppressor proteins, stress response proteins and neoantigens. In other case, tumours suppress the NMD to encourage the expression of oncoproteins for tumour growth and survival. This mechanism augmented in the development of new therapeutics by PTC read-through mechanism and personalized medicine. Detailed studies on NMD surveillance will possibly lead towards development of strategies for improving human health aligning with United Nations sustainable development goals (SDG 3: Good health and well-being). The potential therapeutic applications of NMD pose a challenge in terms of safe and effective modulation. Understanding the complexities of NMD regulation and its interaction with other cellular processes can lead to the development of new interventions for various diseases.
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Affiliation(s)
- Amrita Behera
- Department of Zoology, School of Applied Sciences, Centurion University of Technology and Management, Jatni, Khordha, Odisha, India
| | - Gagan Kumar Panigrahi
- Department of Zoology, School of Applied Sciences, Centurion University of Technology and Management, Jatni, Khordha, Odisha, India.
| | - Annapurna Sahoo
- Department of Zoology, School of Applied Sciences, Centurion University of Technology and Management, Jatni, Khordha, Odisha, India.
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Temaj G, Chichiarelli S, Telkoparan-Akillilar P, Saha S, Nuhii N, Hadziselimovic R, Saso L. Advances in molecular function of UPF1 in Cancer. Arch Biochem Biophys 2024; 756:109989. [PMID: 38621446 DOI: 10.1016/j.abb.2024.109989] [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: 02/06/2024] [Revised: 03/23/2024] [Accepted: 04/10/2024] [Indexed: 04/17/2024]
Abstract
It is known that more than 10 % of genetic diseases are caused by a mutation in protein-coding mRNA (premature termination codon; PTC). mRNAs with an early stop codon are degraded by the cellular surveillance process known as nonsense-mediated mRNA decay (NMD), which prevents the synthesis of C-terminally truncated proteins. Up-frameshift-1 (UPF1) has been reported to be involved in the downregulation of various cancers, and low expression of UPF1 was shown to correlate with poor prognosis. It is known that UPF1 is a master regulator of nonsense-mediated mRNA decay (NMD). UPF1 may also function as an E3 ligase and degrade target proteins without using mRNA decay mechanisms. Increasing evidence indicates that UPF1 could serve as a good biomarker for cancer diagnosis and treatment for future therapeutic applications. Long non-coding RNAs (lncRNAs) have the ability to bind different proteins and regulate gene expression; this role in cancer cells has already been identified by different studies. This article provides an overview of the aberrant expression of UPF1, its functional properties, and molecular processes during cancer for clinical applications in cancer. We also discussed the interactions of lncRNA with UPF1 for cell growth during tumorigenesis.
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Affiliation(s)
- Gazmend Temaj
- Faculty of Pharmacy, College UBT, 10000, Prishtina, Republic of Kosovo.
| | - Silvia Chichiarelli
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, 00185, Rome, Italy.
| | | | - Sarmistha Saha
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura, Uttar Pradesh, India.
| | - Nexhibe Nuhii
- Department of Pharmacy, Faculty of Medical Sciences, State University of Tetovo, 1200, Tetovo, Macedonia.
| | - Rifat Hadziselimovic
- Faculty of Science, University of Sarajevo, 71000, Sarajevo, Bosnia and Herzegovina.
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", La Sapienza University, 00185, Rome, Italy.
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Alshahrani MY, Saleh RO, Hjazi A, Bansal P, Kaur H, Deorari M, Altalbawy FMA, Kareem AH, Hamzah HF, Mohammed BA. Molecular Mechanisms of Tumorgenesis and Metastasis of Long Non-coding RNA (lncRNA) NEAT1 in Human Solid Tumors; An Update. Cell Biochem Biophys 2024; 82:593-607. [PMID: 38750383 DOI: 10.1007/s12013-024-01287-9] [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: 04/18/2024] [Indexed: 08/25/2024]
Abstract
The expression of the nuclear paraspeckle assembly transcript 1 (NEAT1), as a well-known long non-coding RNA (lncRNA), is often upregulated in varied types of cancers and associated with poor survival outcomes in patients suffering from tumors. NEAT1 promotes the tumors growth by influencing the various genes' expression profile that regulate various aspects of tumor cell behavior, in particular tumor growth, metastasis and drug resistance. This suggests that NEAT1 are capable of serving as a new diagnostic biomarker and target for therapeutic intervention. Through interrelation with enhancer of zeste homolog 2 (EZH2), NEAT1 acts as a scaffold RNA molecule, and thus regulating the expression EZH2-associated genes. Additionally, by perform as miRNA sponge, it constrains suppressing the interactions between miRNAs-mediated degradation of target mRNAs. In light of this, NEAT1 inhibition by small interfering RNA (siRNA) hampers tumorgenesis. We summarize recent findings about the expression, biological functions, and regulatory process of NEAT1 in human tumors. It specifically emphasizes the clinical significance of NEAT1 as a novel diagnostic biomarker and a promising therapeutic mark for many types of cancers.
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Affiliation(s)
- Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Raed Obaid Saleh
- Department of Pathological Analysis, College of Applied Science, University of Fallujah, Al-Maarif University College, Al-Anbar, Iraq.
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka, 560069, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh, 247341, India
- Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand, 831001, India
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia.
| | | | - Hamza Fadhel Hamzah
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
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8
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Fang C, Wu W, Ni Z, Liu Y, Luo J, Zhou Y, Gong C, Hu D, Yao C, Chen X, Wang L, Zhu S. Ailanthone inhibits non-small cell lung cancer growth and metastasis through targeting UPF1/GAS5/ULK1 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155333. [PMID: 38518633 DOI: 10.1016/j.phymed.2023.155333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/22/2023] [Accepted: 12/30/2023] [Indexed: 03/24/2024]
Abstract
BACKGROUND Targeting long non-coding RNAs (LncRNAs) is a novel and promising approach in cancer therapy. In our previous study, we investigated the effects of ailanthone (aila), the main active compound derived from the stem barks of Ailanthus altissima (Mill.) Swingle, on the growth of non-small cell lung cancer (NSCLC) cells. Although we observed significant inhibition of NSCLC cell growth of aila, the underlying mechanisms involving LncRNAs, specifically LncRNA growth arrest specific 5 (GAS5), remain largely unknown. METHODS To further explore the impact of aila on NSCLC, we performed a series of experiments. Firstly, we confirmed the inhibitory effect of aila on NSCLC cell growth using multiple assays, including MTT, wound healing, transwell assay, as well as subcutaneous and metastasis tumor mice models in vivo. Next, we utilized cDNA microarray and RT-QPCR to identify GAS5 as the primary target of aila. To verify the importance of GAS5 in aila-induced tumor inhibition, we manipulated GAS5 expression levels by constructing GAS5 over-expression and knockdown NSCLC cell lines. Furthermore, we investigated the upstream and downstream signaling pathways of GAS5 through western blot and RT-QPCR analysis. RESULTS Our results showed that aila effectively increased GAS5 expression, as determined by microarray analysis. We also observed that aila significantly enhanced GAS5 expression in a dose- and time-dependent manner across various NSCLC cell lines. Notably, over-expression of GAS5 led to a significant suppression of NSCLC cell tumor growth; while aila had minimal inhibitory effect on GAS5-knockdown NSCLC cells. Additionally, we discovered that aila inhibited ULK1 and autophagy, and this inhibition was reversed by GAS5 knockdown. Moreover, we found that aila up-regulated GAS5 expression by suppressing UPF1-mediated nonsense-mediated mRNA decay (NMD). CONCLUSION In summary, our findings suggest that aila promotes GAS5 expression by inhibiting UPF1-mediated NMD, leading to the repression of ULK1-mediated autophagy and subsequent inhibitory effects on NSCLC cells. These results indicate that aila is a potent enhancer of GAS5 and holds promising potential for application in NSCLC therapy. However, our research is currently focused only on NSCLC. It remains to be determined whether aila can also inhibit the growth of other types of tumors through the UPF1/GAS5/ULK1 signaling pathway. In future studies, we can further investigate the mechanisms by which aila suppresses other types of tumors and potentially broaden the scope of its application in cancer therapy.
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Affiliation(s)
- Cheng Fang
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenbin Wu
- Experiment Animal Center, Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhongya Ni
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yangli Liu
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiaojiao Luo
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yufu Zhou
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenyuan Gong
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dan Hu
- School of Acupuncture, Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chao Yao
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao Chen
- Department of Nei Jing, School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Lixin Wang
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Shiguo Zhu
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Darmadi D, Chugaeva UY, Saleh RO, Hjazi A, Saleem HM, Ghildiyal P, Alwaily ER, Alawadi A, Alnajar MJ, Ihsan A. Critical roles of long noncoding RNA H19 in cancer. Cell Biochem Funct 2024; 42:e4018. [PMID: 38644608 DOI: 10.1002/cbf.4018] [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: 01/06/2024] [Revised: 03/18/2024] [Accepted: 04/06/2024] [Indexed: 04/23/2024]
Abstract
Long noncoding RNAs (lncRNAs) are a category of noncoding RNAs characterized by their length, often exceeding 200 nucleotides. There is a growing body of data that indicate the significant involvement of lncRNAs in a wide range of disorders, including cancer. lncRNA H19 was among the initial lncRNAs to be identified and is transcribed from the H19 gene. The H19 lncRNA exhibits significant upregulation in a diverse range of human malignancies, such as breast, colorectal, pancreatic, glioma, and gastric cancer. Moreover, the overexpression of H19 is frequently associated with a worse prognosis among individuals diagnosed with cancer. H19 has been shown to have a role in facilitating several cellular processes, including cell proliferation, invasion, migration, epithelial-mesenchymal transition, metastasis, and apoptosis. This article summarizes the aberrant upregulation of H19 in human malignancies, indicating promising avenues for future investigations on cancer diagnostics and therapeutic interventions.
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Affiliation(s)
- Darmadi Darmadi
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, North Sumatera, Indonesia
| | - Uliana Y Chugaeva
- Department of Pediatric, Preventive Dentistry and Orthodontics, Institute of Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Hiba Muwafaq Saleem
- Department of Biology, College of Science, University of Anbar, Ramadi, Iraq
| | - Pallavi Ghildiyal
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Enas R Alwaily
- Microbiology Research Group, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Ahmed Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Hillah, Iraq
| | | | - Ali Ihsan
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, Iraq
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10
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Al-Hawary SIS, Rodrigues P, Bangali H, Hassan ZF, Elawady A. The role of long noncoding RNA DGCR5 in cancers: Focus on molecular targets. Cell Biochem Funct 2024; 42:e3949. [PMID: 38379219 DOI: 10.1002/cbf.3949] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 02/22/2024]
Abstract
Long noncoding RNAs (lncRNAs) are major components of cellular transcripts that are emerging as important players in various biological pathways. Due to their specific expression and functional diversity in a variety of cancers, lncRNAs have promising applications in cancer diagnosis, prognosis, and therapy. Studies have shown that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) with high specificity and accuracy has the potential to become biomarkers in cancers. LncRNA DGCR5 can be noninvasively extracted from body fluids, tissues, and cells, and can be used as independent or auxiliary biomarkers to improve the accuracy of diagnosis or prognosis. Now, the underlying mechanisms of lncRNAs such as DGCR5 were explored as therapeutic targets, which have been investigated in clinical trials of several cancers. The DGCR5 lacks an appropriate animal model, which is necessary to gain greater knowledge of their functions. While some studies on the uses of DGCR5 have been carried out, the small sample size makes them unreliable. In this review, we presented a compilation of recent publications addressing the potential of lncRNA DGCR5 that could be considered as biomarkers or therapeutic targets, with the hopes of providing promised implications for future cancer therapy.
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Affiliation(s)
| | - Paul Rodrigues
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Saudi Arabia
| | - Harun Bangali
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Saudi Arabia
| | | | - Ahmed Elawady
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
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11
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Cha H, Kim M, Ahn N, Jeong SD, Ignatova E, Chi SW, Kim HH, Hwang J. Role of UPF1 in lncRNA-HEIH regulation for hepatocellular carcinoma therapy. Exp Mol Med 2024; 56:344-354. [PMID: 38297160 PMCID: PMC10907594 DOI: 10.1038/s12276-024-01158-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 02/02/2024] Open
Abstract
UPF1, a novel posttranscriptional regulator, regulates the abundance of transcripts, including long noncoding RNAs (lncRNAs), and thus plays an important role in cell homeostasis. In this study, we revealed that UPF1 regulates the abundance of hepatocellular carcinoma upregulated EZH2-associated lncRNA (lncRNA-HEIH) by binding the CG-rich motif, thereby regulating hepatocellular carcinoma (HCC) tumorigenesis. UPF1-bound lncRNA-HEIH was susceptible to degradation mediated by UPF1 phosphorylation via SMG1 and SMG5. According to analysis of RNA-seq and public data on patients with liver cancer, the expression of lncRNA-HEIH increased the levels of miR-194-5p targets and was inversely correlated with miR-194-5p expression in HCC patients. Furthermore, UPF1 depletion upregulated lncRNA-HEIH, which acts as a decoy of miR-194-5p that targets GNA13, thereby promoting GNA13 expression and HCC proliferation. The UPF1/lncRNA-HEIH/miR-194-5p/GNA13 regulatory axis is suggested to play a crucial role in cell progression and may be a suitable target for HCC therapy.
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Affiliation(s)
- Hyunho Cha
- Graduate School for Biomedical Science & Engineering, Hanyang University, Seoul, Korea
| | - Minwoo Kim
- Graduate School for Biomedical Science & Engineering, Hanyang University, Seoul, Korea
| | - Narae Ahn
- Graduate School for Biomedical Science & Engineering, Hanyang University, Seoul, Korea
| | - Seong Dong Jeong
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
| | | | - Sung Wook Chi
- Department of Life Sciences, Korea University, Seoul, Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Korea
| | - Hyeon Ho Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
- Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Jungwook Hwang
- Graduate School for Biomedical Science & Engineering, Hanyang University, Seoul, Korea.
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea.
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12
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Batista DMDO, da Silva JMC, Gigek CDO, Smith MDAC, de Assumpção PP, Calcagno DQ. Metastasis-associated lung adenocarcinoma transcript 1 molecular mechanisms in gastric cancer progression. World J Gastrointest Oncol 2023; 15:1520-1530. [PMID: 37746646 PMCID: PMC10514724 DOI: 10.4251/wjgo.v15.i9.1520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/30/2023] [Accepted: 07/27/2023] [Indexed: 09/13/2023] Open
Abstract
Gastric cancer (GC) remains among the most common cancers worldwide with a high mortality-to-incidence ratio. Accumulated evidence suggests that long noncoding RNAs (lncRNAs) are involved in gastric carcinogenesis. These transcripts are longer than 200 nucleotides and modulate gene expression at multiple molecular levels, inducing or inhibiting biological processes and diseases. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the best-studied lncRNAs with comprehensive actions contributing to cancer progression. This lncRNA regulates gene expression at the transcriptional and posttranscriptional levels through interactions with microRNAs and proteins. In the present review, we discussed the molecular mechanism of MALAT1 and summarized the current knowledge of its expression in GC. Moreover, we highlighted the potential use of MALAT1 as a biomarker, including liquid biopsy.
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Affiliation(s)
| | | | | | - Marília de Arruda Cardoso Smith
- Disciplina de Genética,Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo 04023-900, São Paulo, Brazil
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13
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Nasif S, Colombo M, Uldry AC, Schröder M, de Brot S, Mühlemann O. Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells. NAR Cancer 2023; 5:zcad048. [PMID: 37681034 PMCID: PMC10480688 DOI: 10.1093/narcan/zcad048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/08/2023] [Accepted: 08/25/2023] [Indexed: 09/09/2023] Open
Abstract
Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA decay pathway with roles in cellular stress responses, differentiation, and viral defense. It functions in both quality control and post-transcriptional regulation of gene expression. NMD has also emerged as a modulator of cancer progression, although available evidence supports both a tumor suppressor and a pro-tumorigenic role, depending on the model. To further investigate the role of NMD in cancer, we knocked out the NMD factor SMG7 in the HT1080 human fibrosarcoma cell line, resulting in suppression of NMD function. We then compared the oncogenic properties of the parental cell line, the SMG7-knockout, and a rescue cell line in which we re-introduced both isoforms of SMG7. We also tested the effect of a drug inhibiting the NMD factor SMG1 to distinguish NMD-dependent effects from putative NMD-independent functions of SMG7. Using cell-based assays and a mouse xenograft tumor model, we showed that suppression of NMD function severely compromises the oncogenic phenotype. Molecular pathway analysis revealed that NMD suppression strongly reduces matrix metalloprotease 9 (MMP9) expression and that MMP9 re-expression partially rescues the oncogenic phenotype. Since MMP9 promotes cancer cell migration and invasion, metastasis and angiogenesis, its downregulation may contribute to the reduced tumorigenicity of NMD-suppressed cells. Collectively, our results highlight the potential value of NMD inhibition as a therapeutic approach.
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Affiliation(s)
- Sofia Nasif
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Switzerland
| | - Martino Colombo
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Switzerland
| | - Anne-Christine Uldry
- Proteomics & Mass Spectrometry Core Facility, Department for BioMedical Research, University of Bern, Switzerland
| | - Markus S Schröder
- NCCR RNA & Disease Bioinformatics Support,Department of Biology, ETH Zürich, Switzerland
| | - Simone de Brot
- COMPATH, Institute of Animal Pathology, University of Bern, Switzerland
| | - Oliver Mühlemann
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Switzerland
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14
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Steiner AJ, Zheng Y, Tang Y. Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth. Sci Rep 2023; 13:10152. [PMID: 37349371 PMCID: PMC10287741 DOI: 10.1038/s41598-023-36568-5] [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: 02/21/2023] [Accepted: 06/06/2023] [Indexed: 06/24/2023] Open
Abstract
Soft-tissue sarcomas (STSs) are a rare and diverse group of mesenchymal cancers plagued with aggression, poor response to systemic therapy, and high rates of recurrence. Although STSs generally have low mutational burdens, the most commonly mutated genes are tumor suppressors, which frequently acquire mutations inducing nonsense-mediated mRNA decay (NMD). This suggests that STS cells may exploit NMD to suppress these anti-cancer genes. To examine the role that the NMD factor SMG7 plays in STS, we developed an inducible knockout mouse model in the Trp53-/- background. Here, we isolated a subcutaneous STS and identified it as a rhabdomyosarcoma (RMS). We report that knockout of SMG7 significantly inhibited NMD in our RMS cells, which led to the induction of NMD targets GADD45b and the tumor suppressor GAS5. The loss of NMD and upregulation of these anti-cancer genes were concomitant with the loss of RMS cell viability and inhibited tumor growth. Importantly, SMG7 was dispensable for homeostasis in our mouse embryonic fibroblasts and adult mice. Overall, our data show that the loss of SMG7 induces a strong anti-cancer effect both in vitro and in vivo. We present here the first evidence that disrupting SMG7 function may be tolerable and provide a therapeutic benefit for STS treatment.
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Affiliation(s)
- Alexander J Steiner
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Yang Zheng
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Yi Tang
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA.
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15
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Wang P, Li T, Fang L, Chen D, Qi H, Gu C. UPF1 regulates FOXO1 protein expression by promoting PBK transcription in non-small cell lung cancer. Biochem Biophys Res Commun 2023; 666:10-20. [PMID: 37167719 DOI: 10.1016/j.bbrc.2023.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 04/26/2023] [Accepted: 05/01/2023] [Indexed: 05/13/2023]
Abstract
Up-frameshift protein 1 (UPF1) is essential for nonsense-mediated messenger RNA decay (NMD). It is best known for its cytoprotective role in degrading aberrant and specific RNAs. UPF1 is dysregulated in multiple tumors, which correlates with poor prognosis and low overall survival.However,the role of UPF1 in lung cancer remains unclear.Current study shows that UPF1 could be a potential target for oncology therapies. The results also demonstrated the potential efficiency of UPF1 in regulating the proliferation and metastasis of lung cancer. Our findings suggest that those functions can be attributed to the inhibition of the stability of FOXO1 protein. In addition, PBK participates in the regulation of FOXO1 by UPF1.This result provides a new therapeutic strategy for lung cancer patients.
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Affiliation(s)
- Peng Wang
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Dalian Medical University, Dalian, 116011, China
| | - Tianjiao Li
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Dalian Medical University, Dalian, 116011, China
| | - Lei Fang
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Dalian Medical University, Dalian, 116011, China
| | - Di Chen
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Huan Qi
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
| | - Chundong Gu
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Dalian Medical University, Dalian, 116011, China.
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16
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Zhao B, Fang F, Liao Y, Chen Y, Wang F, Ma Y, Wei C, Zhao J, Ji H, Wang D, Tang D. Novel m7G-related lncRNA signature for predicting overall survival in patients with gastric cancer. BMC Bioinformatics 2023; 24:100. [PMID: 36935487 PMCID: PMC10024859 DOI: 10.1186/s12859-023-05228-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 03/13/2023] [Indexed: 03/21/2023] Open
Abstract
Presenting with a poor prognosis, gastric cancer (GC) remains one of the leading causes of disease and death worldwide. Long non-coding RNAs (lncRNAs) regulate tumor formation and have been long used to predict tumor prognosis. N7-methylguanosine (m7G) is the most prevalent RNA modification. m7G-lncRNAs regulate GC onset and progression, but their precise mechanism in GC is unclear. The objective of this research was the development of a new m7G-related lncRNA signature as a biomarker for predicting GC survival rate and guiding treatment. The Cancer Genome Atlas database helped extract gene expression data and clinical information for GC. Pearson correlation analysis helped point out m7G-related lncRNAs. Univariate Cox analysis helped in identifying m7G-related lncRNA with predictive capability. The Lasso-Cox method helped point out seven lncRNAs for the purpose of establishing an m7G-related lncRNA prognostic signature (m7G-LPS), followed by the construction of a nomogram. Kaplan-Meier analysis, univariate and multivariate Cox regression analysis, calibration plot of the nomogram model, receiver operating characteristic curve and principal component analysis were utilized for the verification of the risk model's reliability. Furthermore, q-PCR helped verify the lncRNAs expression of m7G-LPS in-vitro. The study subjects were classified into high and low-risk groups based on the median value of the risk score. Gene enrichment analysis confirmed the constructed m7G-LPS' correlation with RNA transcription and translation and multiple immune-related pathways. Analysis of the clinicopathological features revealed more progressive features in the high-risk group. CIBERSORT analysis showed the involvement of m7G-LPS in immune cell infiltration. The risk score was correlated with immune checkpoint gene expression, immune cell and immune function score, immune cell infiltration, and chemotherapy drug sensitivity. Therefore, our study shows that m7G-LPS constructed using seven m7G-related lncRNAs can predict the survival time of GC patients and guide chemotherapy and immunotherapy regimens as biomarker.
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Grants
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. 202011117056Y the Academic Science and Technology Innovation Fund for College Students
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. YZ2021075 the Social Development-Health Care Project of Yangzhou, Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- No. LGY2019034 High-level talent "six one projects" top talent scientific research project of Jiangsu Province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- SJCX22_1816 the Graduate Research- Innovation Project in Jiangsu province
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- BE2022773 Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
- High-level talent “six one projects” top talent scientific research project of Jiangsu Province
- Social development project of key R & D plan of Jiangsu Provincial Department of science and technology
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Affiliation(s)
- Bin Zhao
- Department of Clinical Medical College, The Yangzhou School of Clinical Medicine, Dalian Medical University, Yangzhou, 225001, China
| | - Fang Fang
- Department of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Yiqun Liao
- Department of Clinical Medical College, The Yangzhou School of Clinical Medicine, Dalian Medical University, Yangzhou, 225001, China
| | - Yuji Chen
- Department of Clinical Medical College, Yangzhou University, Yangzhou, 225001, China
| | - Fei Wang
- Department of Clinical Medical College, The Yangzhou School of Clinical Medicine, Dalian Medical University, Yangzhou, 225001, China
| | - Yichao Ma
- Department of Clinical Medical College, Yangzhou University, Yangzhou, 225001, China
| | - Chen Wei
- Department of Clinical Medical College, Yangzhou University, Yangzhou, 225001, China
| | - Jiahao Zhao
- Department of Clinical Medical College, Yangzhou University, Yangzhou, 225001, China
| | - Hao Ji
- Department of Clinical Medical College, Yangzhou University, Yangzhou, 225001, China
| | - Daorong Wang
- Department of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Dong Tang
- Department of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China.
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17
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Sun L, Mailliot J, Schaffitzel C. Nonsense-Mediated mRNA Decay Factor Functions in Human Health and Disease. Biomedicines 2023; 11:722. [PMID: 36979701 PMCID: PMC10045457 DOI: 10.3390/biomedicines11030722] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023] Open
Abstract
Nonsense-mediated mRNA decay (NMD) is a cellular surveillance mechanism that degrades mRNAs with a premature stop codon, avoiding the synthesis of C-terminally truncated proteins. In addition to faulty mRNAs, NMD recognises ~10% of endogenous transcripts in human cells and downregulates their expression. The up-frameshift proteins are core NMD factors and are conserved from yeast to human in structure and function. In mammals, NMD diversified into different pathways that target different mRNAs employing additional NMD factors. Here, we review our current understanding of molecular mechanisms and cellular roles of NMD pathways and the involvement of more specialised NMD factors. We describe the consequences of mutations in NMD factors leading to neurodevelopmental diseases, and the role of NMD in cancer. We highlight strategies of RNA viruses to evade recognition and decay by the NMD machinery.
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Affiliation(s)
- Lingling Sun
- School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK
| | - Justine Mailliot
- School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK
| | - Christiane Schaffitzel
- School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK
- Bristol Engineering Biology Centre BrisEngBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK
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18
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Staszewski J, Lazarewicz N, Konczak J, Migdal I, Maciaszczyk-Dziubinska E. UPF1-From mRNA Degradation to Human Disorders. Cells 2023; 12:cells12030419. [PMID: 36766761 PMCID: PMC9914065 DOI: 10.3390/cells12030419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/07/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Up-frameshift protein 1 (UPF1) plays the role of a vital controller for transcripts, ready to react in the event of an incorrect translation mechanism. It is well known as one of the key elements involved in mRNA decay pathways and participates in transcript and protein quality control in several different aspects. Firstly, UPF1 specifically degrades premature termination codon (PTC)-containing products in a nonsense-mediated mRNA decay (NMD)-coupled manner. Additionally, UPF1 can potentially act as an E3 ligase and degrade target proteins independently from mRNA decay pathways. Thus, UPF1 protects cells against the accumulation of misfolded polypeptides. However, this multitasking protein may still hide many of its functions and abilities. In this article, we summarize important discoveries in the context of UPF1, its involvement in various cellular pathways, as well as its structural importance and mutational changes related to the emergence of various pathologies and disease states. Even though the state of knowledge about this protein has significantly increased over the years, there are still many intriguing aspects that remain unresolved.
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Affiliation(s)
- Jacek Staszewski
- Department of Genetics and Cell Physiology, Faculty of Biological Sciences, University of Wroclaw, 50-328 Wroclaw, Poland
- Correspondence: (J.S.); (E.M.-D.)
| | - Natalia Lazarewicz
- Department of Genetics and Cell Physiology, Faculty of Biological Sciences, University of Wroclaw, 50-328 Wroclaw, Poland
- Institute of Genetics and Development of Rennes, CNRS UMR 6290, University of Rennes 1, 35000 Rennes, France
| | - Julia Konczak
- Department of Genetics and Cell Physiology, Faculty of Biological Sciences, University of Wroclaw, 50-328 Wroclaw, Poland
| | - Iwona Migdal
- Department of Genetics and Cell Physiology, Faculty of Biological Sciences, University of Wroclaw, 50-328 Wroclaw, Poland
| | - Ewa Maciaszczyk-Dziubinska
- Department of Genetics and Cell Physiology, Faculty of Biological Sciences, University of Wroclaw, 50-328 Wroclaw, Poland
- Correspondence: (J.S.); (E.M.-D.)
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19
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Wu C, Li H, Chang W, Zhong L, Zhang L, Wen Z, Mai S. Identification and Validation of UPF1 as a Novel Prognostic Biomarker in Renal Clear Cell Carcinoma. Genes (Basel) 2022; 13:2166. [PMID: 36421841 PMCID: PMC9690017 DOI: 10.3390/genes13112166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/18/2022] [Accepted: 11/18/2022] [Indexed: 09/08/2024] Open
Abstract
Background: Up frameshift protein 1 (UPF1) is a key component of nonsense-mediated mRNA decay (NMD) of mRNA containing premature termination codons (PTCs). The dysregulation of UPF1 has been reported in various cancers. However, the expression profile of UPF1 and its clinical significance in clear cell renal cell carcinoma (ccRCC) remains unclear. Methods: In order to detect UPF1 expression in ccRCC and its relationship with the clinical features of ccRCC, bulk RNA sequencing data were analyzed from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and ArrayExpress databases. The impact of UPF1 on the immune microenvironment of ccRCC was evaluated by multiple immune scoring algorithms to identify the cell groups that typically express UPF1 using ccRCC single cell sequencing (scRNA) data. In addition, genes co-expressed with UPF1 were identified by the weighted gene correlation network analysis (WGCNA), followed by KEGG and Reactome enrichment analysis. A series of functional experiments were performed to assess the roles of UPF1 in renal cancer cells. Finally, pan-cancer analysis of UPF1 was also performed. Results: Compared with normal tissues, the expression levels of UPF1 mRNA and protein in tumor tissues of ccRCC patients decreased significantly. In addition, patients with low expression of UPF1 had a worse prognosis. Analysis of the immune microenvironment indicated that UPF1 immune cell infiltration was closely related and the ccRCC scRNA-seq data identified that UPF1 was mainly expressed in macrophages. WGCNA analysis suggested that the functions of co-expressed genes are mainly enriched in cell proliferation and cellular processes. Experimental tests showed that knockdown of UPF1 can promote the invasion, migration and proliferation of ccRCC cells. Lastly, pan-cancer analysis revealed that UPF1 disorders were closely associated with various cancer outcomes. Conclusions: UPF1 may play a tumor suppressive role in ccRCC and modulate the immune microenvironment. The loss of UPF1 can predict the prognosis of ccRCC, making it a promising biomarker and providing a new reference for prevention and treatment.
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Affiliation(s)
- Chun Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Hongmu Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Wuguang Chang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Leqi Zhong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Lin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zhesheng Wen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Shijuan Mai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
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20
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FANG L, QI H, WANG P, WANG S, LI T, XIA T, PIAO H, GU C. UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis. J Zhejiang Univ Sci B 2022; 23:863-875. [PMID: 36226539 PMCID: PMC9561404 DOI: 10.1631/jzus.b2200144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Up-frameshift 1 (UPF1), as the most critical factor in nonsense-mediated messenger RNA (mRNA) decay (NMD), regulates tumor-associated molecular pathways in many cancers. However, the role of UPF1 in lung adenocarcinoma (LUAD) amino acid metabolism remains largely unknown. In this study, we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics. We further confirmed that UPF1 knockdown inhibited activating transcription factor 4 (ATF4) and Ser51 phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), the core proteins in amino acid metabolism reprogramming. In addition, UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells, which depends on the function of ATF4. Clinically, UPF1 mRNA expression is abnormal in LUAD tissues, and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival (OS) in LUAD patients. Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.
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Affiliation(s)
- Lei FANG
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian116011, China
| | - Huan QI
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, China
| | - Peng WANG
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian116011, China
| | - Shiqing WANG
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian116011, China
| | - Tianjiao LI
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian116011, China
| | - Tian XIA
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, China
| | - Hailong PIAO
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, China,Hailong PIAO,
| | - Chundong GU
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian116011, China,Chundong GU,
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21
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Tan K, Stupack DG, Wilkinson MF. Nonsense-mediated RNA decay: an emerging modulator of malignancy. Nat Rev Cancer 2022; 22:437-451. [PMID: 35624152 PMCID: PMC11009036 DOI: 10.1038/s41568-022-00481-2] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2022] [Indexed: 12/11/2022]
Abstract
Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that selectively degrades RNAs harbouring truncating mutations that prematurely terminate translation, including nonsense, frameshift and some splice-site mutations. Recent studies show that NMD shapes the mutational landscape of tumours by selecting for mutations that tend to downregulate the expression of tumour suppressor genes but not oncogenes. This suggests that NMD can benefit tumours, a notion further supported by the finding that mRNAs encoding immunogenic neoantigen peptides are typically targeted for decay by NMD. Together, this raises the possibility that NMD-inhibitory therapy could be of therapeutic benefit against many tumour types, including those with a high load of neoantigen-generating mutations. Complicating this scenario is the evidence that NMD can also be detrimental for many tumour types, and consequently tumours often have perturbed NMD. NMD may suppress tumour generation and progression by degrading subsets of specific normal mRNAs, including those encoding stress-response proteins, signalling factors and other proteins beneficial for tumours, as well as pro-tumour non-coding RNAs. Together, these findings suggest that NMD-modulatory therapy has the potential to provide widespread therapeutic benefit against diverse tumour types. However, whether NMD should be stimulated or repressed requires careful analysis of the tumour to be treated.
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Affiliation(s)
- Kun Tan
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Dwayne G Stupack
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA.
- UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
| | - Miles F Wilkinson
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA.
- Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA.
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22
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Guo T, You K, Chen X, Sun Y, Wu Y, Wu P, Jiang Y. RBM47 inhibits hepatocellular carcinoma progression by targeting UPF1 as a DNA/RNA regulator. Cell Death Dis 2022; 8:320. [PMID: 35831298 PMCID: PMC9279423 DOI: 10.1038/s41420-022-01112-3] [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: 05/16/2022] [Revised: 06/30/2022] [Accepted: 06/30/2022] [Indexed: 11/16/2022]
Abstract
The mechanisms by which the tumor behaviors of hepatocellular carcinoma (HCC) support growth and metastasis remain largely unknown, and it has become increasingly apparent that molecular dysregulation is of considerable importance for cellular signaling pathways. Recently, RNA-binding motif protein 47 (RBM47) has been suggested to function as a tumor regulator by acting as an RNA binding protein (RBP), but its role in HCC remains ambiguous. Here, in HCC, we identified that RBM47 had an inhibitory influence on tumor behaviors in vitro and accordingly suppressed the growth and metastasis of xenograft tumors in vivo. Additionally, RBM47 was verified to positively regulate Upframeshift 1 (UPF1), which is a crucial protein involved in the nonsense-mediated RNA decay (NMD) process and was previously determined to be an HCC suppressor. Mechanistically, the stability of UPF1 mRNA was demonstrated to be enhanced with its 3’UTR bound by RBM47, which acted as an RNA binding protein. Meanwhile, RBM47 was also proven to promote the transcription of UPF1 as a transcription factor. Taken together, we concluded that RBM47 functioned as a tumor suppressor by upregulating UPF1, acting as a DNA/RNA binding protein at the transcriptional and posttranscriptional levels.
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Affiliation(s)
- Tao Guo
- Department of Pathophysiology, School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China
| | - Ke You
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Xi Chen
- School of Stomatology, Weifang Medical University, Weifang, 261053, China
| | - Yuqi Sun
- School of Clinical Medicine, Weifang Medical University, Weifang, 261031, China
| | - Ying Wu
- Liuzhou Key Laboratory of Infectious Disease Immunity Research, Guangxi Health Commission Key Laboratory of Clinical Biotechnology, Liuzhou People's Hospital affiliated to Guangxi Medical University, Liuzhou, 545006, China
| | - Ping Wu
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510000, China
| | - Yingying Jiang
- School of Stomatology, Weifang Medical University, Weifang, 261053, China. .,Department of Dentistry, Affiliated Hospital of Weifang Medical University, Weifang, 261035, China.
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23
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Lee S, Hwang Y, Kim TH, Jeong J, Choi D, Hwang J. UPF1 Inhibits Hepatocellular Carcinoma Growth through DUSP1/p53 Signal Pathway. Biomedicines 2022; 10:biomedicines10040793. [PMID: 35453543 PMCID: PMC9029930 DOI: 10.3390/biomedicines10040793] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 03/24/2022] [Indexed: 12/21/2022] Open
Abstract
Human hepatocellular carcinoma (HCC) has a high mortality rate because of the dearth of effective treatments. Multiple studies have shown that overexpression of UPF1, a key nonsense-mediated mRNA decay (NMD) factor, reduces HCC growth through various cell signaling pathways. However, the mechanism by which UPF1 expression retards HCC proliferation through the regulation of RNA stability remains unclear. By employing various UPF1 variants and transcriptome analysis, we revealed that overexpression of UPF1 variants, not UPF1-mediated NMD, reduces HCC tumorigenesis. Additionally, UPF1 variant overexpression reduced tumorigenesis in xenografted mice. Transcriptome analysis indicated that the level of dual specificity phosphatase 1 (DUSP1) was increased by UPF1 variants via posttranscriptional regulation. The UPF1 overexpression-mediated increase of DUSP1 activated tumor suppressor signaling, ultimately inhibiting cell growth. In this study, we highlighted the function of UPF1 as a tumor suppressor in HCC growth.
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Affiliation(s)
- Suman Lee
- Graduate School for Biomedical Science & Engineering, Hanyang University, Seoul 04763, Korea; (S.L.); (Y.H.)
| | - Yukyung Hwang
- Graduate School for Biomedical Science & Engineering, Hanyang University, Seoul 04763, Korea; (S.L.); (Y.H.)
| | - Tae Hun Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul 04763, Korea; (T.H.K.); (J.J.); (D.C.)
| | - Jaemin Jeong
- Department of Surgery, Hanyang University College of Medicine, Seoul 04763, Korea; (T.H.K.); (J.J.); (D.C.)
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul 04763, Korea; (T.H.K.); (J.J.); (D.C.)
| | - Jungwook Hwang
- Graduate School for Biomedical Science & Engineering, Hanyang University, Seoul 04763, Korea; (S.L.); (Y.H.)
- Correspondence: ; Tel.: +82-2-2220-2427; Fax: +82-2-2220-2422
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24
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Khawar MB, Hamid SE, Jan T, Abbasi MH, Idnan M, Sheikh N. Diagnostic, prognostic and therapeutic potential of long noncoding RNAs in cancer. Mol Biol Rep 2022; 49:2311-2319. [PMID: 35072835 DOI: 10.1007/s11033-022-07180-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/19/2022] [Indexed: 12/27/2022]
Abstract
Long noncoding RNAs (lncRNAs) are longer than 200 nucleotides in length and undergo splicing, capping, polyadenylation, and editing just like mRNA. Evidence is growing that they regulate transcription, splicing, RNA degradation, and translation of genes and that their expression has been linked to a variety of illnesses, including cancer. The advancement of next-generation and high-throughput sequencing has changed the way lncRNAs are identified and characterized, revealing a relationship between lncRNAs and several tumor types. Since then, they have gained a significant attraction as a promising candidate in cancer diagnosis, prognosis, and therapy. Furthermore, they are a good candidate for consideration as tumor biomarkers due to their high stability, better tissue/cell selectivity, aberrant expression in certain malignancies, and easy and noninvasive detection. In addition, lncRNAs are being examined as therapeutic targets in clinical trials for a variety of malignancies. This review highlights the potential of lncRNAs as biomarkers or therapeutic targets in light of the current progress, clinical investigations, and patents filed so far.
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Affiliation(s)
- Muhammad Babar Khawar
- Applied Molecular Biology and Biomedicine Lab, Department of Zoology, University of Narowal, Narowal, Pakistan.
| | - Syeda Eisha Hamid
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Tayyba Jan
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | | | - Muhammad Idnan
- Department of Zoology, University of Okara, Okara, Pakistan
| | - Nadeem Sheikh
- Cell and Molecular Biology Lab, Institute of Zoology, University of the Punjab, Lahore, Pakistan.
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25
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Li J, Quan X, Lei S, Chen G, Hong J, Huang Z, Wang Q, Song W, Yang X. LncRNA MEG3 alleviates PFOS induced placental cell growth inhibition through its derived miR-770 targeting PTX3. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 293:118542. [PMID: 34801623 DOI: 10.1016/j.envpol.2021.118542] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/14/2021] [Accepted: 11/15/2021] [Indexed: 06/13/2023]
Abstract
Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant. Exposure to PFOS has been associated with abnormal fetal development. The long non-coding RNA (lncRNA) has been showed to play a role in fetal growth restriction (FGR), preeclampsia (PE) and other pregnancy complications. Whether the lncRNA contributes to PFOS-induced toxicity in the placenta remains unknown. In this study, we investigated the function of lncRNA MEG3 and its derived miR-770 in PFOS-induced placental toxicity. Pregnant mice received gavage administration of different concentrations of PFOS (0.5, 2.5, and 12.5 mg/kg/day) from GD0 to GD17, and HTR-8/SVneo cells were treated with PFOS in the concentrations of 0, 10-1, 1, 10 μM. We found that expression levels of miR-770 and its host gene MEG3 were reduced in mice placentas and HTR-8/SVneo cells with exposure of PFOS. A significant hypermethylation was observed at MEG3 promoter in placentas of mice gestational-treated with PFOS. We also confirmed that MEG3 and miR-770 overexpression alleviated the cell growth inhibition induced by PFOS. Furthermore, PTX3 (Pentraxin 3) was identified as the direct target of miR-770 and it was enhanced after PFOS exposure. In summary, our results suggested that MEG3 alleviate PFOS-induced placental cell inhibition through MEG3/miR-770/PTX3 axis.
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Affiliation(s)
- Jing Li
- School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Xiaojie Quan
- School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China
| | - Saifei Lei
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Gang Chen
- School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China
| | - Jiawei Hong
- School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China
| | - Zhenyao Huang
- School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China
| | - Qi Wang
- School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China
| | - Weiyi Song
- School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China
| | - Xinxin Yang
- School of Public Health, Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China
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26
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Hu D, Lou X, Meng N, Li Z, Teng Y, Zou Y, Wang F. Peripheral Blood-Based DNA Methylation of Long Non-Coding RNA H19 and Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promoters are Potential Non-Invasive Biomarkers for Gastric Cancer Detection. Cancer Control 2021; 28:10732748211043667. [PMID: 34615385 PMCID: PMC8504648 DOI: 10.1177/10732748211043667] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction The early diagnosis and detection could greatly improve the clinical outcome of gastric cancer (GC) patients. However, the non-invasive biomarkers for GC detection remain to be identified. Method We used online databases (GEPIA, UALCAN, Kaplan-Meier plotter, TIMER, and MEXPRESS) to explore the association between H19 or metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression in tissues and the occurrence, development, prognosis, the levels of immune cell infiltration, and methylation of GC; the correlation between mRNA expression and DNA methylation levels of genes were also examined. Methylation levels of H19 or MALAT1 in peripheral blood were compared between 150 GC patients and 100 healthy controls (HCs). Predictive nomograms were constructed among female and male groups for GC diagnosis. The calibration curves, Hosmer–Lemeshow test, and decision curve analysis were also used to examine the nomograms’ predictive ability and clinical values. Results Using multiple online databases, we found that the mRNA expressions of H19 and MALAT1 in tissues were related to the occurrence of GC, and such expressions were associated with immune cell infiltration of GC and negatively correlated with DNA methylation levels of H19 and MALAT1. H19 gene, H19C island, and MALAT1B island, as well as 20 CpG sites were hypermethylated in peripheral blood of GC patients compared with HCs; similar results were also found in female and male groups (P < .05 for all). The combination of H19c3, H19c4, MALAT1b12, and age, as well as the combination of H19b7, H19c1, H19c5, and age in the nomograms could distinguish GC patients from HCs in the female group and male group, respectively. Conclusion We found statistically significant hypermethylation of H19 and MALAT1 promoters in GC patients, and meaningful sensitivity and specificity of MALAT1 and H19 methylation in discriminating GC and HCs were observed in both female and male groups, which indicates that the peripheral blood-based DNA methylation of H19 and MALAT1 could act as potential non-invasive biomarkers for the diagnosis of GC.
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Affiliation(s)
- Dingtao Hu
- Department of Oncology, 36639The First Affiliated Hospital of Anhui Medical University, China
| | - Xiaoqi Lou
- Department of Oncology, 36639The First Affiliated Hospital of Anhui Medical University, China
| | - Nana Meng
- Department of Quality Management Office, 533251The Second Affiliated Hospital of Anhui Medical University, China
| | - Zhen Li
- Department of Epidemiology and Biostatistics, School of Public Health of Anhui Medical University, China
| | - Ying Teng
- Department of Epidemiology and Biostatistics, School of Public Health of Anhui Medical University, China
| | - Yanfeng Zou
- Department of Epidemiology and Biostatistics, School of Public Health of Anhui Medical University, China
| | - Fang Wang
- Department of Oncology, 36639The First Affiliated Hospital of Anhui Medical University, China
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27
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Zhang M, Chen H, Qin P, Cai T, Li L, Chen R, Liu S, Chen H, Lin W, Chen H, Strickland AL, Xiong H, Jiang Q. UPF1 impacts on mTOR signaling pathway and autophagy in endometrioid endometrial carcinoma. Aging (Albany NY) 2021; 13:21202-21215. [PMID: 34520393 PMCID: PMC8457587 DOI: 10.18632/aging.203421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/30/2021] [Indexed: 11/25/2022]
Abstract
Most EEC cases are associated with activities of the mTOR pathway, which regulates protein synthesis, cell growth and autophagy. While Up-Frameshift 1(UPF1) is a key protein factor in the nonsense-mediated mRNA degradation pathway (NMD), its role in carcinogenesis of EEC remains unclear. In this study, we first evaluated the expression level of UPF1 in EEC tissues and cell lines. Then, we investigated the effect of UPF1 on cellular function and mTOR signaling pathway; these effects were further validated in vivo. Finally, its effect on autophagy was evaluated by western blot and GFP-mRFP-LC3 staining. UPF1 expression in the EEC tissue samples was significantly higher than that of matched normal tissue samples. Overexpression of UPF1 promoted migration and invasion of EEC cells. Conversely, depletion of UPF1 suppressed migration and invasion of EEC cells. In addition, overexpression of UPF1 increased the in vivo growth of our EEC xenograft tumors. Finally, UPF1 increased the activity of the mTOR/P70S6K/4EBP1 signaling pathway and inhibited autophagy in EEC cells. These findings suggest that UPF1 functions as an oncogene to promote EEC carcinogenesis. Our findings propose UPF1 as a new potential therapeutic target for EEC.
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Affiliation(s)
- Minfen Zhang
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.,Department of Pathology, First Affiliated Hospital, Changsha 410005, China
| | - Hui Chen
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Ping Qin
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Tonghui Cai
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Lingjun Li
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Ruichao Chen
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Shaoyan Liu
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Hui Chen
- Department of Pathology, First Affiliated Hospital, Changsha 410005, China
| | - Wanrun Lin
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hao Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Amanda L Strickland
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Hanzhen Xiong
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
| | - Qingping Jiang
- Department of Pathology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.,Key Laboratory of Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China
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28
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Inhibition of the lncRNA Coded within Transglutaminase 2 Gene Impacts Several Relevant Networks in MCF-7 Breast Cancer Cells. Noncoding RNA 2021; 7:ncrna7030049. [PMID: 34449674 PMCID: PMC8395837 DOI: 10.3390/ncrna7030049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
Long non-coding RNAs are nucleotide molecules that regulate transcription in numerous cellular processes and are related to the occurrence of many diseases, including cancer. In this regard, we recently discovered a polyadenylated long non-coding RNA (named TG2-lncRNA) encoded within the first intron of the Transglutaminase type 2 gene (TGM2), which is related to tumour proliferation in human cancer cell lines. To better characterize this new biological player, we investigated the effects of its suppression in MCF-7 breast cancer cells, using siRNA treatment and RNA-sequencing. In this way, we found modifications in several networks associated to biological functions relevant for tumorigenesis (apoptosis, chronic inflammation, angiogenesis, immunomodulation, cell mobility, and epithelial–mesenchymal transition) that were originally attributed only to Transglutaminase type 2 protein but that could be regulated also by TG2-lncRNA. Moreover, our experiments strongly suggest the ability of TG2-lncRNA to directly interact with important transcription factors, such as RXRα and TP53, paving the way for several regulatory loops that can potentially influence the phenotypic behaviour of MCF-7 cells. These considerations imply the need to further investigate the relative relevance of the TG2 protein itself and/or other gene products as key regulators in the organization of breast cancer program.
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29
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Karousis ED, Gypas F, Zavolan M, Mühlemann O. Nanopore sequencing reveals endogenous NMD-targeted isoforms in human cells. Genome Biol 2021; 22:223. [PMID: 34389041 PMCID: PMC8361881 DOI: 10.1186/s13059-021-02439-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/26/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Nonsense-mediated mRNA decay (NMD) is a eukaryotic, translation-dependent degradation pathway that targets mRNAs with premature termination codons and also regulates the expression of some mRNAs that encode full-length proteins. Although many genes express NMD-sensitive transcripts, identifying them based on short-read sequencing data remains a challenge. RESULTS To identify and analyze endogenous targets of NMD, we apply cDNA Nanopore sequencing and short-read sequencing to human cells with varying expression levels of NMD factors. Our approach detects full-length NMD substrates that are highly unstable and increase in levels or even only appear when NMD is inhibited. Among the many new NMD-targeted isoforms that our analysis identifies, most derive from alternative exon usage. The isoform-aware analysis reveals many genes with significant changes in splicing but no significant changes in overall expression levels upon NMD knockdown. NMD-sensitive mRNAs have more exons in the 3΄UTR and, for those mRNAs with a termination codon in the last exon, the length of the 3΄UTR per se does not correlate with NMD sensitivity. Analysis of splicing signals reveals isoforms where NMD has been co-opted in the regulation of gene expression, though the main function of NMD seems to be ridding the transcriptome of isoforms resulting from spurious splicing events. CONCLUSIONS Long-read sequencing enables the identification of many novel NMD-sensitive mRNAs and reveals both known and unexpected features concerning their biogenesis and their biological role. Our data provide a highly valuable resource of human NMD transcript targets for future genomic and transcriptomic applications.
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Affiliation(s)
- Evangelos D Karousis
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland
| | - Foivos Gypas
- Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058, Basel, Switzerland
| | - Mihaela Zavolan
- Biozentrum, University of Basel and Swiss Institute of Bioinformatics, Klingelbergstrasse 50-70, 4056, Basel, Switzerland
| | - Oliver Mühlemann
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland.
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30
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Konishi H, Kashima S, Goto T, Ando K, Sakatani A, Tanaka H, Ueno N, Moriichi K, Okumura T, Fujiya M. The Identification of RNA-Binding Proteins Functionally Associated with Tumor Progression in Gastrointestinal Cancer. Cancers (Basel) 2021; 13:cancers13133165. [PMID: 34202873 PMCID: PMC8269357 DOI: 10.3390/cancers13133165] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 11/18/2022] Open
Abstract
Simple Summary Previous investigations described bioinformatic analyses based on the mRNA expression and somatic mutation as useful strategies for identifying cancer-associated molecules that were potential candidates of therapeutic targets. However, these data included secondary changes and non-functional alterations that do not influence tumor progression. Investigations, including our own studies, have shown that some RBPs shuttle cytoplasm and nuclei, and their affinity to RNAs is regulated by posttranslational modifications, such as phosphorylation. Therefore, the functional assessment of individual molecules is the most suitable strategy for identifying cancer-associated genes with or without expressional changes and mutations. This report showed for the first time that a functional assessment using an siRNA library was useful for identifying therapeutic targets from molecular groups, including RBPs, that had not been identified by expressional and mutational analyses. Abstract Previous investigations have indicated that RNA-binding proteins (RBPs) are key molecules for the development of organs, differentiation, cell growth and apoptosis in cancer cells as well as normal cells. A bioinformatics analysis based on the mRNA expression and a somatic mutational database revealed the association between aberrant expression/mutations of RBPs and cancer progression. However, this method failed to detect functional alterations in RBPs without changes in the expression, thus leading to false negatives. To identify major tumor-associated RBPs, we constructed an siRNA library based on the database of RBPs and assessed the influence on the growth of colorectal, pancreatic and esophageal cancer cells. A comprehensive analysis of siRNA functional screening findings using 1198 siRNAs targeting 416 RBPs identified 41 RBPs in which 50% inhibition of cell growth was observed in cancer cells. Among these RBPs, 12 showed no change in the mRNA expression and no growth suppression in non-cancerous cells when downregulated by specific siRNAs. We herein report for the first time cancer-promotive RBPs identified by a novel functional assessment using an siRNA library of RBPs combined with expressional and mutational analyses.
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Affiliation(s)
- Hiroaki Konishi
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Asahikawa 078-8510, Japan;
| | - Shin Kashima
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (S.K.); (T.G.); (K.A.); (A.S.); (N.U.); (K.M.); (T.O.)
| | - Takuma Goto
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (S.K.); (T.G.); (K.A.); (A.S.); (N.U.); (K.M.); (T.O.)
| | - Katsuyoshi Ando
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (S.K.); (T.G.); (K.A.); (A.S.); (N.U.); (K.M.); (T.O.)
| | - Aki Sakatani
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (S.K.); (T.G.); (K.A.); (A.S.); (N.U.); (K.M.); (T.O.)
| | - Hiroki Tanaka
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa 078-8510, Japan;
| | - Nobuhiro Ueno
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (S.K.); (T.G.); (K.A.); (A.S.); (N.U.); (K.M.); (T.O.)
| | - Kentaro Moriichi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (S.K.); (T.G.); (K.A.); (A.S.); (N.U.); (K.M.); (T.O.)
| | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (S.K.); (T.G.); (K.A.); (A.S.); (N.U.); (K.M.); (T.O.)
| | - Mikihiro Fujiya
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Asahikawa 078-8510, Japan;
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan; (S.K.); (T.G.); (K.A.); (A.S.); (N.U.); (K.M.); (T.O.)
- Correspondence: ; Tel.: +81-166-68-2462
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Liu Y, Hu Z, Zhang Y, Wang C. Long non-coding RNAs in Epstein-Barr virus-related cancer. Cancer Cell Int 2021; 21:278. [PMID: 34034760 PMCID: PMC8144696 DOI: 10.1186/s12935-021-01986-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/13/2021] [Indexed: 12/17/2022] Open
Abstract
Epstein Barr-virus (EBV) is related to several cancers. Long non-coding RNAs (lncRNAs) act by regulating target genes and are involved in tumourigenesis. However, the role of lncRNAs in EBV-associated cancers is rarely reported. Understanding the role and mechanism of lncRNAs in EBV-associated cancers may contribute to diagnosis, prognosis and clinical therapy in the future. EBV encodes not only miRNAs, but also BART lncRNAs during latency and the BHLF1 lncRNA during both the latent and lytic phases. These lncRNAs can be targeted regulate inflammation, invasion, and migration and thus tumourigenesis. The products of EBV also directly and indirectly regulate host lncRNAs, including LINC00312, NORAD CYTOR, SHNG8, SHNG5, MINCR, lncRNA-BC200, LINC00672, MALATI1, LINC00982, LINC02067, IGFBP7-AS1, LOC100505716, LOC100128494, NAG7 and RP4-794H19.1, to facilitate tumourigenesis using different mechanisms. Additionally, lncRNAs have been previously validated to interact with microRNAs (miRNAs), and lncRNAs and miRNAs mutually suppress each other. The EBV-miR-BART6-3p/LOC553103/STMN1 axis inhibits EBV-associated tumour cell proliferation. Additionally, H. pylori-EBV co-infection promotes inflammatory lesions and results in EMT. HPV-EBV co-infection inhibits the transition from latency to lytic replication. KSHV-EBV co-infection aggravates tumourigenesis in huNSG mice. COVID-19-EBV co-infection may activate the immune system to destroy a tumour, although this situation is rare and the mechanism requires further confirmation. Hopefully, this information will shed some light on tumour therapy strategies tumourigenesis. Additionally, this strategy benefits for infected patients by preventing latency to lytic replication. Understanding the role and expression of lnRNAs in these two phases of EBV is critical to control the transition from latency to the lytic replication phase. This review presents differential expressed lncRNAs in EBV-associated cancers and provides resources to aid in developing superior strategies for clinical therapy.
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Affiliation(s)
- Yitong Liu
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Zhizhong Hu
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Yang Zhang
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
| | - Chengkun Wang
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
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32
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Syllaios A, Moris D, Karachaliou GS, Sakellariou S, Karavokyros I, Gazouli M, Schizas D. Pathways and role of MALAT1 in esophageal and gastric cancer. Oncol Lett 2021; 21:343. [PMID: 33747200 PMCID: PMC7967938 DOI: 10.3892/ol.2021.12604] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Esophageal cancer (EC) and gastric cancer (GC) often have an unfavorable prognosis. Therefore, research is being conducted to identify the molecular mechanisms underlying the tumorigenesis and progression of GC and EC, and to indicate novel therapeutic targets and clinically applicable biomarkers. The dysregulations and roles of long non-coding RNAs (lncRNAs) have been widely reported, and current published literature has shown that lncRNAs play important regulatory roles in the carcinogenesis and progression of EC and GC. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been investigated in a number of studies with regard to its pathogenic pathways and association with the prognosis of gastric and esophageal malignancies. As literature on the topic of MALAT1 in EC and GC continues to emerge, the present review aims to summarize all current knowledge on the association between MALAT1 expression and esophagogastric malignancies and to describe the pathogenic pathways and possible prognostic role of MALAT1 in esophagogastric cancer. As research studies on MALAT1 pathways in esophagogastric malignancies are ongoing, new possibilities for the diagnosis, prognosis and therapy of GC and EC are likely to be identified.
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Affiliation(s)
- Athanasios Syllaios
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens 11527, Greece
| | - Dimitrios Moris
- Department of Surgery, Duke University Medical Center, Durham, NC 27707, USA
| | - Georgia Sofia Karachaliou
- Department of Medicine, Division of Hematology/Oncology, Duke University Medical Center, Durham, NC 27707, USA
| | - Stratigoula Sakellariou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Ioannis Karavokyros
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens 11527, Greece
| | - Maria Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens 11527, Greece
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33
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Nogueira G, Fernandes R, García-Moreno JF, Romão L. Nonsense-mediated RNA decay and its bipolar function in cancer. Mol Cancer 2021; 20:72. [PMID: 33926465 PMCID: PMC8082775 DOI: 10.1186/s12943-021-01364-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/19/2021] [Indexed: 12/17/2022] Open
Abstract
Nonsense-mediated decay (NMD) was first described as a quality-control mechanism that targets and rapidly degrades aberrant mRNAs carrying premature termination codons (PTCs). However, it was found that NMD also degrades a significant number of normal transcripts, thus arising as a mechanism of gene expression regulation. Based on these important functions, NMD regulates several biological processes and is involved in the pathophysiology of a plethora of human genetic diseases, including cancer. The present review aims to discuss the paradoxical, pro- and anti-tumorigenic roles of NMD, and how cancer cells have exploited both functions to potentiate the disease. Considering recent genetic and bioinformatic studies, we also provide a comprehensive overview of the present knowledge of the advantages and disadvantages of different NMD modulation-based approaches in cancer therapy, reflecting on the challenges imposed by the complexity of this disease. Furthermore, we discuss significant advances in the recent years providing new perspectives on the implications of aberrant NMD-escaping frameshifted transcripts in personalized immunotherapy design and predictive biomarker optimization. A better understanding of how NMD differentially impacts tumor cells according to their own genetic identity will certainly allow for the application of novel and more effective personalized treatments in the near future.
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Affiliation(s)
- Gonçalo Nogueira
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisbon, Portugal.,BioISI - Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisbon, Portugal
| | - Rafael Fernandes
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisbon, Portugal.,BioISI - Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisbon, Portugal
| | - Juan F García-Moreno
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisbon, Portugal.,BioISI - Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisbon, Portugal
| | - Luísa Romão
- Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisbon, Portugal. .,BioISI - Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisbon, Portugal.
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Abstract
Long non-coding RNAs (LncRNAs) can bind to other proteins or RNAs to regulate gene expression, and its role in tumors has been extensively studied. A common RNA binding protein, UPF1, is also a key factor in a variety of RNA decay pathways. RNA decay pathways serve to control levels of particular RNA molecules. The expression of UPF1 is often dysregulated in tumors, an observation which suggests that UPF1 contributes to development of a variety of tumors. Herein, we review evidence from studies of fourteen lncRNAs interact with UPF1. The interaction between lncRNA and UPFI provide fundamental basis for cell transformation and tumorigenic growth.
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Affiliation(s)
- Junjian He
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
| | - Xiaoxin Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
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35
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Chen B, Wang H, Li D, Lin X, Ma Z, Zeng Y. Up-frameshift Protein 1 Promotes Tumor Progression by Regulating Apoptosis and Epithelial-Mesenchymal Transition of Colorectal Cancer. Technol Cancer Res Treat 2021; 20:15330338211064438. [PMID: 34939866 PMCID: PMC8721398 DOI: 10.1177/15330338211064438] [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: 06/21/2021] [Revised: 10/26/2021] [Accepted: 11/15/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Recently, accumulating evidence confirmed that up-frameshift protein 1 (UPF1) was aberrantly expressed in various cancers. However, the molecular mechanism mediated by UPF1 underlying colorectal carcinogenesis remains unclear. Method: Immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction analysis were used to determine the expression level of UPF1 in colorectal cancer (CRC) tissues. CCK-8, EdU, transwell assay, and flow cytometry were performed to investigate the biological significance of UPF1. Epithelial-mesenchymal transition (EMT) and apoptosis associated markers were detected by western blotting. Results: We found that UPF1 expression was upregulated in CRC tissues and cell lines. Clinical analysis revealed that high UPF1 expression was positively correlated with advanced stage, lymph node metastasis and shorter survival. Knockdown of UPF1 suppressed cell proliferation and cell cycle progression. Functionally, UPF1 promotes tumor metastasis by inducing epithelial to mesenchymal transition. Further investigations revealed that knockdown of UPF1 promoted apoptosis through triggering DNA damage. Conclusions: Taken together, this research revealed that UPF1 plays an oncogenic role in CRC via regulating EMT and apoptosis and may be a potential therapeutic target for CRC.
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Affiliation(s)
- Binlie Chen
- The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China
- Medical College, Shantou University, Shantou, Guangdong, People's Republic of China
| | - Huaiming Wang
- The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China
| | - Danfeng Li
- The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China
| | - Xiaosheng Lin
- The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China
| | - Zhiyan Ma
- The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China
- Medical College, Shantou University, Shantou, Guangdong, People's Republic of China
| | - Yongming Zeng
- The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China
- Yongming Zeng, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, 57 Changping Road, Shantou, 515041, People's Republic of China.
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Li J, Quan XJ, Chen G, Hong JW, Wang Q, Xu LL, Wang BH, Yu ZH, Yu HM. PFOS-induced placental cell growth inhibition is partially mediated by lncRNA H19 through interacting with miR-19a and miR-19b. CHEMOSPHERE 2020; 261:127640. [PMID: 32738709 DOI: 10.1016/j.chemosphere.2020.127640] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/01/2020] [Accepted: 07/05/2020] [Indexed: 05/15/2023]
Abstract
Perfluorooctane sulfonic acid (PFOS), a persistent environmental pollutant, has been associated with decreased birth weight. The dysregulation of long non-coding RNA (lncRNA) H19 has been implicated in pregnancy complications such as intra-uterine growth retardation (IUGR), preeclampsia (PE), however, the expression and function of H19 in PFOS-exerted detrimental effects in the placenta remains to be unveiled. Here, we explored the role of H19 in PFOS-induced placental toxicity. Results showed that PFOS caused decreased cell growth in human HTR-8/SVneo cells. Expression of H19 was increased, while miR-19a and miR-19b expression were decreased in mice placenta tissues and in HTR-8/SVneo cells exposed to PFOS. A significant hypomethylation was observed at the H19 promoter in the placentas of mice that were gestational exposed to high dose of PFOS. H19 was confirmed to bind with miR-19a and miR-19b, targeting SMAD4. Furthermore, H19 appeared to partially improve the cell growth of HTR-8/SVneo cells exposed to PFOS via upregulation of miR-19a and miR-19b. In summary, our findings revealed that H19/miR-19a and miR-19b/SMAD4 axis exerted important functions in PFOS-induced placenta cell toxicity.
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Affiliation(s)
- Jing Li
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Xiao-Jie Quan
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Gang Chen
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Jia-Wei Hong
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Qi Wang
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Lin-Lin Xu
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Bing-Hua Wang
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Ze-Hua Yu
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
| | - Hong-Min Yu
- School of Public Health, Xuzhou Medical College, 209 Tong-Shan Road, Xuzhou, Jiangsu, 221002, China.
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Qian Y, Shi L, Luo Z. Long Non-coding RNAs in Cancer: Implications for Diagnosis, Prognosis, and Therapy. Front Med (Lausanne) 2020; 7:612393. [PMID: 33330574 PMCID: PMC7734181 DOI: 10.3389/fmed.2020.612393] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/09/2020] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are major components of cellular transcripts that are arising as important players in various biological pathways. They have received extensive attention in recent years, regarded to be involved in both developmental processes and various diseases. Due to their specific expression and functional diversity in a variety of cancers, lncRNAs have promising applications in cancer diagnosis, prognosis and therapy. Studies have shown that lncRNAs with high specificity and accuracy have the potential to become biomarkers in cancers. LncRNAs can be noninvasively extracted from body fluids, tissues and cells, and can be used as independent or auxiliary biomarkers to improve the accuracy of diagnosis or prognosis. Currently, the most well-recognized lncRNA is PCA3, which has been approved for use in the diagnosis of prostate cancer. Moreover, the underlying mechanisms of lncRNAs were explored as therapeutic targets, which have been investigated in clinical trials of several cancers. In this review, we presented a compilation of recent publications, clinical trials and patents, addressing the potential of lncRNAs that could be considered as biomarkers or therapeutic targets, with the hopes of providing promised implications for future cancer therapy.
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Affiliation(s)
| | - Lei Shi
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Zhong Luo
- School of Life Sciences, Chongqing University, Chongqing, China
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38
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Fu S, Wang Y, Li H, Chen L, Liu Q. Regulatory Networks of LncRNA MALAT-1 in Cancer. Cancer Manag Res 2020; 12:10181-10198. [PMID: 33116873 PMCID: PMC7575067 DOI: 10.2147/cmar.s276022] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/03/2020] [Indexed: 12/18/2022] Open
Abstract
Long noncoding (lnc)RNAs are a group of RNAs with a length greater than 200 nt that do not encode a protein but play an essential role in regulating the expression of target genes in normal biological contexts as well as pathologic processes including tumorigenesis. The lncRNA metastasis-associated lung adenocarcinoma transcript (MALAT)-1 has been widely studied in cancer. In this review, we describe the known functions of MALAT-1; its mechanisms of action; and associated signaling pathways and their clinical significance in different cancers. In most malignancies, including lung, colorectal, thyroid, and other cancers, MALAT-1 functions as an oncogene and is upregulated in tumors and tumor cell lines. MALAT-1 has a distinct mechanism of action in each cancer type and is thus at the center of large gene regulatory networks. Dysregulation of MALAT-1 affects cellular processes such as alternative splicing, epithelial–mesenchymal transition, apoptosis, and autophagy, which ultimately results in the abnormal cell proliferation, invasion, and migration that characterize cancers. In other malignancies, such as glioma and endometrial carcinoma, MALAT-1 functions as a tumor suppressor and thus forms additional regulatory networks. The current evidence indicates that MALAT-1 and its associated signaling pathways can serve as diagnostic or prognostic biomarker or therapeutic target in the treatment of many cancers.
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Affiliation(s)
- Shijian Fu
- The First Affiliated Hospital of Harbin Medical University, Harbin 150081, People's Republic of China
| | - Yanhong Wang
- Department of Laboratory Medicine, Yuebei People's Hospital of Shaoguan, The Affiliated Hospital of Shantou University, Shaoguan 512025, People's Republic of China
| | - Hang Li
- The First Affiliated Hospital of Harbin Medical University, Harbin 150081, People's Republic of China
| | - Leilei Chen
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Capital Medical University, Beijing 100029, People's Republic of China
| | - Quanzhong Liu
- Department of Medical Genetics, Harbin Medical University, Harbin 150081, People's Republic of China
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Wang X, Yu X, Wei W, Liu Y. Long noncoding RNA MACC1-AS1 promotes the stemness of nonsmall cell lung cancer cells through promoting UPF1-mediated destabilization of LATS1/2. ENVIRONMENTAL TOXICOLOGY 2020; 35:998-1006. [PMID: 32401390 DOI: 10.1002/tox.22936] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/04/2020] [Accepted: 04/22/2020] [Indexed: 06/11/2023]
Abstract
The roles of long noncoding RNA (lncRNA) MACC1-AS1 have been revealed in various tumors. This work aims to explore the roles of lncRNA MACC1-AS1 in the stemness of nonsmall cell lung cancer (NSCLC) cells and the underlying mechanism. We showed that overexpression of MACC1-AS1 enhanced the stemness of NSCLC cells, which is evident as the increased expression of cancer stem cell transcription factors, ALDH1 activity, and sphere-formation capacity, while knockdown of MACC1-AS1 decreased it. RNA-sequencing analysis revealed that the Hippo pathway was mostly enriched in NSCLC cell with MACC1-AS1 overexpression. Further mRNA and western blot analysis showed that ectopic expression of MACC1-AS1 regulated the expression LATS1/2, the critical regulator of Hippo pathway. Additionally, it was found that MACC1-AS1 interacted with up-frameshift 1 (UPF1) to modulate mRNA decay of LATS1/2. Overexpression of LAST1/2 attenuated the promoting effects of MACC1-AS1 overexpression on the stemness of NSCLC cells. Therefore, our results demonstrate the effects of the novel MACC1-AS1/UPF1/LATS1/2 axis in NSCLC cell stemness.
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Affiliation(s)
- Xiaojun Wang
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Xinnian Yu
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei Wei
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuanhua Liu
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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MiR-210 in exosomes derived from CAFs promotes non-small cell lung cancer migration and invasion through PTEN/PI3K/AKT pathway. Cell Signal 2020; 73:109675. [PMID: 32446904 DOI: 10.1016/j.cellsig.2020.109675] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Cancer-associated fibroblasts (CAFs) function as a crucial factor in tumor progression by carrying exosomes to neighboring cells. This study was assigned to expound the underlying mechanism of CAFs-derived exosomal miR-210 in non-small cell lung cancer (NSCLC) progression. METHOD CAFs and normal fibroblasts (NFs) were isolated and identified. Exosomes secreted from CAFs and NFs were isolated to analyze their effects on tumor volume and epithelial-mesenchymal transition (EMT). Exosomal miR-210 expression level was measured. The effects of exosomal miR-210 and UPF1 on cell viability, EMT, PTEN/PI3K/AKT signal pathway were determined. Dual-luciferase reporter gene assay was utilized to validate the binding of UPF1 to miR-210. RESULTS CAFs-derived exosomes (CAFs-exo) were successfully extracted and proven to be uptake by lung cancer cells. Up-regulated expression level of miR-210 was found in CAFs-exo, which was then proved to enhance cell migration, proliferation, invasion abilities and EMT in NSCLC cells. Overexpression of miR-210 can also inhibit UPF1 and PTEN, but activate the PTEN/PI3K/AKT pathway. UPF1 was a target gene of miR-210. MiR-210 can up-regulate UPF1 expression level to activate PTEN/PI3K/AKT pathway. CONCLUSION MiR-210 secreted by CAFs-exo could promote EMT by targeting UPF1 and activating PTEN/PI3K/AKT pathway, thereby promoting NSCLC migration and invasion.
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Xing TR, Chen P, Wu JM, Gao LL, Yang W, Cheng Y, Tong LB. UPF1 Participates in the Progression of Endometrial Cancer by Inhibiting the Expression of lncRNA PVT1. Onco Targets Ther 2020; 13:2103-2114. [PMID: 32210576 PMCID: PMC7074825 DOI: 10.2147/ott.s233149] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 12/18/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Endometrial carcinoma (EC) is the primary cause of death associated with cancer globally. Thus, the possible molecular mechanism of EC needs further exploration. Up-frameshift protein 1 (UPF1) is an ATPase depending on RNA/DNA and RNA helicase depending on ATP. Long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was dysregulated in diverse diseases. METHODS qRT-PCR and Western blot were applied to detect UPF1 and PVT1 in EC. CCK-8, colony formation, and Transwell assays were used to test the effects of UPF1/PVT1 on cell proliferation and migration. Cells were cultured with actinomycin D to observe mRNA stability, and RNA immunoprecipitation assay was applied to verified the relationship between UPF1 and PVT1. Glucose consumption and lactate generation were measured when cells were transfected with siRNA. RESULTS Results demonstrated that the expression of UPF1 exhibited a remarkable decrement in EC tissues relative to that in non-tumor tissues. Subsequent functional experiments suggested that UPF1 decrement stimulated EC cells to grow and migrate. Moreover, UPF1 was discovered to be linked to PVT1 and had an inverse correlation with PVT1. Besides, PVT1 expression affected EC growth and migration, and PVT1 decrement alleviated the influence of UPF1 decrement on EC growth and migration and strengthened glycolysis in EC. CONCLUSION In this study, we found that UPF1 was down-regulated in EC tissues, and UPF1 might exert its role by regulating the expression of PVT1.
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Affiliation(s)
- Tian-rong Xing
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
| | - Ping Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
| | - Jia-mei Wu
- Department of Pathophysiology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
| | - Li-li Gao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
| | - Wei Yang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
| | - Yu Cheng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
| | - Li-bo Tong
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
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Han S, Cao D, Sha J, Zhu X, Chen D. LncRNA ZFPM2-AS1 promotes lung adenocarcinoma progression by interacting with UPF1 to destabilize ZFPM2. Mol Oncol 2020; 14:1074-1088. [PMID: 31919993 PMCID: PMC7191191 DOI: 10.1002/1878-0261.12631] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/21/2019] [Accepted: 01/08/2020] [Indexed: 11/08/2022] Open
Abstract
Lung adenocarcinoma (LUAD), a histological subclass of non-small-cell lung cancer, is globally the leading cause of cancer-related deaths. Long noncoding RNAs (lncRNAs) are emerging as cancer regulators. Zinc finger protein multitype 2 antisense RNA 1 (ZFPM2-AS1) is an oncogene in gastric cancer, but its functions have not been investigated in LUAD. We showed that ZFPM2-AS1 expression is high in LUAD samples based on GEPIA database (http://gepia.cancer-pku.cn/) and validated ZFPM2-AS1 upregulation in LUAD cell lines. Functionally, ZFPM2-AS1 facilitated proliferation, invasion, and epithelial-to-mesenchymal transition of LUAD cells. Thereafter, we found that ZFPM2 was negatively regulated by ZFPM2-AS1, and identified the suppressive effect of ZFPM2 regulation by ZFPM2-AS1 on LUAD progression. Mechanistically, we showed that ZFPM2-AS1 interacted with up-frameshift 1 (UPF1) to regulate mRNA decay of ZFPM2. Rescue assays in vitro and in vivo confirmed that ZFPM2-AS1 regulated LUAD progression and tumor growth through ZFPM2. Taken together, our findings demonstrate a role for the ZFPM2-AS1-UPF1-ZFPM2 axis in LUAD progression, suggesting ZFPM2-AS1 as a new potential target for LUAD treatment.
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Affiliation(s)
- Shuhua Han
- Department of Pulmonary Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Dandan Cao
- Department of Pulmonary Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jun Sha
- Department of Pulmonary Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xiaoli Zhu
- Department of Pulmonary Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Dongqin Chen
- The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, China
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Ghafouri-Fard S, Taheri M. Long non-coding RNA signature in gastric cancer. Exp Mol Pathol 2019; 113:104365. [PMID: 31899194 DOI: 10.1016/j.yexmp.2019.104365] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/18/2019] [Accepted: 12/28/2019] [Indexed: 02/07/2023]
Abstract
Gastric cancer as a common human malignancy has been associated with aberrant expressions of several coding and non-coding genes. Long non-coding RNAs (lncRNAs) as regulators of gene expressions at different genomic, transcriptomic and post-transcriptomic levels are among putative biomarkers and therapeutic targets in gastric cancer. In the present study, we have searched available literature and listed lncRNAs that are involved in the pathogenesis of gastric cancer. In addition, we discuss associations between expressions of these lncRNAs and tumoral features or risk factors for gastric cancer. Based on the established role of lncRNAs in regulation of genomic stability, cell cycle, apoptosis, angiogenesis and other aspects of cell physiology, the potential of these transcripts as therapeutic targets in gastric cancer should be evaluated in future studies.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Xu E, Liang X, Ji Z, Zhao S, Li L, Lang J. Blocking long noncoding RNA MALAT1 restrained the development of laryngeal and hypopharyngeal carcinoma. Eur Arch Otorhinolaryngol 2019; 277:611-621. [PMID: 31792655 PMCID: PMC6981317 DOI: 10.1007/s00405-019-05732-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 11/11/2019] [Indexed: 12/12/2022]
Abstract
Purpose The long non-coding RNA MALAT1 is a predictive marker in several solid tumors with highly conserved sequences. However, the role of non-coding RNA in development of laryngeal or hypopharyngeal cancer remains unclear. Methods Tumor tissues and adjacent non-cancer tissues of 24 patients were collected. We detected the expression of MALAT1 in laryngeal cancer tissues and hypopharyngeal cancer tissues. Moreover, we developed a MALAT1 silencing model in human laryngeal tumor cells by transfecting MALAT1 small interfering RNA into human laryngeal carcinoma cell line Hep-2 and pharyngeal carcinoma cell line FaDu with Lipofectamine 2000 system. Cell cycle analysis, Cell Counting Kit-8 assay, Transwell assay, quantitative reverse transcription PCR, and wound-healing assays were performed to evaluate the impact of MALAT1 depletion on laryngeal or hypopharyngeal cancer cell’s growth, proliferation, apoptosis, invasion and migration. Results MALAT1 was significantly up-regulated in laryngeal and hypopharyngeal carcinoma cells. MALAT1 down-regulation induced the increased apoptosis of both cell lines and suppressed cells’ proliferation. Cells were arrested in G1/G2 phase and cells of S phase were significantly decreased. Down-regulation of MALAT1 expression can also inhibit the migration and invasion of laryngeal squamous cell carcinoma cell (Hep-2) and hypopharyngeal cancer cell (FaDu). Conclusion In summary, our deactivation model of MALAT1 disentangled the active function of it as a regulator of gene expression governing the hallmarks of laryngeal and hypopharyngeal cancer. Blocking this long non-coding RNA may restrain the development of laryngeal cancer.
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Affiliation(s)
- Enhong Xu
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiaoben Liang
- Department of Otolaryngology Head and Neck Surgery, Children's Hospital of Shanghai, Shanghai, China
| | - Zhenhua Ji
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shuwei Zhao
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Li Li
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Juntian Lang
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
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A Humanized Yeast Phenomic Model of Deoxycytidine Kinase to Predict Genetic Buffering of Nucleoside Analog Cytotoxicity. Genes (Basel) 2019; 10:genes10100770. [PMID: 31575041 PMCID: PMC6826991 DOI: 10.3390/genes10100770] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/17/2019] [Accepted: 09/23/2019] [Indexed: 12/22/2022] Open
Abstract
Knowledge about synthetic lethality can be applied to enhance the efficacy of anticancer therapies in individual patients harboring genetic alterations in their cancer that specifically render it vulnerable. We investigated the potential for high-resolution phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, comprehensive, and quantitative assessment of drug–gene interaction for gemcitabine and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures yet distinct antitumor efficacy. Human deoxycytidine kinase (dCK) was conditionally expressed in the Saccharomyces cerevisiae genomic library of knockout and knockdown (YKO/KD) strains, to globally and quantitatively characterize differential drug–gene interaction for gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, histone modification, chromatin remodeling, and apoptosis-related processes influence gemcitabine specifically, while drug–gene interaction specific to cytarabine was less enriched in gene ontology. Processes having influence over both drugs were DNA repair and integrity checkpoints and vesicle transport and fusion. Non-gene ontology (GO)-enriched genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics data were integrated to identify yeast–human homologs with correlated differential gene expression and drug efficacy, thus providing a unique resource to predict whether differential gene expression observed in cancer genetic profiles are causal in tumor-specific responses to cytotoxic agents.
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Li Y, Guo D, Ren M, Zhao Y, Wang X, Chen Y, Liu Y, Lu G, He S. Long non-coding RNA SNAI3-AS1 promotes the proliferation and metastasis of hepatocellular carcinoma by regulating the UPF1/Smad7 signalling pathway. J Cell Mol Med 2019; 23:6271-6282. [PMID: 31264769 PMCID: PMC6714236 DOI: 10.1111/jcmm.14513] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/09/2019] [Accepted: 06/11/2019] [Indexed: 01/04/2023] Open
Abstract
Emerging evidence has indicated that deregulation of long non-coding RNAs (lncRNAs) can contribute to the progression of human cancers, including hepatocellular carcinoma (HCC). However, the role and exact mechanism of most lncRNAs in tumours remains largely unknown. In the current study, we found a novel long non-coding RNA termed SNAI3-AS1 which was generally up-regulated in HCC tissues compared with normal control. Higher expression of SNAI3-AS1 was significantly correlated with shorter overall survival of HCC patients. Knockdown of SNAI3-AS1 inhibited the proliferation and metastasis of HCC cells in vitro, whereas overexpression of SNAI3-AS1 promoted the proliferation and metastasis of HCC cells. Further investigations showed that SNAI3-AS1 could affect HCC tumorigenesis by binding up-frameshift protein 1 (UPF1), regulating Smad7 expression and activating TGF-β/Smad pathway. Functionally, SNAI3-AS1 promoted HCC growth and metastasis by inducing tumour epithelial to mesenchymal transition (EMT). Taken together, these findings showed that SNAI3-AS1 promotes the progression of HCC by regulating the UPF1 and activating TGF-β/Smad pathway.
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Affiliation(s)
- Yarui Li
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Dan Guo
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Mudan Ren
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yan Zhao
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Xin Wang
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yifei Chen
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yaping Liu
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Guifang Lu
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Shuixiang He
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
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Xie X, Lin J, Liu J, Huang M, Zhong Y, Liang B, Song X, Gu S, Chang X, Huang D, Tang A. A novel lncRNA NR4A1AS up-regulates orphan nuclear receptor NR4A1 expression by blocking UPF1-mediated mRNA destabilization in colorectal cancer. Clin Sci (Lond) 2019; 133:1457-1473. [PMID: 31253658 DOI: 10.1042/cs20181061] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 06/19/2019] [Accepted: 06/27/2019] [Indexed: 02/05/2023]
Abstract
Long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and cancer progression. The orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) acts as an oncogene, and is involved in colorectal cancer (CRC) development. However, the mechanism through which lncRNA regulates NR4A1 expression remains unknown. We aimed to identify lncRNAs that regulate NR4A1 and assess their underlying mechanisms in CRC. We first identified an antisense lncRNA of NR4A1 that was up-regulated in CRC tissues and cells with rapid amplification of cDNA ends (RACE), and designated it as NR4A1AS. Spearman correlation analysis showed that NR4A1AS was positively correlated with NR4A1 mRNA levels in 37 CRC tissues. Mechanistically, NR4A1AS stabilized NR4A1 mRNA by forming RNA-RNA complexes via partial base-pairing and up-regulated NR4A1 expression in CRC cells. RNA immunoprecipitation (RIP) assays revealed that knockdown of NR4A1AS expression by siRNA enhanced up-frameshift 1 (UPF1) recruitment to NR4A1 mRNA, thereby decreasing NR4A1 mRNA stability. Moreover, depletion of NR4A1AS was found to mimic the effect of NR4A1 knockdown, specifically by suppressing cell proliferation, migration and invasion, and inducing apoptosis and cell cycle arrest. Accordingly, restoring NR4A1 expression ameliorated the effects of NR4A1AS knockdown on tumor growth and metastasis of CRC cells in vitro and in vivo Thus, we conclude that NR4A1AS up-regulates NR4A1 expression by forming RNA-RNA complexes and blocking UPF1-mediated mRNA destabilization, and it functions in tumor growth and metastasis of CRC cells at least partly through regulating NR4A1, suggesting that NR4A1AS might be as a potential target for RNA-based anti-CRC drug studies.
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MESH Headings
- Animals
- Apoptosis
- Caco-2 Cells
- Cell Cycle Checkpoints
- Cell Movement
- Cell Proliferation
- Colorectal Neoplasms/enzymology
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/pathology
- Gene Expression Regulation, Neoplastic
- HCT116 Cells
- Humans
- Male
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Invasiveness
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- RNA Helicases/genetics
- RNA Helicases/metabolism
- RNA Stability
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Signal Transduction
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Tumor Burden
- Up-Regulation
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Affiliation(s)
- Xina Xie
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Institute of Translational Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
- Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou 515041, China
| | - Jiatian Lin
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Jianlan Liu
- Department of Pathology, Shenzhen People's Hospital, Shenzhen 518000, China
| | - Meihui Huang
- Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou 515041, China
- Department of Pathology and Central Laboratory, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou 515041, China
| | - Yuantang Zhong
- Department of Urinary Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen 518035, China
| | - Bin Liang
- Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou 515041, China
| | - Xuhong Song
- Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou 515041, China
| | - Songgang Gu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Xiaolan Chang
- Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou 515041, China
| | - Dongyang Huang
- Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou 515041, China
| | - Aifa Tang
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Institute of Translational Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
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Zhang J, Zhang S, Zuo L, Yue W, Li S, Xin S, Liu L, Lu J. Differential expression profiling of lncRNAs related to Epstein‐Barr virus infection in the epithelial cells. J Med Virol 2019; 91:1845-1855. [DOI: 10.1002/jmv.25516] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/05/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Jing Zhang
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya HospitalCentral South University Changsha China
- Department of Microbiology, School of Basic Medical ScienceCentral South University Changsha China
| | - Siwei Zhang
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya HospitalCentral South University Changsha China
- Department of Microbiology, School of Basic Medical ScienceCentral South University Changsha China
| | - Lielian Zuo
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya HospitalCentral South University Changsha China
- Department of Microbiology, School of Basic Medical ScienceCentral South University Changsha China
| | - Wenxing Yue
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya HospitalCentral South University Changsha China
- Department of Microbiology, School of Basic Medical ScienceCentral South University Changsha China
| | - Shen Li
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya HospitalCentral South University Changsha China
- Department of Microbiology, School of Basic Medical ScienceCentral South University Changsha China
| | - Shuyu Xin
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya HospitalCentral South University Changsha China
- Department of Microbiology, School of Basic Medical ScienceCentral South University Changsha China
| | - Lingzhi Liu
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya HospitalCentral South University Changsha China
- Department of Microbiology, School of Basic Medical ScienceCentral South University Changsha China
| | - Jianhong Lu
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya HospitalCentral South University Changsha China
- Department of Microbiology, School of Basic Medical ScienceCentral South University Changsha China
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Bure IV, Nemtsova MV, Zaletaev DV. Roles of E-cadherin and Noncoding RNAs in the Epithelial-mesenchymal Transition and Progression in Gastric Cancer. Int J Mol Sci 2019; 20:ijms20122870. [PMID: 31212809 PMCID: PMC6627057 DOI: 10.3390/ijms20122870] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/03/2019] [Accepted: 06/11/2019] [Indexed: 02/08/2023] Open
Abstract
The epithelial–mesenchymal transition (EMT) is thought to be at the root of invasive and metastatic cancer cell spreading. E-cadherin is an important player in this process, which forms the structures that establish and maintain cell–cell interactions. A partial or complete loss of E-cadherin expression in the EMT is presumably mediated by mechanisms that block the expression of E-cadherin regulators and involve the E-cadherin-associated transcription factors. The protein is involved in several oncogenic signaling pathways, such as the Wnt/β-catenin, Rho GTPase, and EGF/EGFR, whereby it plays a role in many tumors, including gastric cancer. Such noncoding transcripts as microRNAs and long noncoding RNAs—critical components of epigenetic control of gene expression in carcinogenesis—contribute to regulation of the E-cadherin function by acting directly or through numerous factors controlling transcription of its gene, and thus affecting not only cancer cell proliferation and metastasis, but also the EMT. This review focuses on the role of E-cadherin and the non-coding RNAs-mediated mechanisms of its expressional control in the EMT during stomach carcinogenesis.
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Affiliation(s)
- Irina V Bure
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia.
| | - Marina V Nemtsova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia.
- Research Centre for Medical Genetics, Moskvorechie st., 1, Moscow 115522, Russia.
| | - Dmitry V Zaletaev
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia.
- Research Centre for Medical Genetics, Moskvorechie st., 1, Moscow 115522, Russia.
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50
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Pervouchine D, Popov Y, Berry A, Borsari B, Frankish A, Guigó R. Integrative transcriptomic analysis suggests new autoregulatory splicing events coupled with nonsense-mediated mRNA decay. Nucleic Acids Res 2019; 47:5293-5306. [PMID: 30916337 PMCID: PMC6547761 DOI: 10.1093/nar/gkz193] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 03/12/2019] [Indexed: 11/12/2022] Open
Abstract
Nonsense-mediated decay (NMD) is a eukaryotic mRNA surveillance system that selectively degrades transcripts with premature termination codons (PTC). Many RNA-binding proteins (RBP) regulate their expression levels by a negative feedback loop, in which RBP binds its own pre-mRNA and causes alternative splicing to introduce a PTC. We present a bioinformatic analysis integrating three data sources, eCLIP assays for a large RBP panel, shRNA inactivation of NMD pathway, and shRNA-depletion of RBPs followed by RNA-seq, to identify novel such autoregulatory feedback loops. We show that RBPs frequently bind their own pre-mRNAs, their exons respond prominently to NMD pathway disruption, and that the responding exons are enriched with nearby eCLIP peaks. We confirm previously proposed models of autoregulation in SRSF7 and U2AF1 genes and present two novel models, in which (i) SFPQ binds its mRNA and promotes switching to an alternative distal 3'-UTR that is targeted by NMD, and (ii) RPS3 binding activates a poison 5'-splice site in its pre-mRNA that leads to a frame shift and degradation by NMD. We also suggest specific splicing events that could be implicated in autoregulatory feedback loops in RBM39, HNRNPM, and U2AF2 genes. The results are available through a UCSC Genome Browser track hub.
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Affiliation(s)
- Dmitri Pervouchine
- Skolkovo Institute of Science and Technology, Ulitsa Nobelya 3, Moscow 121205, Russia
- Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskiye Gory 1-73, 119234 Moscow, Russia
| | - Yaroslav Popov
- Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskiye Gory 1-73, 119234 Moscow, Russia
| | - Andy Berry
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SA Hinxton, Cambridge, UK
| | - Beatrice Borsari
- Center for Genomic Regulation, The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
| | - Adam Frankish
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SA Hinxton, Cambridge, UK
| | - Roderic Guigó
- Center for Genomic Regulation, The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
- Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
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