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Assal RA, Rashwan HH, Zakaria ZI, Sweillam JH, Fouda YM, Abdelhamid AM, Youness RA. Deciphering the mysteries of MEG3 LncRNA and its implications in genitourinary cancers. Front Oncol 2025; 15:1519103. [PMID: 40242248 PMCID: PMC12000830 DOI: 10.3389/fonc.2025.1519103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/28/2025] [Indexed: 04/18/2025] Open
Abstract
Maternally expressed gene 3 (MEG3), a long non-coding RNA, plays a pivotal role in various biological processes, including tumorigenesis. Aberrant expression of MEG3 has been implicated in several cancers, including genitourinary malignancies. This comprehensive review explores the multifaceted functions of MEG3 in the context of genitourinary cancers through unravelling the molecular mechanisms underlying the influence of MEG3 on cellular proliferation, apoptosis, invasion, and metastasis. Additionally, we discuss the potential clinical implications of MEG3 as a biomarker and therapeutic target in genitourinary cancers. By unraveling the intricate role of MEG3 in these biological processes, this review aims to contribute to the development of novel strategies for the diagnosis and treatment of genitourinary malignancies.
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Affiliation(s)
- Reem A. Assal
- Department of Pharmacology and Toxicology, Heliopolis University for Sustainable Development (HU), Cairo, Egypt
| | - Hannah H. Rashwan
- Bioinformatics Group, Center for Informatics Science (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt
| | - Zeina I. Zakaria
- Faculty of Biology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Jana H. Sweillam
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University, Cairo, Egypt
| | - Yasmine M. Fouda
- Faculty of Medicine, Al-Kasr Al Ainy, Cairo University, Cairo, Egypt
| | | | - Rana A. Youness
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University, Cairo, Egypt
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2
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Wan Q, Zhao C, Zhao R. Progress of Pyruvate Kinase M2 in Hepatocellular Carcinoma-Associated Signaling Pathway. Tissue Eng Part C Methods 2025; 31:101-107. [PMID: 40105913 DOI: 10.1089/ten.tec.2024.0368] [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] [Indexed: 03/21/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive liver tumor with a unique metabolic profile and a shift to glycolytic metabolism. This review discusses the contribution of pyruvate kinase M2 (PKM2) to HCC development and its potential as a target for therapy. We carried out a broad literature review on PKM2, focusing on its role in the glycolytic pathway and special interactions with key signaling pathways like Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) and Mitogen-activated protein kinase (MAPK). PKM2 also performs a dual role in energy metabolism and signal transduction in HCC. PKM2 is paramount in the induction of HCC by regulating cellular metabolism and oncogenic signaling pathways. It promotes tumor growth, survival, and metastasis through interaction with the PI3K/AKT/mTOR and MAPK pathways. PKM2 is a key factor in HCC pathogenesis, with a dual impact on metabolism and signaling. Its properties may open the way for developing novel therapeutic interventions against HCC. Thus, PKM2 inhibition may offer further opportunities for tumor growth blockade, which could meaningfully improve patients' clinical outcomes.
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Affiliation(s)
- Qi Wan
- Second Hospital of Lanzhou University, Lanzhou, China
| | - Chunlian Zhao
- Second Hospital of Lanzhou University, Lanzhou, China
| | - Rui Zhao
- Second Hospital of Lanzhou University, Lanzhou, China
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3
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Coan M, Haefliger S, Ounzain S, Johnson R. Targeting and engineering long non-coding RNAs for cancer therapy. Nat Rev Genet 2024; 25:578-595. [PMID: 38424237 DOI: 10.1038/s41576-024-00693-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2024] [Indexed: 03/02/2024]
Abstract
RNA therapeutics (RNATx) aim to treat diseases, including cancer, by targeting or employing RNA molecules for therapeutic purposes. Amongst the most promising targets are long non-coding RNAs (lncRNAs), which regulate oncogenic molecular networks in a cell type-restricted manner. lncRNAs are distinct from protein-coding genes in important ways that increase their therapeutic potential yet also present hurdles to conventional clinical development. Advances in genome editing, oligonucleotide chemistry, multi-omics and RNA engineering are paving the way for efficient and cost-effective lncRNA-focused drug discovery pipelines. In this Review, we present the emerging field of lncRNA therapeutics for oncology, with emphasis on the unique strengths and challenges of lncRNAs within the broader RNATx framework. We outline the necessary steps for lncRNA therapeutics to deliver effective, durable, tolerable and personalized treatments for cancer.
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Affiliation(s)
- Michela Coan
- School of Biology and Environmental Science, University College Dublin, Dublin, Ireland
- Conway Institute of Biomedical and Biomolecular Research, University College Dublin, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Simon Haefliger
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | | | - Rory Johnson
- School of Biology and Environmental Science, University College Dublin, Dublin, Ireland.
- Conway Institute of Biomedical and Biomolecular Research, University College Dublin, Dublin, Ireland.
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
- Department for BioMedical Research, University of Bern, Bern, Switzerland.
- FutureNeuro, SFI Research Centre for Chronic and Rare Neurological Diseases, Dublin, Ireland.
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TANG CHAO, ZHONG CHUNYU, ZHU JUNHAO, YUAN FENG, YANG JIN, XU YONG, MA CHIYUAN. GNAS mutations suppress cell invasion by activating MEG3 in growth hormone-secreting pituitary adenoma. Oncol Res 2024; 32:1079-1091. [PMID: 38827318 PMCID: PMC11136687 DOI: 10.32604/or.2024.046007] [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: 09/14/2023] [Accepted: 12/08/2023] [Indexed: 06/04/2024] Open
Abstract
Approximately 30%-40% of growth hormone-secreting pituitary adenomas (GHPAs) harbor somatic activating mutations in GNAS (α subunit of stimulatory G protein). Mutations in GNAS are associated with clinical features of smaller and less invasive tumors. However, the role of GNAS mutations in the invasiveness of GHPAs is unclear. GNAS mutations were detected in GHPAs using a standard polymerase chain reaction (PCR) sequencing procedure. The expression of mutation-associated maternally expressed gene 3 (MEG3) was evaluated with RT-qPCR. MEG3 was manipulated in GH3 cells using a lentiviral expression system. Cell invasion ability was measured using a Transwell assay, and epithelial-mesenchymal transition (EMT)-associated proteins were quantified by immunofluorescence and western blotting. Finally, a tumor cell xenograft mouse model was used to verify the effect of MEG3 on tumor growth and invasiveness. The invasiveness of GHPAs was significantly decreased in mice with mutated GNAS compared with that in mice with wild-type GNAS. Consistently, the invasiveness of mutant GNAS-expressing GH3 cells decreased. MEG3 is uniquely expressed at high levels in GHPAs harboring mutated GNAS. Accordingly, MEG3 upregulation inhibited tumor cell invasion, and conversely, MEG3 downregulation increased tumor cell invasion. Mechanistically, GNAS mutations inhibit EMT in GHPAs. MEG3 in mutated GNAS cells prevented cell invasion through the inactivation of the Wnt/β-catenin signaling pathway, which was further validated in vivo. Our data suggest that GNAS mutations may suppress cell invasion in GHPAs by regulating EMT through the activation of the MEG3/Wnt/β-catenin signaling pathway.
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Affiliation(s)
- CHAO TANG
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China
| | - CHUNYU ZHONG
- Department of Neurosurgery, Children’s Hospital of Nanjing Medical University, Nanjing, 210019, China
| | - JUNHAO ZHU
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China
| | - FENG YUAN
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China
| | - JIN YANG
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China
| | - YONG XU
- Affiliated Eye Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - CHIYUAN MA
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China
- Affiliated Eye Hospital, Nanjing Medical University, Nanjing, 210029, China
- Department of Neurosurgery, Jinling Hospital, Southern Medical University, Nanjing, 210002, China
- Department of Neurosurgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, China
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Yang Y, Tian Z, He L, Meng H, Xie X, Yang Z, Wang X, Zhao Y, Huang C. RhoGDIβ inhibition via miR-200c/AUF1/SOX2/miR-137 axis contributed to lncRNA MEG3 downregulation-mediated malignant transformation of human bronchial epithelial cells. Mol Carcinog 2024; 63:977-990. [PMID: 38376344 DOI: 10.1002/mc.23702] [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: 11/20/2023] [Revised: 01/22/2024] [Accepted: 02/06/2024] [Indexed: 02/21/2024]
Abstract
Nickel pollution is a recognized factor contributing to lung cancer. Understanding the molecular mechanisms of its carcinogenic effects is crucial for lung cancer prevention and treatment. Our previous research identified the downregulation of a long noncoding RNA, maternally expressed gene 3 (MEG3), as a key factor in transforming human bronchial epithelial cells (HBECs) into malignant cells following nickel exposure. In our study, we found that deletion of MEG3 also reduced the expression of RhoGDIβ. Notably, artificially increasing RhoGDIβ levels counteracted the malignant transformation caused by MEG3 deletion in HBECs. This indicates that the reduction in RhoGDIβ contributes to the transformation of HBECs due to MEG3 deletion. Further exploration revealed that MEG3 downregulation led to enhanced c-Jun activity, which in turn promoted miR-200c transcription. High levels of miR-200c subsequently increased the translation of AUF1 protein, stabilizing SOX2 messenger RNA (mRNA). This stabilization affected the regulation of miR-137, SP-1 protein translation, and the suppression of RhoGDIβ mRNA transcription and protein expression, leading to cell transformation. Our study underscores the co-regulation of RhoGDIβ expression by long noncoding RNA MEG3, multiple microRNAs (miR-200c and miR-137), and RNA-regulated transcription factors (c-Jun, SOX2, and SP1). This intricate network of molecular events sheds light on the nature of lung tumorigenesis. These novel findings pave the way for developing targeted strategies for the prevention and treatment of human lung cancer based on the MEG3/RhoGDIβ pathway.
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Affiliation(s)
- Yichao Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Guangzhou Medical University, Guangdong, Guangzhou, China
| | - Zhongxian Tian
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lijiong He
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hao Meng
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaomin Xie
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ziyi Yang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xinxing Wang
- Laboratory of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin, China
| | - Yunping Zhao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chuanshu Huang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Upadhyay S, Khan S, Hassan MI. Exploring the diverse role of pyruvate kinase M2 in cancer: Navigating beyond glycolysis and the Warburg effect. Biochim Biophys Acta Rev Cancer 2024; 1879:189089. [PMID: 38458358 DOI: 10.1016/j.bbcan.2024.189089] [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: 12/20/2023] [Revised: 02/25/2024] [Accepted: 03/03/2024] [Indexed: 03/10/2024]
Abstract
Pyruvate Kinase M2, a key enzyme in glycolysis, has garnered significant attention in cancer research due to its pivotal role in the metabolic reprogramming of cancer cells. Originally identified for its association with the Warburg effect, PKM2 has emerged as a multifaceted player in cancer biology. The functioning of PKM2 is intricately regulated at multiple levels, including controlling the gene expression via various transcription factors and non-coding RNAs, as well as adding post-translational modifications that confer distinct functions to the protein. Here, we explore the diverse functions of PKM2, encompassing newly emerging roles in non-glycolytic metabolic regulation, immunomodulation, inflammation, DNA repair and mRNA processing, beyond its canonical role in glycolysis. The ever-expanding list of its functions has recently grown to include roles in subcellular compartments such as the mitochondria and extracellular milieu as well, all of which make PKM2 an attractive drug target in the pursuit of therapeutics for cancer.
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Affiliation(s)
- Saurabh Upadhyay
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Shumayila Khan
- International Health Division, Indian Council of Medical Research, Ansari Nagar, New Delhi 110029, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
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Rashwan HH, Taher AM, Hassan HA, Awaji AA, Kiriacos CJ, Assal RA, Youness RA. Harnessing the supremacy of MEG3 LncRNA to defeat gastrointestinal malignancies. Pathol Res Pract 2024; 256:155223. [PMID: 38452587 DOI: 10.1016/j.prp.2024.155223] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
Evidence suggests that long non-coding RNAs (lncRNAs) play a pivotal role in the carcinogenesis and progression of various human malignancies including gastrointestinal malignancies. This comprehensive review reports the functions and mechanisms of the lncRNA maternally expressed gene 3 (MEG3) involved in gastrointestinal malignancies. It summarizes its roles in mediating the regulation of cellular proliferation, apoptosis, migration, invasiveness, epithelial-to-mesenchymal transition, and drug resistance in several gastrointestinal cancers such as colorectal cancer, gall bladder cancer, pancreatic cancer, gastric cancer, esophageal cancer, cholangiocarcinoma, gastrointestinal stromal tumors and most importantly, hepatocellular carcinoma. In addition, the authors briefly highlight its implicated mechanistic role and interactions with different non-coding RNAs and oncogenic signaling cascades. This review presents the rationale for developing non coding RNA-based anticancer therapy via harnessing the power of MEG3 in gastrointestinal malignancies.
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Affiliation(s)
- H H Rashwan
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; Bioinformatics Group, Center for Informatics Science (CIS), School of Information Technology and Computer Science (ITCS), Nile University, 12677, Giza, Egypt
| | - A M Taher
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - H A Hassan
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - A A Awaji
- Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - C J Kiriacos
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - R A Assal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - R A Youness
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt.
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Amini A, Esmaeili F, Golpich M. Possible role of lncRNAs in amelioration of Parkinson's disease symptoms by transplantation of dopaminergic cells. NPJ Parkinsons Dis 2024; 10:56. [PMID: 38472261 PMCID: PMC10933336 DOI: 10.1038/s41531-024-00661-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/14/2024] [Indexed: 03/14/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) are biomarkers for diagnosis and treatment of Parkinson's disease (PD). Since dopaminergic cell transplantation is a clinical method to treat PD, this study investigated the effects of dopaminergic cell therapy on the expression of some lncRNAs and genes related to PD. In this study, Twenty-eight rats were randomly assigned to four experimental groups. The control group (Sal group) received saline injections. The Par group was a PD rat model with 6-hydroxydopamine (6-OHDA) injection in right striatum (ST). PD animals were transplanted by undifferentiated P19 stem cells (Par-E group), and P19-derived dopaminergic cells (Par-N group). Cell transplant effects were evaluated using behavioral tests (cylinder, open field, and rotarod tests), and histological methods (H&E and Nissl staining, and immunohistochemistry). Moreover, the expression of lncRNAs MALAT1, MEG3, and SNHG1, alongside specific neuronal (synaptophysin) and dopaminergic (tyrosine hydroxylase) markers was evaluated by qRT-PCR. Behavioral and histopathological examinations revealed that cell transplantation partially compensated dopaminergic cell degeneration in ST and substantia nigra (SN) of PD rats. The expression of MALAT1, SNHG1, and MEG3 was decreased in the ST of the Par group, while MEG3 and SNHG1 gene expression was increased in PBMC relative to the Sal group. In PBMC of the Par-N group, all three lncRNAs showed a reduction in their expression. Conversely, MALAT1 and SNHG1 expression was increased in ST tissue, while MEG3 gene expression was decreased compared to the Sal group. In conclusion, dopaminergic cell transplantation could change the lncRNAs expression. Furthermore, it partially improves symptoms in PD rats.
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Affiliation(s)
- A Amini
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - F Esmaeili
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - M Golpich
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
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Wei H, Wu X, Huang L, Long C, Lu Q, Huang Z, Huang Y, Li W, Pu J. LncRNA MEG3 Reduces the Ratio of M2/M1 Macrophages Through the HuR/CCL5 Axis in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:543-562. [PMID: 38496248 PMCID: PMC10943271 DOI: 10.2147/jhc.s449090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/07/2024] [Indexed: 03/19/2024] Open
Abstract
Objective Tumor-associated macrophages play a crucial role in the development of hepatocellular carcinoma (HCC). Our study aimed to investigate the relationship between long coding RNA (lncRNA) maternally expressed gene 3 (MEG3), RNA-binding protein human antigen R (HuR), and messenger RNA C-C motif chemokine 5 (CCL5) in the modulation of M1 and M2 macrophage polarization in HCC. Methods To induce M1 or M2 polarization, LPS/IFNγ- or IL4/IL13 were used to treat bone marrow derived macrophages (BMDMs). The localization of MEG3 in M1 and M2 macrophages was assessed using fluorescence in situ hybridization assay. Expression levels of MEG3, HuR, CCL5, M1, and M2 markers were measured by RT-qPCR or immunofluorescence staining. Flow cytometry was performed to determine the proportion of F4/80+CD206+ and F4/80+CD68+ cells. RNA pulldown assay was performed to detect the binding of lncRNA MEG3 and HuR. The impacts of HuR on CCL5 stability and activity of CCL5 promoter were evaluated using actinomycin D treatment and luciferase reporter assay. Cell migration, invasiveness, and angiogenesis were assessed using transwell migration and invasion assays and a tube formation assay. A mixture of Huh-7 cells and macrophages were injected into nude mice to explore the effect of MEG3 on tumorigenesis. Results MEG3 promoted M1-like polarization while dampening M2-like polarization of BMDMs. MEG3 bound to HuR in M1 and M2 macrophages. HuR downregulated CCL5 by inhibiting CCL5 transcription in macrophages. In addition, overexpression of MEG3 suppressed cell metastasis, invasion, and angiogenesis by obstructing macrophage M2 polarization. MEG3 inhibited tumorigenesis in HCC via promotion of M1-like polarization and inhibition of M2-like polarization. Rescue experiments showed that depletion of CCL5 in M2 macrophages reversed MEG3-induced suppressive effect on cell migration, invasion, and tube formation. Conclusion MEG3 suppresses HCC progression by promoting M1-like while inhibiting M2-like macrophage polarization via binding to HuR and thus upregulating CCL5.
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Affiliation(s)
- Huamei Wei
- Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
| | - Xianjian Wu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
| | - Lizheng Huang
- Graduate College of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
| | - Chen Long
- Graduate College of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
| | - Qi Lu
- Graduate College of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
| | - Zheng Huang
- Graduate College of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
| | - Yanyan Huang
- Graduate College of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
| | - Wenchuan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
| | - Jian Pu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China
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Mahato RK, Bhattacharya S, Khullar N, Sidhu IS, Reddy PH, Bhatti GK, Bhatti JS. Targeting long non-coding RNAs in cancer therapy using CRISPR-Cas9 technology: A novel paradigm for precision oncology. J Biotechnol 2024; 379:98-119. [PMID: 38065367 DOI: 10.1016/j.jbiotec.2023.12.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/30/2023] [Accepted: 12/03/2023] [Indexed: 12/25/2023]
Abstract
Cancer is the second leading cause of death worldwide, despite recent advances in its identification and management. To improve cancer patient diagnosis and care, it is necessary to identify new biomarkers and molecular targets. In recent years, long non-coding RNAs (lncRNAs) have surfaced as important contributors to various cellular activities, with growing proof indicating their substantial role in the genesis, development, and spread of cancer. Their unique expression profiles within specific tissues and their wide-ranging functionalities make lncRNAs excellent candidates for potential therapeutic intervention in cancer management. They are implicated in multiple hallmarks of cancer, such as uncontrolled proliferation, angiogenesis, and immune evasion. This review article explores the innovative application of CRISPR-Cas9 technology in targeting lncRNAs as a cancer therapeutic strategy. The CRISPR-Cas9 system has been widely applied in functional genomics, gene therapy, and cancer research, offering a versatile platform for lncRNA targeting. CRISPR-Cas9-mediated targeting of lncRNAs can be achieved through CRISPR interference, activation or the complete knockout of lncRNA loci. Combining CRISPR-Cas9 technology with high-throughput functional genomics makes it possible to identify lncRNAs critical for the survival of specific cancer subtypes, opening the door for tailored treatments and personalised cancer therapies. CRISPR-Cas9-mediated lncRNA targeting with other cutting-edge cancer therapies, such as immunotherapy and targeted molecular therapeutics can be used to overcome the drug resistance in cancer. The synergy of lncRNA research and CRISPR-Cas9 technology presents immense potential for individualized cancer treatment, offering renewed hope in the battle against this disease.
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Affiliation(s)
- Rahul Kumar Mahato
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Srinjan Bhattacharya
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Naina Khullar
- Department of Zoology, Mata Gujri College, Fatehgarh Sahib, Punjab, India
| | - Inderpal Singh Sidhu
- Department of Zoology, Sri Guru Gobind Singh College, Sector 26, Chandigarh, India
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Pharmacology & Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Departments of Neurology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India.
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
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Wang K, Lu Y, Li H, Zhang J, Ju Y, Ouyang M. Role of long non-coding RNAs in metabolic reprogramming of gastrointestinal cancer cells. Cancer Cell Int 2024; 24:15. [PMID: 38184562 PMCID: PMC10770979 DOI: 10.1186/s12935-023-03194-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 12/26/2023] [Indexed: 01/08/2024] Open
Abstract
Metabolic reprogramming, which is recognized as a hallmark of cancer, refers to the phenomenon by which cancer cells change their metabolism to support their increased biosynthetic demands. Tumor cells undergo substantial alterations in metabolic pathways, such as glycolysis, oxidative phosphorylation, pentose phosphate pathway, tricarboxylic acid cycle, fatty acid metabolism, and amino acid metabolism. Latest studies have revealed that long non-coding RNAs (lncRNAs), a group of non-coding RNAs over 200 nucleotides long, mediate metabolic reprogramming in tumor cells by regulating the transcription, translation and post-translational modification of metabolic-related signaling pathways and metabolism-related enzymes through transcriptional, translational, and post-translational modifications of genes. In addition, lncRNAs are closely related to the tumor microenvironment, and they directly or indirectly affect the proliferation and migration of tumor cells, drug resistance and other processes. Here, we review the mechanisms of lncRNA-mediated regulation of glucose, lipid, amino acid metabolism and tumor immunity in gastrointestinal tumors, aiming to provide more information on effective therapeutic targets and drug molecules for gastrointestinal tumors.
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Affiliation(s)
- Kang Wang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China
| | - Yan Lu
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China
| | - Haibin Li
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China
| | - Jun Zhang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China
- Guangdong Medical University, Dongguan, 523808, China
| | - Yongle Ju
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China.
| | - Manzhao Ouyang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China.
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Yu W, Zeng F, Xiao Y, Chen L, Qu H, Hong J, Qu C, Cheng G. Targeting PKM2 improves the gemcitabine sensitivity of intrahepatic cholangiocarcinoma cells via inhibiting β-catenin signaling pathway. Chem Biol Interact 2024; 387:110816. [PMID: 38000456 DOI: 10.1016/j.cbi.2023.110816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/09/2023] [Accepted: 11/20/2023] [Indexed: 11/26/2023]
Abstract
Gemcitabine is considered the standard first-line chemotherapeutic agent for patients with intrahepatic cholangiocarcinoma (ICC). However, its therapeutic efficacy is hampered by the development of chemoresistance. Pyruvate kinase M2 (PKM2), a crucial mediator of the final step in glycolysis, has been implicated in the origination and advancement of diverse malignancies. Its expression is increased in many tumor types and this may correlate with increased drug sensitivity. However, the specific effect of PKM2 on the gemcitabine sensitivity in ICC remains to be elucidated. In this research, we aimed to elucidate the role and functional significance of PKM2 in ICC, as well as the heightened susceptibility of ICC cells to gemcitabine by targeting PKM2 and the underlying molecular mechanisms. Immunohistochemical and immunofluorescence analyses revealed elevated expression of PKM2 in both tumor cells and macrophages in human ICC tissues. Reducing PKM2 levels significantly restrained the proliferation of tumor cells, impeded cell cycle advance, induced programmed cell death, and suppressed metastasis. In addition, knockdown or pharmacological inhibition of PKM2 could enhance the response of ICC cells to gemcitabine in vitro. Interestingly, conditioned medium co-culture system suggested that conditioned medium from M2 macrophages increased gemcitabine sensitivity of ICC cells. However, silencing PKM2 or pharmacological inhibition of PKM2 in M2 macrophages did not ameliorate the gemcitabine resistance mediated by M2 macrophages derived conditioned medium. Mechanistically, downregulation of PKM2 repressed the expression of β-catenin and its downstream transcriptional targets, thereby hindering the propagation of β-catenin signaling cascade. Finally, the results of the subcutaneous xenograft experiment in nude mice provided compelling evidence of a synergistic interaction between PKM2-IN-1 and gemcitabine in vivo. In summary, we reported that PKM2 may function as an advantageous target for increasing the sensitivity of ICC to gemcitabine treatment. Targeting PKM2 improves the gemcitabine sensitivity of ICC cells via inhibiting β-catenin signaling pathway.
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Affiliation(s)
- Wenna Yu
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Fuling Zeng
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, 510630, China
| | - Yang Xiao
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, 510630, China
| | - Liuyan Chen
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, 510630, China
| | - Hengdong Qu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, 510630, China
| | - Jian Hong
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, 510630, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Chen Qu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, 510630, China.
| | - Guohua Cheng
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China.
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13
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Li K, Gong Q, Xiang XD, Guo G, Liu J, Zhao L, Li J, Chen N, Li H, Zhang LJ, Zhou CY, Wang ZY, Zhuang L. HNRNPA2B1-mediated m 6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis. J Transl Med 2023; 21:382. [PMID: 37308993 DOI: 10.1186/s12967-023-04190-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 05/08/2023] [Indexed: 06/14/2023] Open
Abstract
BACKGROUND Accumulating data indicate that N6-methyladenosine (m6A) RNA methylation and lncRNA deregulation act crucial roles in cancer progression. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m6A "reader" has been reported to be an oncogene in multiple malignancies. We herein aimed to elucidate the role and underlying mechanism by which HNRNPA2B1-mediated m6A modification of lncRNAs contributes to non-small cell lung cancer (NSCLC). METHODS The expression levels of HNRNPA2B1 and their association with the clinicopathological characteristics and prognosis in NSCLC were determined by RT-qPCR, Western blot, immunohistochemistry and TCGA dataset. Then, the role of HNRNPA2B1 in NSCLC cells was assessed by in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. HNRNPA2B1-mediated m6A modification of lncRNAs was screened by m6A-lncRNA epi-transcriptomic microarray and verified by methylated RNA immunoprecipitation (Me-RIP). The lncRNA MEG3-specific binding with miR-21-5p was evaluated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses. RESULTS We found that upregulation of HNRNPA2B1 was associated with distant metastasis and poor survival, representing an independent prognostic factor in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis in vitro and in vivo, whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was an m6A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased MEG3 m6A levels but increased its mRNA levels. Furthermore, lncRNA MEG3 could act as a sponge of miR-21-5p to upregulate PTEN and inactivate PI3K/AKT signaling, leading to the suppression of cell proliferation and invasion. Low expression of lncRNA MEG3 or elevated expression of miR-21-5p indicated poor survival in patients with NSCLC. CONCLUSIONS Our findings uncover that HNRNPA2B1-mediated m6A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis and may provide a therapeutic target for NSCLC.
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Affiliation(s)
- Ke Li
- Department of Cancer Biotherapy Center, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, Yunnan, China
| | - Quan Gong
- Department of Rehabilitation and Palliative Medicine, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Number 519 Kunzhou Road, Kunming, 650118, Yunnan, China
| | - Xu-Dong Xiang
- Department of Thoracic Surgery, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, Yunnan, China
| | - Gang Guo
- Department of Thoracic Surgery, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, Yunnan, China
| | - Jia Liu
- Laboratory Zoology Department, Kunming Medical University, Kunming, 650500, Yunnan, China
| | - Li Zhao
- Department of Anesthesiology, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, Yunnan, China
| | - Jun Li
- Department of Rehabilitation and Palliative Medicine, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Number 519 Kunzhou Road, Kunming, 650118, Yunnan, China
| | - Nan Chen
- Department of Thoracic Surgery, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, Yunnan, China
| | - Heng Li
- Department of Thoracic Surgery, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, Yunnan, China
| | - Li-Juan Zhang
- Department of Rehabilitation and Palliative Medicine, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Number 519 Kunzhou Road, Kunming, 650118, Yunnan, China
| | - Chun-Yan Zhou
- Department of Rehabilitation and Palliative Medicine, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Number 519 Kunzhou Road, Kunming, 650118, Yunnan, China
| | - Zhi-Yong Wang
- Department of Rehabilitation and Palliative Medicine, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Number 519 Kunzhou Road, Kunming, 650118, Yunnan, China
| | - Li Zhuang
- Department of Rehabilitation and Palliative Medicine, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Number 519 Kunzhou Road, Kunming, 650118, Yunnan, China.
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Salazar A, Chavarria V, Flores I, Ruiz S, Pérez de la Cruz V, Sánchez-García FJ, Pineda B. Abscopal Effect, Extracellular Vesicles and Their Immunotherapeutic Potential in Cancer Treatment. Molecules 2023; 28:molecules28093816. [PMID: 37175226 PMCID: PMC10180522 DOI: 10.3390/molecules28093816] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
The communication between tumor cells and the microenvironment plays a fundamental role in the development, growth and further immune escape of the tumor. This communication is partially regulated by extracellular vesicles which can direct the behavior of surrounding cells. In recent years, it has been proposed that this feature could be applied as a potential treatment against cancer, since several studies have shown that tumors treated with radiotherapy can elicit a strong enough immune response to eliminate distant metastasis; this phenomenon is called the abscopal effect. The mechanism behind this effect may include the release of extracellular vesicles loaded with damage-associated molecular patterns and tumor-derived antigens which activates an antigen-specific immune response. This review will focus on the recent discoveries in cancer cell communications via extracellular vesicles and their implication in tumor development, as well as their potential use as an immunotherapeutic treatment against cancer.
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Affiliation(s)
- Aleli Salazar
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| | - Víctor Chavarria
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
- Immunoregulation Lab, Department of Immunology, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Itamar Flores
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| | - Samanta Ruiz
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| | - Verónica Pérez de la Cruz
- Neurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| | | | - Benjamin Pineda
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
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15
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Zhang Z, Shi S, Li J, Costa M. Long Non-Coding RNA MEG3 in Metal Carcinogenesis. TOXICS 2023; 11:toxics11020157. [PMID: 36851033 PMCID: PMC9962265 DOI: 10.3390/toxics11020157] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 01/31/2023] [Indexed: 06/06/2023]
Abstract
Most transcripts from human genomes are non-coding RNAs (ncRNAs) that are not translated into proteins. ncRNAs are divided into long (lncRNAs) and small non-coding RNAs (sncRNAs). LncRNAs regulate their target genes both transcriptionally and post-transcriptionally through interactions with proteins, RNAs, and DNAs. Maternally expressed gene 3 (MEG3), a lncRNA, functions as a tumor suppressor. MEG3 regulates cell proliferation, cell cycle, apoptosis, hypoxia, autophagy, and many other processes involved in tumor development. MEG3 is downregulated in various cancer cell lines and primary human cancers. Heavy metals, such as hexavalent chromium (Cr(VI)), arsenic, nickel, and cadmium, are confirmed human carcinogens. The exposure of cells to these metals causes a variety of cancers. Among them, lung cancer is the one that can be induced by exposure to all of these metals. In vitro studies have demonstrated that the chronic exposure of normal human bronchial epithelial cells (BEAS-2B) to these metals can cause malignant cell transformation. Metal-transformed cells have the capability to cause an increase in cell proliferation, resistance to apoptosis, elevated migration and invasion, and properties of cancer stem-like cells. Studies have revealed that MEG is downregulated in Cr(VI)-transformed cells, nickel-transformed cells, and cadmium (Cd)-transformed cells. The forced expression of MEG3 reduces the migration and invasion of Cr(VI)-transformed cells through the downregulation of the neuronal precursor of developmentally downregulated protein 9 (NEDD9). MEG3 suppresses the malignant cell transformation of nickel-transformed cells. The overexpression of MEG3 decreases Bcl-xL, causing reduced apoptosis resistance in Cd-transformed cells. This paper reviews the current knowledge of lncRNA MEG3 in metal carcinogenesis.
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16
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Upregulation LncRNA MEG3 expression suppresses proliferation and metastasis in melanoma via miR-208/SOX4. Mol Cell Biochem 2023; 478:407-414. [PMID: 35838912 DOI: 10.1007/s11010-022-04515-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 06/24/2022] [Indexed: 02/02/2023]
Abstract
Long non-coding RNAs (lncRNAs) regulate gene expression and play a significant role in cancer progression. Previously, downregulation of lncRNA MEG3 was shown to associate with poor clinical outcomes in melanoma patients. The basis for this association has not been described and the aims of this study were to identify a role for lncRNA MEG3 in melanoma and to describe its regulatory mechanism of action. RT-qPCR was used to detect lncRNA MEG3 expression in melanoma cells and tissues. Luciferase reporter assays were used to identify lncRNA MEG3 downstream targets. Melanoma cells were transfected with various expression vectors and these transfected cells were assessed for; migration, colony formation, proliferation, in vivo tumorigenesis, and metastatic potential. Melanoma cell lines were found to be sensitive to lncRNA MEG3 expression levels and overexpression was found to inhibit melanoma cell proliferation and invasion, both in vitro and in vivo. Luciferase reporter assays identified miR-208 and SOX4 as downstream targets of lncRNA MEG3. Overexpression of miR-208 and silencing of SOX4 rescued invasion and proliferation by cells that overexpressed lncRNA MEG3. Moreover, lncRNA MEG3 inhibited cancer stem cell differentiation and suppressed melanoma progression and metastasis through inhibition of miR-208 by SOX4.
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lncRNA MEG3 Promotes PDK4/GSK-3 β/ β-Catenin Axis in MEFs by Targeting miR-532-5p. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:3563663. [PMID: 36778210 PMCID: PMC9908332 DOI: 10.1155/2023/3563663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 05/16/2022] [Accepted: 09/26/2022] [Indexed: 02/04/2023]
Abstract
Studies reported the positive and negative osteogenic effects of MEG3 in mesenchymal stem cells (MSCs). This study aims at clarifying the osteogenic potential of MEG3 and the underlying mechanism. Bone morphogenetic protein 9- (BMP9-) transfected MSCs were recruited as an osteogenic model in vitro, and ectopic bone formation were used in vivo to explore the effect of MEG3 on osteogenesis. We found that overexpression of MEG3 facilitated BMP9-induced osteogenic markers, ALP activities, and matrix mineralization. However, knockdown of MEG3 attenuated BMP9-induced osteogenic markers. MEG3 increased the phosphorylation of GSK-3β and the protein level of β-catenin. Pyruvate dehydrogenase kinase 4 (PDK4) can also combine with GSK-3β and increase the latter phosphorylation. Moreover, MEG3 increased the mRNA level of PDK4. The ceRNA analysis showed that MEG3 may regulate the expression of PDK4 via microRNA 532-5p (miR-532-5p). The MEG3-enhanced GSK-3β/β-catenin axis can be attenuated by miR-532-5p, and miR-532-5p inhibitor partly rescued endogenous PDK4 and MEG3-mediated expression of PDK4. MEG3 may potentiate PDK4 and GSK-3β/β-catenin by inhibiting miR-532-5p.
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18
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Mangiavacchi A, Morelli G, Orlando V. Behind the scenes: How RNA orchestrates the epigenetic regulation of gene expression. Front Cell Dev Biol 2023; 11:1123975. [PMID: 36760365 PMCID: PMC9905133 DOI: 10.3389/fcell.2023.1123975] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/16/2023] [Indexed: 01/26/2023] Open
Abstract
Non-coding DNA accounts for approximately 98.5% of the human genome. Once labeled as "junk DNA", this portion of the genome has undergone a progressive re-evaluation and it is now clear that some of its transcriptional products, belonging to the non-coding RNAs (ncRNAs), are key players in cell regulatory networks. A growing body of evidence demonstrates the crucial impact of regulatory ncRNAs on mammalian gene expression. Here, we focus on the defined relationship between chromatin-interacting RNAs, particularly long non-coding RNA (lncRNA), enhancer RNA (eRNA), non-coding natural antisense transcript (ncNAT), and circular RNA (circRNA) and epigenome, a common ground where both protein and RNA species converge to regulate cellular functions. Through several examples, this review provides an overview of the variety of targets, interactors, and mechanisms involved in the RNA-mediated modulation of loci-specific epigenetic states, a fundamental evolutive strategy to orchestrate mammalian gene expression in a timely and reversible manner. We will discuss how RNA-mediated epigenetic regulation impacts development and tissue homeostasis and how its alteration contributes to the onset and progression of many different human diseases, particularly cancer.
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19
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Long Non-Coding RNAs as Novel Targets for Phytochemicals to Cease Cancer Metastasis. Molecules 2023; 28:molecules28030987. [PMID: 36770654 PMCID: PMC9921150 DOI: 10.3390/molecules28030987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/31/2022] [Accepted: 01/11/2023] [Indexed: 01/21/2023] Open
Abstract
Metastasis is a multi-step phenomenon during cancer development leading to the propagation of cancer cells to distant organ(s). According to estimations, metastasis results in over 90% of cancer-associated death around the globe. Long non-coding RNAs (LncRNAs) are a group of regulatory RNA molecules more than 200 base pairs in length. The main regulatory activity of these molecules is the modulation of gene expression. They have been reported to affect different stages of cancer development including proliferation, apoptosis, migration, invasion, and metastasis. An increasing number of medical data reports indicate the probable function of LncRNAs in the metastatic spread of different cancers. Phytochemical compounds, as the bioactive agents of plants, show several health benefits with a variety of biological activities. Several phytochemicals have been demonstrated to target LncRNAs to defeat cancer. This review article briefly describes the metastasis steps, summarizes data on some well-established LncRNAs with a role in metastasis, and identifies the phytochemicals with an ability to suppress cancer metastasis by targeting LncRNAs.
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20
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Sarfaraz N, Somarowthu S, Bouchard MJ. The interplay of long noncoding RNAs and hepatitis B virus. J Med Virol 2023; 95:e28058. [PMID: 35946066 DOI: 10.1002/jmv.28058] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/01/2022] [Accepted: 08/08/2022] [Indexed: 01/11/2023]
Abstract
Hepatitis B Virus (HBV) infections remain a major global health burden with an estimated 296 million people living with a chronic infection and 884,000 HBV-related deaths annually. Notably, patients with a chronic hepatitis B (CHB) infection are at a 30-fold greater risk of developing hepatocellular carcinoma (HCC), the most common type of primary liver cancer, which is the 3rd deadliest cancer worldwide. Several groups have assessed HBV-related aberrant expression of host-cell long noncoding RNAs (lncRNAs) and how altered expression of specific lncRNAs affects HBV replication and progression to associated disease states. Given the challenges in establishing effective HBV models and analyzing transcriptomic data, this review focuses on lncRNA expression data primarily collected from clinical patient samples and primary human hepatocytes, with the subsequent mechanism of action analysis in cell lines or other model systems. Ultimately, understanding HBV-induced lncRNA-expression dysregulation could lead to new treatments and biomarkers for HBV infection and its associated diseases.
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Affiliation(s)
- Nima Sarfaraz
- Graduate Program in Molecular and Cell Biology and Genetics, Graduate School of Biomedical Sciences and Professional Studies, College of Medicine, Drexel University, Philadelphia, Pennsylvania, USA
| | - Srinivas Somarowthu
- Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, Pennsylvania, USA
| | - Michael J Bouchard
- Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, Pennsylvania, USA
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21
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Nassar A, Kodi T, Satarker S, Chowdari Gurram P, Upadhya D, SM F, Mudgal J, Nampoothiri M. Astrocytic MicroRNAs and Transcription Factors in Alzheimer's Disease and Therapeutic Interventions. Cells 2022; 11:cells11244111. [PMID: 36552875 PMCID: PMC9776935 DOI: 10.3390/cells11244111] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes and neurodegeneration contribute to the altered morphology, gene expression, and function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain cholesterol levels as well as glutamatergic and inflammatory signaling, all of which contribute to general brain homeostasis. Neural electrical activity, synaptic plasticity processes, learning, and memory are dependent on the astrocyte-neuron crosstalk. Here, we review the involvement of astrocytic microRNAs that potentially regulate cholesterol metabolism, glutamate uptake, and inflammation in Alzheimer's disease (AD). The interaction between astrocytic microRNAs and long non-coding RNA and transcription factors specific to astrocytes also contributes to the pathogenesis of AD. Thus, astrocytic microRNAs arise as a promising target, as AD conditions are a worldwide public health problem. This review examines novel therapeutic strategies to target astrocyte dysfunction in AD, such as lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, and nanoparticles.
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Affiliation(s)
- Ajmal Nassar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Triveni Kodi
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Prasada Chowdari Gurram
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Dinesh Upadhya
- Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Fayaz SM
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
- Correspondence:
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22
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Xu J, Wang X, Zhu C, Wang K. A review of current evidence about lncRNA MEG3: A tumor suppressor in multiple cancers. Front Cell Dev Biol 2022; 10:997633. [PMID: 36544907 PMCID: PMC9760833 DOI: 10.3389/fcell.2022.997633] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) is a lncRNA located at the DLK1-MEG3 site of human chromosome 14q32.3. The expression of MEG3 in various tumors is substantially lower than that in normal adjacent tissues, and deletion of MEG3 expression is involved in the occurrence of many tumors. The high expression of MEG3 could inhibit the occurrence and development of tumors through several mechanisms, which has become a research hotspot in recent years. As a member of tumor suppressor lncRNAs, MEG3 is expected to be a new target for tumor diagnosis and treatment. This review discusses the molecular mechanisms of MEG3 in different tumors and future challenges for the diagnosis and treatment of cancers through MEG3.
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Affiliation(s)
- Jie Xu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chunming Zhu
- Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, China,*Correspondence: Chunming Zhu, ; Kefeng Wang,
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China,*Correspondence: Chunming Zhu, ; Kefeng Wang,
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23
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Sommerauer C, Kutter C. Noncoding RNAs in liver physiology and metabolic diseases. Am J Physiol Cell Physiol 2022; 323:C1003-C1017. [PMID: 35968891 DOI: 10.1152/ajpcell.00232.2022] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The liver holds central roles in detoxification, energy metabolism and whole-body homeostasis but can develop malignant phenotypes when being chronically overwhelmed with fatty acids and glucose. The global rise of metabolic-associated fatty liver disease (MAFLD) is already affecting a quarter of the global population. Pharmaceutical treatment options against different stages of MAFLD do not yet exist and several clinical trials against hepatic transcription factors and other proteins have failed. However, emerging roles of noncoding RNAs, including long (lncRNA) and short noncoding RNAs (sRNA), in various cellular processes pose exciting new avenues for treatment interventions. Actions of noncoding RNAs mostly rely on interactions with proteins, whereby the noncoding RNA fine-tunes protein function in a process termed riboregulation. The developmental stage-, disease stage- and cell type-specific nature of noncoding RNAs harbors enormous potential to precisely target certain cellular pathways in a spatio-temporally defined manner. Proteins interacting with RNAs can be categorized into canonical or non-canonical RNA binding proteins (RBPs) depending on the existence of classical RNA binding domains. Both, RNA- and RBP-centric methods have generated new knowledge of the RNA-RBP interface and added an additional regulatory layer. In this review, we summarize recent advances of how of RBP-lncRNA interactions and various sRNAs shape cellular physiology and the development of liver diseases such as MAFLD and hepatocellular carcinoma.
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Affiliation(s)
- Christian Sommerauer
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, grid.4714.6Karolinska Institute, Stockholm, Sweden
| | - Claudia Kutter
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, grid.4714.6Karolinska Institute, Stockholm, Sweden
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Zhang Y, Shi J, Luo J, Liu C, Zhu L. Regulatory mechanisms and potential medical applications of HNF1A-AS1 in cancers. Am J Transl Res 2022; 14:4154-4168. [PMID: 35836869 PMCID: PMC9274608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/18/2022] [Indexed: 06/15/2023]
Abstract
Long noncoding RNAs (lncRNAs) are defined as a class of non-protein-coding RNAs that are longer than 200 nucleotides. Previous studies have shown that lncRNAs play a vital role in the progression of multiple diseases, which highlights their potential for medical applications. The lncRNA hepatocyte nuclear factor 1 homeobox A (HNF1A) antisense RNA 1 (HNF1A-AS1) is known to be abnormally expressed in multiple cancers. HNF1A-AS1 exerts its oncogenic roles through a variety of molecular mechanisms. Moreover, aberrant HNF1A-AS1 expression is associated with diverse clinical features in cancer patients. Therefore, HNF1A-AS1 is a promising biomarker for tumor diagnosis and prognosis and thus a potential candidate for tumor therapy. This review summarizes current studies on the role and the underlying mechanisms of HNF1A-AS1 various cancer types, including gastric cancer, liver cancer, glioma, lung cancer, colorectal cancer, breast cancer, bladder cancer, osteosarcoma, esophageal adenocarcinoma, hemangioma, oral squamous cell carcinoma, laryngeal squamous cell carcinoma, cervical cancer, as well as gastroenteropancreatic neuroendocrine neoplasms. We also describe the diagnostic, prognostic, and therapeutic value of HNF1A-AS1 for multiple cancer patients.
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Affiliation(s)
- Yang Zhang
- Department of Geriatric Respiratory and Sleep, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Jiang Shi
- Department of Geriatric Respiratory and Sleep, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Junfang Luo
- Department of Geriatric Respiratory and Sleep, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Cong Liu
- Department of Geriatric Respiratory and Sleep, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Lixu Zhu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
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Alquraishi M, Chahed S, Alani D, Puckett DL, Dowker PD, Hubbard K, Zhao Y, Kim JY, Nodit L, Fatima H, Donohoe D, Voy B, Chowanadisai W, Bettaieb A. Podocyte specific deletion of PKM2 ameliorates LPS-induced podocyte injury through beta-catenin. Cell Commun Signal 2022; 20:76. [PMID: 35637461 PMCID: PMC9150347 DOI: 10.1186/s12964-022-00884-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 04/19/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is associated with a severe decline in kidney function caused by abnormalities within the podocytes' glomerular matrix. Recently, AKI has been linked to alterations in glycolysis and the activity of glycolytic enzymes, including pyruvate kinase M2 (PKM2). However, the contribution of this enzyme to AKI remains largely unexplored. METHODS Cre-loxP technology was used to examine the effects of PKM2 specific deletion in podocytes on the activation status of key signaling pathways involved in the pathophysiology of AKI by lipopolysaccharides (LPS). In addition, we used lentiviral shRNA to generate murine podocytes deficient in PKM2 and investigated the molecular mechanisms mediating PKM2 actions in vitro. RESULTS Specific PKM2 deletion in podocytes ameliorated LPS-induced protein excretion and alleviated LPS-induced alterations in blood urea nitrogen and serum albumin levels. In addition, PKM2 deletion in podocytes alleviated LPS-induced structural and morphological alterations to the tubules and to the brush borders. At the molecular level, PKM2 deficiency in podocytes suppressed LPS-induced inflammation and apoptosis. In vitro, PKM2 knockdown in murine podocytes diminished LPS-induced apoptosis. These effects were concomitant with a reduction in LPS-induced activation of β-catenin and the loss of Wilms' Tumor 1 (WT1) and nephrin. Notably, the overexpression of a constitutively active mutant of β-catenin abolished the protective effect of PKM2 knockdown. Conversely, PKM2 knockdown cells reconstituted with the phosphotyrosine binding-deficient PKM2 mutant (K433E) recapitulated the effect of PKM2 depletion on LPS-induced apoptosis, β-catenin activation, and reduction in WT1 expression. CONCLUSIONS Taken together, our data demonstrates that PKM2 plays a key role in podocyte injury and suggests that targetting PKM2 in podocytes could serve as a promising therapeutic strategy for AKI. TRIAL REGISTRATION Not applicable. Video abstract.
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Affiliation(s)
- Mohammed Alquraishi
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
- Present Address: Department of Community Health Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Samah Chahed
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
| | - Dina Alani
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
| | - Dexter L. Puckett
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
| | - Presley D. Dowker
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
| | - Katelin Hubbard
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
| | - Yi Zhao
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
- Present Address: Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105 USA
| | - Ji Yeon Kim
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
| | - Laurentia Nodit
- Department of Pathology, University of Tennessee Medical Center, Knoxville, TN 37920 USA
| | - Huma Fatima
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL USA
| | - Dallas Donohoe
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
| | - Brynn Voy
- Tennessee Agricultural Experiment Station, University of Tennessee Institute of Agriculture, Knoxville, TN 37996-0840 USA
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996-0840 USA
| | - Winyoo Chowanadisai
- Department of Nutrition, Oklahoma State University, Stillwater, OK 74078 USA
| | - Ahmed Bettaieb
- Department of Nutrition, The University of Tennessee Knoxville, 1215 Cumberland Avenue, 229 Jessie Harris Building, Knoxville, TN 37996-0840 USA
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996-0840 USA
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996-0840 USA
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Zhong C, Yao Q, Han J, Yang J, Jiang F, Zhang Q, Zhou H, Hu Y, Wang W, Zhang Y, Sun Y. SNP rs322931 (C>T) in miR-181b and rs7158663 (G>A) in MEG3 aggravate the inflammatory response of anal abscess in patients with Crohn's disease. Aging (Albany NY) 2022; 14:3313-3324. [PMID: 35422450 PMCID: PMC9037263 DOI: 10.18632/aging.204014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 11/23/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND The MEG3/miR-181b signaling has been implicated in the pathogenesis of several diseases including Crohn's disease. This work aimed to study the correlation between SNPs in MEG3/miR-181b and the severity of anal abscess in patients with Crohn's disease. METHODS Quantitative real-time PCR was performed to analyze the expression of MEG3 and miR-181b. ELISA was carried out to examine the expression of TNF-α, IL-1β, IL-6, CRP, SSA, AAT, AAG and HPT in the peripheral blood of patients with Crohn's disease. Luciferase assay was performed to explore the role of miR-181b in the expression of MEG3 and TNF-α. RESULTS The expression of MEG3 and miR-181b in the peripheral blood of patients with Crohn's disease was remarkably associated with the rs322931 and rs7158663 polymorphisms. rs322931 (C>T) in miR-181b and rs7158663 (G>A) in MEG3 significantly promoted the expression of TNF-α, IL-1β, IL-6, CRP, SSA, AAT, AAG and HPT. Luciferase assay demonstrated that miR-181b was capable of repressing the expression of MEG3 and TNF-α through binding to their specific binding sites. Moreover, alteration of MEG3 and miR-181b expression also showed a remarkable impact on the MEG3/miR-181b/TNF-α signaling pathway in THP-1 cells. CONCLUSIONS In conclusion, our study demonstrated that two SNPs, rs322931 (C>T) in miR-181b and rs7158663 (G>A) in MEG3, could aggravate the inflammatory response of anal abscess in patients with Crohn's disease via modulating the MEG3/miR-181b/TNF-α signaling pathway.
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Affiliation(s)
- Chaoxiang Zhong
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Qiuju Yao
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Jing Han
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Jie Yang
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Fei Jiang
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Qiong Zhang
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Haiyi Zhou
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Yuchao Hu
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Wei Wang
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Yan Zhang
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
| | - Ye Sun
- Anorectal, Shuyang County's Hospital of TCM, Shuyang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Shuyang 223600, Jiangsu, China
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Sasa GBK, Xuan C, Chen M, Jiang Z, Ding X. Clinicopathological implications of lncRNAs, immunotherapy and DNA methylation in lung squamous cell carcinoma: a narrative review. Transl Cancer Res 2022; 10:5406-5429. [PMID: 35116387 PMCID: PMC8799054 DOI: 10.21037/tcr-21-1607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/16/2021] [Indexed: 11/06/2022]
Abstract
Objective To explore the clinicopathological impact of lncRNAs, immunotherapy, and DNA methylation in lung squamous cell carcinoma (LUSC), emphasizing their exact roles in carcinogenesis and modes of action. Background LUSC is the second most prevalent form, accounting for around 30% of non-small cell lung cancer (NSCLC). To date, molecular-targeted treatments have significantly improved overall survival in lung adenocarcinoma patients but have had little effect on LUSC therapy. As a result, there is an urgent need to discover new treatments for LUSC that are based on existing genomic methods. Methods In this review, we summarized and analyzed recent research on the biological activities and processes of lncRNA, immunotherapy, and DNA methylation in the formation of LUSC. The relevant studies were retrieved using a thorough search of Pubmed, Web of Science, Science Direct, Google Scholar, and the university's online library, among other sources. Conclusions LncRNAs are the primary components of the mammalian transcriptome and are emerging as master regulators of a number of cellular processes, including the cell cycle, differentiation, apoptosis, and growth, and are implicated in the pathogenesis of a variety of cancers, including LUSC. Understanding their role in LUSC in detail may help develop innovative treatment methods and tactics for LUSC. Meanwhile, immunotherapy has transformed the LUSC treatment and is now considered the new standard of care. To get a better knowledge of LUSC biology, it is critical to develop superior modeling systems. Preclinical models, particularly those that resemble human illness by preserving the tumor immune environment, are essential for studying cancer progression and evaluating novel treatment targets. DNA methylation, similarly, is a component of epigenetic alterations that regulate cellular function and contribute to cancer development. By methylating the promoter regions of tumor suppressor genes, abnormal DNA methylation silences their expression. DNA methylation indicators are critical in the early detection of lung cancer, predicting therapy efficacy, and tracking treatment resistance. As such, this review seeks to explore the clinicopathological impact of lncRNAs, immunotherapy, and DNA methylation in LUSC, emphasizing their exact roles in carcinogenesis and modes of action.
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Affiliation(s)
- Gabriel B K Sasa
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Cheng Xuan
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Meiyue Chen
- The fourth affiliated hospital, Zhejiang University of Medicine, Hangzhou, China
| | - Zhenggang Jiang
- Department of Science Research and Information Management, Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, China
| | - Xianfeng Ding
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
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Huang X, Wu W, Jing D, Yang L, Guo H, Wang L, Zhang W, Pu F, Shao Z. Engineered exosome as targeted lncRNA MEG3 delivery vehicles for osteosarcoma therapy. J Control Release 2022; 343:107-117. [PMID: 35077741 DOI: 10.1016/j.jconrel.2022.01.026] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 12/27/2021] [Accepted: 01/18/2022] [Indexed: 12/18/2022]
Abstract
Exosomes as nanosized membrane vesicles, could targeted deliver therapeutic agents by modification with target ligands. Exosome-derived non-coding RNAs play a vital role in the development of tumors. Previous evidences reveal that long non-coding RNA maternally expressed gene 3 (lncRNA MEG3) has anti-tumor properties. Whereas, the inhibitory effects of exosome-derived lncRNA MEG3 in osteosarcoma (OS) remain largely unknown. In this study, we utilize the engineering technology to combine exosome and lncRNA for tumor-targeting therapy of OS. We elucidated the anti-OS effects of lncRNA MEG3, and then prepared the c(RGDyK)-modified and MEG3-loaded exosomes (cRGD-Exo-MEG3). The engineered exosomes cRGD-Exo-MEG3 could deliver more efficiently to OS cells both in vitro and in vivo. In this way, cRGD-Exo-MEG3 facilitate the anti-OS effects of MEG3 significantly, with the help of enhanced tumor-targeting therapy. This study elucidates that engineered exosomes as targeted lncRNA MEG3 delivery vehicles have potentially therapeutic effects for OS.
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Affiliation(s)
- Xin Huang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Wei Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Doudou Jing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lingkai Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Haoyu Guo
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lutong Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weiyue Zhang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Feifei Pu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Wang W, Yang T, Li D, Huang Y, Bai G, Li Q. LINC00491 promotes cell growth and metastasis through miR-324-5p/ROCK1 in liver cancer. J Transl Med 2021; 19:504. [PMID: 34876144 PMCID: PMC8650505 DOI: 10.1186/s12967-021-03139-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 11/07/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND LINC00491 was involved in some tumors development, but its function in liver cancer has not been reported. This study aimed to investigate LINC00491 expression and function in liver cancer progression. METHODS Sixty liver cancer cases were enrolled. LINC00491, miR-324-5p and rho-associated kinase 1 (ROCK1) expression in liver cancer patients and cells were detected by quantitative reverse transcription-polymerase chain reaction and Western blot. HUH-7 and SK-Hep-1 cells were transfected to modulate LINC00491, miR-324-5p and ROCK1 expression. Cell counting kit-8 assay, colony formation assay, wound healing assay, Transwell experiment, Tunel assay and flow cytometry were performed to detected HUH-7 and SK-Hep-1 cells proliferation, migration, invasion, apoptosis and cell cycle. Biotin-RNA pull-down assay and Dual-Luciferase Reporter Assay was performed to detect the binding among LINC00491, miR-324-5p and ROCK1. Xenograft tumor and lung metastasis was performed using nude mice. Xenograft tumor and lung tissues of mice were experienced immunohistochemistry and hematoxylin-eosin staining. RESULTS LINC00491 was highly expressed in liver cancer cases, associating with poor prognosis. si-LINC00491 inhibited proliferation, colony formation, invasion, migration, and induced cell cycle G1 arrest and apoptosis in HUH-7 and SK-Hep-1 cells. LINC00491 overexpression showed opposite effects. LINC00491 promoted ROCK1 expression by reducing miR-324-5p. miR-324-5p up-regulation or ROCK1 knockdown reversed LINC00491 promotion on liver SK-Hep-1 cells malignant phenotype. LINC00491 facilitated xenograft tumor growth and lung metastasis in mice. CONCLUSION LINC00491 was highly expressed in liver cancer patients, associating with poor prognosis. LINC00491 facilitated liver cancer progression by sponging miR-324-5p/ROCK1. LINC00491 might be a potential treatment target of liver cancer.
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Affiliation(s)
- Wei Wang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China
| | - Tao Yang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China
| | - Dongsheng Li
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China
| | - Yinpeng Huang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China
| | - Guang Bai
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China
| | - Qing Li
- Department of Nephrology, The Third Affiliated Hospital of Jinzhou Medical University, No. 2 Section 5 Heping Road, Jinzhou, 121000, China.
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Liu J, Zhi Q, Liu Y, Wang Y, Chen L, Ke Y, Zeng L, Wu X, Yang X, Guleng B, Liu H, Ren J. Insulin promotes hepatocarcinoma tumorigenesis by up-regulating PKM2 expression. Exp Cell Res 2021; 408:112872. [PMID: 34648844 DOI: 10.1016/j.yexcr.2021.112872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/02/2021] [Accepted: 10/05/2021] [Indexed: 11/22/2022]
Abstract
Insulin, as a growth factor, can increase the risk of certain types of cancer. The present study showed that insulin promoted the proliferation of hepatocellular carcinoma cells in vitro and in vivo through pyruvate kinase M2 (PKM2), which is a rate-limiting enzyme in the process of glycolysis. Moreover, the expression of PKM2 was up-regulated by insulin at the posttranslational level in a nuclear orphan receptor TR3-dependent manner. In addition, insulin could enhance the interaction between PKM2 and TR3 and protect PKM2 from degradation. Our results identified a specific mechanism of insulin affecting cancer metabolism and thus promoting cancer progression, and they contribute to a better understanding of the observation that insulin is linked to an increased cancer risk under hyperinsulinemic conditions.
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Affiliation(s)
- Jingjing Liu
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China; Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China.
| | - Qiang Zhi
- Faculty of Clinical Medicine, School of Medicine, Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China
| | - Yunpeng Liu
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China; Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China
| | - Ying Wang
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China
| | - Linlin Chen
- Faculty of Clinical Medicine, School of Medicine, Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China
| | - Yuhao Ke
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China
| | - Lingsu Zeng
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China
| | - Xiaoling Wu
- Faculty of Clinical Medicine, School of Medicine, Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China
| | - Xiaoning Yang
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China; Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China
| | - Bayasi Guleng
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China; Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China; Faculty of Clinical Medicine, School of Medicine, Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China; Faculty of Clinical Medicine & Institute of Mirobial Ecology, Medical College of Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China; Department of Digestive Disease, School of Medicine, Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China
| | - Hao Liu
- General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, PR China
| | - Jianlin Ren
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China; Xiamen Key Laboratory of Intestinal Microbiome and Human Health, Zhongshan Hospital Affiliated to Xiamen University, 201 Hubin South Road, Xiamen, 361004, Fujian Province, PR China; Faculty of Clinical Medicine, School of Medicine, Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China; Faculty of Clinical Medicine & Institute of Mirobial Ecology, Medical College of Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China; Department of Digestive Disease, School of Medicine, Xiamen University, 168 University Road, Xiamen, 361005, Fujian Province, PR China.
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Huang X, Zhang W, Pu F, Zhang Z. LncRNA MEG3 promotes chemosensitivity of osteosarcoma by regulating antitumor immunity via miR-21-5p/p53 pathway and autophagy. Genes Dis 2021; 10:531-541. [DOI: 10.1016/j.gendis.2021.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 10/12/2021] [Accepted: 11/07/2021] [Indexed: 12/01/2022] Open
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Chen J, LaGue E, Li J, Yang C, Hackett EP, Mendoza M, Alger JR, DeBerardinis RJ, Corbin IR, Billingsley KL, Park JM. Profiling Carbohydrate Metabolism in Liver and Hepatocellular Carcinoma with [ 13C]-Glycerate Probes. ANALYSIS & SENSING 2021; 1:196-202. [PMID: 35693130 PMCID: PMC9187054 DOI: 10.1002/anse.202100034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
The interplay between glycolysis and gluconeogenesis is central to carbohydrate metabolism. Here, we describe novel methods to assess carbohydrate metabolism using [13C]-probes derived from glycerate, a molecule whose metabolic fate in mammals remains underexplored. Isotope-based studies were conducted via NMR and mass spectrometry analyses of freeze-clamped liver tissue extracts after [2,3-13C2]glycerate infusion. The ex vivo investigations were correlated with in vivo measurements using hyperpolarized [1-13C]glycerate. Application of [13C]glycerate to N-nitrosodiethylamine (DEN)-treated rats provided further assessments of intermediary carbohydrate metabolism in hepatocellular carcinoma. This method afforded direct analyses of control versus DEN tissues, and altered ratios of 13C metabolic products as well as unique glycolysis intermediates were observed in the DEN liver/tumor. Isotopomer studies showed increased glycerate uptake and altered carbohydrate metabolism in the DEN rats.
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Affiliation(s)
- Jun Chen
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8568 (USA)
| | - Evan LaGue
- Department of Chemistry and Biochemistry, California State University, Fullerton, 800 State College Blvd. Fullerton, CA 92834-6866 (USA)
| | - Junjie Li
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8568 (USA)
| | - Chendong Yang
- Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8502 (USA)
| | - Edward P Hackett
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8568 (USA)
| | - Manuel Mendoza
- Department of Chemistry and Biochemistry, California State University, Fullerton, 800 State College Blvd. Fullerton, CA 92834-6866 (USA)
| | - Jeffry R Alger
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8568 (USA)
| | - Ralph J DeBerardinis
- Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8502 (USA)
| | - Ian R Corbin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8568 (USA)
| | - Kelvin L Billingsley
- Department of Chemistry and Biochemistry, California State University, Fullerton, 800 State College Blvd. Fullerton, CA 92834-6866 (USA)
| | - Jae Mo Park
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8568 (USA)
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Luo Y, Lin J, Zhang J, Song Z, Zheng D, Chen F, Zhuang X, Li A, Liu X. LncRNA SNHG17 Contributes to Proliferation, Migration, and Poor Prognosis of Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2021; 2021:9990338. [PMID: 34557456 PMCID: PMC8455207 DOI: 10.1155/2021/9990338] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 08/22/2021] [Accepted: 08/27/2021] [Indexed: 01/20/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been substantially reported to have critical roles in regulating tumorigenesis in recent years. However, the expression pattern and biological function of SNHG17 in hepatocellular carcinoma (HCC) remain unclear. Bioinformatics analysis and qRT-PCR were performed to detect the expression pattern of SNHG17 in HCC tissues, adjacent nontumorous tissues, and cell lines. The effect of SNHG17 on proliferation, migration, and apoptosis of HCC was investigated by knockdown and overexpressing SNHG17 in HCC cell lines. RNA sequencing was utilized to explore the underlying mechanism. Utilizing publicly available TCGA-LIHC, GSE102079 HCC datasets, and qRT-PCR, we found SNHG17 was significantly upregulated in HCC tissues and cell lines and was notably associated with larger tumor size, poorly differentiation, presence of vascular invasion, and advanced TNM stage. Furthermore, gain- and loss-of-function studies demonstrated that SNHG17 promoted cell proliferation and migration and inhibited apoptosis of HCC. By employing RNA sequencing, we found knockdown of SNHG17 caused 1037 differentially expressed genes, highly enriched in several pathways, including metabolic, PI3K-Akt, cell adhesion, regulation of cell proliferation, and apoptotic pathway; among them, 92 were overlapped with SNHG17-related genes in the TCGA-LIHC dataset. Furthermore, ERH, TBCA, TDO2, and PDK4 were successfully validated and found significantly dysregulated in HCC tissues. Moreover, HCC patients with higher SNHG17 expression had a relatively poor overall survival and disease-free survival, and ERH and PDK4 also played a marked role in the prognosis of HCC. Broadly, our findings illustrate that SNHG17 acts as a noncoding oncogene in HCC progression, suggesting its potential value as a novel target for HCC therapy.
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Affiliation(s)
- Yue Luo
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Junhao Lin
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Jiakang Zhang
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Zhenghui Song
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Dayong Zheng
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Fengsheng Chen
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Xuefen Zhuang
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Aimin Li
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Xinhui Liu
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
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Chhipa AS, Patel S. Targeting pyruvate kinase muscle isoform 2 (PKM2) in cancer: What do we know so far? Life Sci 2021; 280:119694. [PMID: 34102192 DOI: 10.1016/j.lfs.2021.119694] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 04/29/2021] [Accepted: 05/28/2021] [Indexed: 12/24/2022]
Abstract
Cancer is a leading cause of death globally. Cancer cell transformation is the result of intricate crosstalk between intracellular components and proteins. A characteristic feature of cancer cells is the ability to reprogram their metabolic pathways to ensure their infinite proliferative potential. Pyruvate kinase muscle isoform 2 (PKM2) is a glycolytic enzyme that plays crucial roles in cancer, apart from carrying out its metabolic roles. PKM2 is involved in all the major events associated with cancer growth. Modulation of PKM2 activity (dimer inhibition or tetramer activation) has been successful in controlling cancer. However, recent studies provide contrary evidences regarding the oncogenic functions of PKM2. Moreover, several studies have highlighted the cancerous roles of PKM1 isoform in certain contexts. The present review aims at providing the current updates regarding PKM2 targeting in cancer. Further, the review discusses the contradictory results that suggest that both the isoforms of PKM can lead to cancer growth. In conclusion, the review emphasizes revisiting the approaches to target cancer metabolism through PKM to find novel and effective targets for anticancer therapy.
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Affiliation(s)
| | - Snehal Patel
- Department of Pharmacology, Nirma University, Ahmedabad, Gujarat, India.
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35
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Huang P, Zhu S, Liang X, Zhang Q, Liu C, Song L. Revisiting Lung Cancer Metastasis: Insight From the Functions of Long Non-coding RNAs. Technol Cancer Res Treat 2021; 20:15330338211038488. [PMID: 34431723 PMCID: PMC8392855 DOI: 10.1177/15330338211038488] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Globally, lung cancer is the most common cause of cancer-related deaths. After
diagnosis at all stages, <7% of patients survive for 10 years. Thus,
diagnosis at later stages and the lack of effective and personalized drugs
reflect a significant need to better understand the mechanisms underpinning lung
cancer progression. Metastasis should be responsible for the high lethality and
recurrence rates seen in lung cancer. Metastasis depends on multiple crucial
steps, including epithelial–mesenchymal transition, vascular remodeling, and
colonization. Therefore, in-depth investigations of metastatic molecular
mechanisms can provide valuable insights for lung cancer treatment. Recently,
long noncoding RNAs (lncRNAs) have attracted considerable attention owing to
their complex roles in cancer progression. In lung cancer, multiple lncRNAs have
been reported to regulate metastasis. In this review, we highlight the major
molecular mechanisms underlying lncRNA-mediated regulation of lung cancer
metastasis, including (1) lncRNAs acting as competing endogenous RNAs, (2)
lncRNAs regulating the transduction of several signal pathways, and (3) lncRNA
coordination with enhancer of zeste homolog 2. Thus, lncRNAs appear to execute
their functions on lung cancer metastasis by regulating angiogenesis, autophagy,
aerobic glycolysis, and immune escape. However, more comprehensive studies are
required to characterize these lncRNA regulatory networks in lung cancer
metastasis, which can provide promising and innovative novel therapeutic
strategies to combat this disease.
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Affiliation(s)
- Peng Huang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Shaomi Zhu
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Xin Liang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Qinxiu Zhang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Chi Liu
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
| | - Linjiang Song
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China
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Role of Long Non-Coding RNAs in Pulmonary Arterial Hypertension. Cells 2021; 10:cells10081892. [PMID: 34440661 PMCID: PMC8394897 DOI: 10.3390/cells10081892] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/21/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a debilitating condition of the pulmonary circulatory system that occurs in patients of all ages and if untreated, eventually leads to right heart failure and death. Despite existing medical treatment options that improve survival and quality of life, the disease remains incurable. Thus, there is an urgent need to develop novel therapies to treat this disease. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in pulmonary vascular remodeling and PAH. LncRNAs are implicated in pulmonary arterial endothelial dysfunction by modulating endothelial cell proliferation, angiogenesis, endothelial mesenchymal transition, and metabolism. LncRNAs are also involved in inducing different pulmonary arterial vascular smooth muscle cell phenotypes, such as cell proliferation, apoptosis, migration, regulation of the phenotypic switching, and cell cycle. LncRNAs are essential regulators of gene expression that affect various diseases at the chromatin, transcriptional, post-translational, and even post-translational levels. Here, we focus on the role of LncRNAs and their molecular mechanisms in the pathogenesis of PAH. We also discuss the current research challenge and potential biomarker and therapeutic potentials of lncRNAs in PAH.
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Xu X, Zhong Z, Shao Y, Yi Y. Prognostic Value of MEG3 and Its Correlation With Immune Infiltrates in Gliomas. Front Genet 2021; 12:679097. [PMID: 34220951 PMCID: PMC8242350 DOI: 10.3389/fgene.2021.679097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/10/2021] [Indexed: 12/24/2022] Open
Abstract
Accumulating evidence has revealed that dysregulated lncRNA expression contributes to the onset and progression of cancer. However, the mechanistic role of lncRNA in glioma progression and tumor immunology remains largely unknown. This study aimed to evaluate the significance of maternally expressed gene 3 (MEG3) in the prognosis of and its immune-related roles in gliomas. The expression levels of MEG3 were analyzed using Oncomine and TIMER database. As an important imprinted gene, the copy number variation (CNV) of MEG3 in both glioblastoma multiforme (GBM) and low-grade glioma (LGG) were analyzed using GSCALite database, whereas its prognostic significance was assessed using PrognoScan and GEPIA databases. The relationship between MEG3 and tumor-infiltrated immune cells was analyzed using TIMER. Results showed that MEG3 expression was lower in most of the human cancer tissues than in the normal tissues. We also found that heterozygous deletion of MEG3 occurred more frequent than heterozygous amplification in gliomas, and mRNA expression of MEG3 was significantly positively correlated with its CNV in both the GBM and LGG group. Survival analysis showed that the CNV level of MEG3 had significant correlation with overall survival (OS) and progression-free survival (PFS) compared with wild type in LGG. Lower MEG3 expression was related with poor prognosis. Further analysis showed that in GBM, MEG3 expression level was significantly positively correlated with that of infiltrating CD8+ T cells and significantly negatively correlated with that of infiltrating dendritic cells. In LGG, MEG3 expression level was significantly negatively correlated with levels of infiltrating B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Univariate Cox survival analysis demonstrated that only the level of infiltrating dendritic cells significantly affected the survival time of patients with GBM, while all six types of immune cells had a significant effect on the survival time of patients with LGG. Furthermore, MEG3 expression showed strong correlations with multiple immune markers in gliomas, especially in LGG. The current findings suggest that MEG3 expression might serve as a possible prognostic marker and potential immunotherapeutic target for gliomas.
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Affiliation(s)
- Xiaoping Xu
- Department of Neurosurgery, The Second People's Hospital of Yibin, Yibin, China
| | - Zhenglan Zhong
- Department of Health Examination, The Second People's Hospital of Yibin, Yibin, China
| | - Yongxiang Shao
- Department of Neurosurgery, The Second People's Hospital of Yibin, Yibin, China
| | - Yong Yi
- Department of Neurosurgery, The Second People's Hospital of Yibin, Yibin, China
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38
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Tetraarsenic oxide affects non-coding RNA transcriptome through deregulating polycomb complexes in MCF7 cells. Adv Biol Regul 2021; 80:100809. [PMID: 33932728 DOI: 10.1016/j.jbior.2021.100809] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/30/2021] [Accepted: 04/08/2021] [Indexed: 11/23/2022]
Abstract
Non-coding RNAs (ncRNAs) play important and diverse roles in mammalian cell biology and pathology. Although the functions of an increasing number of ncRNAs have been identified, the mechanisms underlying ncRNA gene expression remain elusive and are incompletely understood. Here, we investigated ncRNA gene expression in Michigan cancer foundation 7 (MCF7), a malignant breast cancer cell line, on treatment of tetraarsenic oxide (TAO), a potential anti-cancer drug. Our genomic analyses found that TAO up- or down-regulated ncRNA genes genome-wide. A subset of identified ncRNAs with critical biological and clinical functions were validated by real-time quantitative polymerase chain reaction. Intriguingly, these TAO-regulated genes included CDKN2B-AS, HOXA11-AS, SHH, and DUSP5 that are known to interact with or be targeted by polycomb repressive complexes (PRCs). In addition, the PRC subunits were enriched in these TAO-regulated ncRNA genes and TAO treatment deregulated the expression of PRC subunits. Strikingly, TAO decreased the cellular and gene-specific levels of EZH2 expression and H3K27me3. In particular, TAO reduced EZH2 and H3K27me3 and increased transcription at MALAT1 gene. Inhibiting the catalytic activity of EZH2 using GSK343 increased representative TAO-inducible ncRNA genes. Together, our findings suggest that the expression of a subset of ncRNA genes is regulated by PRC2 and that TAO could be a potent epigenetic regulator through PRCs to modulate the ncRNA gene expression in MCF7 cells.
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Zhu S, Guo Y, Zhang X, Liu H, Yin M, Chen X, Peng C. Pyruvate kinase M2 (PKM2) in cancer and cancer therapeutics. Cancer Lett 2021; 503:240-248. [PMID: 33246091 DOI: 10.1016/j.canlet.2020.11.018] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 10/12/2020] [Accepted: 11/15/2020] [Indexed: 02/07/2023]
Abstract
Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme of glycolysis, is a critical regulator in tumor metabolism. PKM2 has been demonstrated to overexpressed in various cancers and promoted proliferation and metastasis of tumor cells. The errant expression of PKM2 has inspired people to investigate the function of PKM2 and the therapeutic potential in cancer. In addition, some studies have shown that the upregulation of PKM2 in tumor tissues is associated with the altered expression of lncRNAs and the poor survival. Therefore, researchers have begun to unravel the specific molecular mechanisms of lncRNA-mediated PKM2 expression in cancer metabolism. As the tumor microenvironment (TME) is essential in tumor development, it is necessary to identify the role of PKM2 in TME. In this review, we will introduce the role of PKM2 in different cancers as well as TME, and summarize the molecular mechanism of PKM2-related lncRNAs in cancer metabolism. We expect that this work will lead to a better understanding of the molecular mechanisms of PKM2 that may help in developing therapeutic strategies in clinic for researchers.
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Affiliation(s)
- Susi Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, China; Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, Hunan, China; Research Center of Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yeye Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, China; Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, Hunan, China; Research Center of Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xu Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, China; Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, Hunan, China; Research Center of Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hong Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, China; Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, Hunan, China; Research Center of Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mingzhu Yin
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, China; Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, Hunan, China; Research Center of Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, China; Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, Hunan, China; Research Center of Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, China; Xiangya Clinical Research Center for Cancer Immunotherapy, Central South University, Changsha, Hunan, China; Research Center of Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Gao W. Long non-coding RNA MEG3 as a candidate prognostic factor for induction therapy response and survival profile in childhood acute lymphoblastic leukemia patients. Scand J Clin Lab Invest 2021; 81:194-200. [PMID: 33600264 DOI: 10.1080/00365513.2021.1881998] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Childhood acute lymphoblastic leukemia (cALL) is a common hematological malignancy in children with unfavorable prognosis. Identifying novel prognostic factors is critical to optimize personalized treatment and improve their long-term outcomes. Thus, this study aimed to explore the correlation of longitudinal change of long non-coding RNA maternally expressed gene 3 (lnc-MEG3) with induction therapy response and survival profile in cALL patients. Totally 117 cALL patients and 50 pediatric patients (as controls) were recruited. Their lnc-MEG3 expressions from bone marrow mononuclear cells were detected by reverse transcription-quantitative polymerase chain reaction (before induction treatment and at day 15 after induction treatment). For their survival profile, the event-free survival (EFS) and overall survival (OS) were analyzed using follow-up data. Lnc-MEG3 expression was decreased in cALL patients (vs. controls) (p < .001). Meanwhile, higher baseline lnc-MEG3 expression was correlated with good prednisone response at day 8 (p = .001) and good bone marrow response at day 15 (p = .046) in cALL patients. However, no correlation of baseline lnc-MEG3 expression with immunophenotype (p = .088), or risk stratification (p = .155) in cALL patients was found. Notably, lnc-MEG3 expression was elevated during induction therapy (p < .001). Furthermore, lnc-MEG3 expression at day 15 was associated with good bone marrow response (p = .001) and its increment was also correlated with good bone marrow response (p = .022). More importantly, high lnc-MEG3 expression at baseline and day 15 were associated with prolonged EFS (both p < .05) and OS (both p < .05) in cALL patients. Lnc-MEG3 may serve as a prognostic factor for induction therapy response and survival profile in cALL patients.
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Affiliation(s)
- Wenjin Gao
- Department of Hematology/Oncology, Xi'an Children's Hospital, Xi'an, China
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41
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Gao L, Shao T, Zheng W, Ding J. Curcumin suppresses tumor growth of gemcitabine-resistant non-small cell lung cancer by regulating lncRNA-MEG3 and PTEN signaling. Clin Transl Oncol 2021; 23:1386-1393. [PMID: 33566305 DOI: 10.1007/s12094-020-02531-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Lung cancer is one of the most aggressive malignancies and the efficacy of chemotherapy or concurrent chemoradiation is limited in clinical application. Curcumin has been reported to block cancer development by modulating multiple signaling pathways. However, whether curcumin can inhibit gemcitabine-resistant non-small cell lung cancer through regulation of lncRNA and the involved molecular mechanisms are rarely reported. MATERIALS AND METHODS MTT assay, clonogenic assay, apoptosis assay, qRT-PCR, Western blotting, immunohistochemistry, xenograft experiment were carried out in the present study. RESULTS The results showed that curcumin suppressed gemcitabine-resistant non-small cell lung cancer cell proliferation and induced apoptosis. Curcumin upregulated the expression of lncRNA-MEG3 and PTEN, and MEG3 overexpression could increase the level of PTEN expression, while MEG3 knockdown decreased the level of PTEN expression in gemcitabine-resistant non-small cell lung cancer cells. Curcumin treatment failed to inhibit the proliferation and induce apoptosis in MEG3 knockdown or PTEN knockdown cells. CONCLUSIONS These findings show the antitumor activity of curcumin for potential clinical application in gemcitabine-resistant non-small cell lung cancer treatment.
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Affiliation(s)
- L Gao
- Department of Integrated Traditional Chinese and Western Medicine, First Ward of Oncology, Hangzhou Cancer Hospital, No.34 Yanguan Street, Hangzhou, Zhejiang, 310000, People's Republic of China
| | - T Shao
- Department of Integrated Traditional Chinese and Western Medicine, First Ward of Oncology, Hangzhou Cancer Hospital, No.34 Yanguan Street, Hangzhou, Zhejiang, 310000, People's Republic of China
| | - W Zheng
- Department of Integrated Traditional Chinese and Western Medicine, First Ward of Oncology, Hangzhou Cancer Hospital, No.34 Yanguan Street, Hangzhou, Zhejiang, 310000, People's Republic of China
| | - J Ding
- Department of Integrated Traditional Chinese and Western Medicine, First Ward of Oncology, Hangzhou Cancer Hospital, No.34 Yanguan Street, Hangzhou, Zhejiang, 310000, People's Republic of China.
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42
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Liu M, Chen L, Wu J, Lin Z, Huang S. Long noncoding RNA MEG3 expressed in human dental pulp regulates LPS-Induced inflammation and odontogenic differentiation in pulpitis. Exp Cell Res 2021; 400:112495. [PMID: 33524362 DOI: 10.1016/j.yexcr.2021.112495] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 01/16/2021] [Indexed: 12/19/2022]
Abstract
Pulpitis refers to inflammation of the inner pulp by invading microbes, and tissue repair occurs due to odontogenic differentiation of human dental pulp cells (hDPCs) with multidifferentiation potential. Long noncoding RNAs (lncRNAs) can modulate numerous pathological and biological processes; however, the role of lncRNAs in the inflammation and regeneration of the dentin-pulp complex in pulpitis is unclear. Here, we performed high-throughput sequencing to identify differentially expressed lncRNAs between human normal and inflamed pulp and concluded that lncMEG3 (lncRNA maternally expressed gene 3, MEG3) was significantly upregulated in both inflamed pulp and LPS-treated hDPCs. MEG3 expression in the pulp tissue was detected using the RNAscope® technique. RNA pulldown assays identified the MEG3-interacting proteins and the potential mechanisms. With MEG3 knockdown, we investigated the role of MEG3 in the secretion of inflammatory cytokines in LPS-treated hDPCs and odontogenic differentiation of hDPCs. MEG3 downregulation inhibited the secretion of TNF-α, IL-1β and IL-6 in LPS-treated hDPCs, and the p38/MAPK signaling pathway may be related to this effect. MEG3 knockdown promoted odontogenic differentiation of hDPCs by regulating the Wnt/β-catenin signaling pathway. Our study suggested that MEG3 has a negative effect on inflammation and regeneration of the dentin-pulp complex in pulpitis.
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Affiliation(s)
- Minxia Liu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou, 510055, China.
| | - Lingling Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou, 510055, China.
| | - Jinyan Wu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou, 510055, China.
| | - Zhengmei Lin
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou, 510055, China.
| | - Shuheng Huang
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou, 510055, China.
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Puckett DL, Alquraishi M, Chowanadisai W, Bettaieb A. The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs. Int J Mol Sci 2021; 22:1171. [PMID: 33503959 PMCID: PMC7865720 DOI: 10.3390/ijms22031171] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 01/17/2023] Open
Abstract
Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.
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Affiliation(s)
- Dexter L. Puckett
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996, USA; (D.L.P.); (M.A.)
| | - Mohammed Alquraishi
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996, USA; (D.L.P.); (M.A.)
| | - Winyoo Chowanadisai
- Department of Nutrition, Oklahoma State University, Stillwater, OK 74078, USA;
| | - Ahmed Bettaieb
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996, USA; (D.L.P.); (M.A.)
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Lee HY, Son SW, Moeng S, Choi SY, Park JK. The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer. Int J Mol Sci 2021; 22:ijms22020627. [PMID: 33435156 PMCID: PMC7827914 DOI: 10.3390/ijms22020627] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/02/2021] [Accepted: 01/06/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer is a global health concern, and the prognosis of patients with cancer is associated with metastasis. Multistep processes are involved in cancer metastasis. Accumulating evidence has shown that cancer cells acquire the capacity of anoikis resistance and anchorage-independent cell growth, which are critical prerequisite features of metastatic cancer cells. Multiple cellular factors and events, such as apoptosis, survival factors, cell cycle, EMT, stemness, autophagy, and integrins influence the anoikis resistance and anchorage-independent cell growth in cancer. Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are dysregulated in cancer. They regulate cellular signaling pathways and events, eventually contributing to cancer aggressiveness. This review presents the role of miRNAs and lncRNAs in modulating anoikis resistance and anchorage-independent cell growth. We also discuss the feasibility of ncRNA-based therapy and the natural features of ncRNAs that need to be contemplated for more beneficial therapeutic strategies against cancer.
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Lei GL, Fan HX, Wang C, Niu Y, Li TL, Yu LX, Hong ZX, Yan J, Wang XL, Zhang SG, Ren MJ, Yang PH. Long non-coding ribonucleic acid W5 inhibits progression and predicts favorable prognosis in hepatocellular carcinoma. World J Gastroenterol 2021; 27:55-68. [PMID: 33505150 PMCID: PMC7789065 DOI: 10.3748/wjg.v27.i1.55] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/27/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Accumulating evidence has revealed that several long non-coding ribonucleic acids (lncRNAs) are crucial in the progress of hepatocellular carcinoma (HCC). AIM To classify a long non-coding RNA, i.e., lncRNA W5, and to determine the clinical significance and potential roles of lncRNA W5 in HCC. METHODS The results showed that lncRNA W5 expression was significantly downregulated in HCC cell lines and tissues. Analysis of the association between lncRNA W5 expression levels and clinicopathological features suggested that low lncRNA W5 expression was related to large tumor size (P < 0.01), poor histological grade (P < 0.05) and serious portal vein tumor thrombosis (P < 0.05). Furthermore, Kaplan-Meier survival analysis showed that low expression of lncRNA W5 predicts poor overall survival (P = 0.016). RESULTS Gain-of-loss function experiments, including cell counting kit8 assays, colony formation assays, and transwell assays, were performed in vitro to investigate the biological roles of lncRNA W5. In vitro experiments showed that ectopic overexpression of lncRNA W5 suppressed HCC cell proliferation, migration and invasion; conversely, silencing of lncRNA W5 promoted cell proliferation, migration and invasion. In addition, acting as a tumor suppressor gene in HCC, lncRNA W5 inhibited the growth of HCC xenograft tumors in vivo. CONCLUSION These results showed that lncRNA W5 is down-regulated in HCC, and it may suppress HCC progression and predict poor clinical outcomes in patients with HCC. LncRNA W5 may serve as a potential HCC prognostic biomarker in addition to a therapeutic target.
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Affiliation(s)
- Guang-Lin Lei
- Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Hong-Xia Fan
- Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, Inner Mongolia, China
| | - Cheng Wang
- First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Yan Niu
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, Inner Mongolia, China
| | - Tie-Ling Li
- First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Ling-Xiang Yu
- Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Zhi-Xian Hong
- Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jin Yan
- Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Xi-Liang Wang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
| | - Shao-Geng Zhang
- Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ming-Ji Ren
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, Inner Mongolia, China
| | - Peng-Hui Yang
- Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
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Karimzadeh MR, Seyedtaghia MR, Soudyab M, Nezamnia M, Kidde J, Sahebkar A. Exosomal Long Noncoding RNAs: Insights into Emerging Diagnostic and Therapeutic Applications in Lung Cancer. JOURNAL OF ONCOLOGY 2020; 2020:7630197. [PMID: 33224198 PMCID: PMC7671817 DOI: 10.1155/2020/7630197] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 10/20/2020] [Accepted: 10/25/2020] [Indexed: 12/24/2022]
Abstract
Lung cancer is the most common cause of cancer-related deaths worldwide. Annually, millions of people die from lung cancer because of late detection and ineffective therapies. Recently, exosomes have been introduced as new therapeutic players with the potential to improve upon current diagnostic and treatment options. Exosomes are small membranous vesicles produced during endosomal merging. This allows for cell packaging of nucleic acids, proteins, and lipids and transfer to adjacent or distant cells. While exosomes are a part of normal intercellular signaling, they also allow malignant cells to transfer oncogenic material leading to tumor spread and metastasis. Exosomes are an interesting field of discovery for biomarkers and therapeutic targets. Among exosomal materials, lncRNAs have priority; lncRNAs are a class of noncoding RNAs longer than 200 base pairs. In the case of cancer, primary interest regards their oncogene and tumor suppressor functions. In this review, the advantages of exosomal lncRNAs as biomarkers and therapeutic targets will be discussed in addition to reviewing studies of their application in lung cancer.
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Affiliation(s)
- Mohammad Reza Karimzadeh
- Department of Medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Mohammad Reza Seyedtaghia
- Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Soudyab
- Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maria Nezamnia
- Department of Obstetrics and Gynecology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Jason Kidde
- Department of Emergency Medicine, University of Utah, Salt Lake City, UT, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Halal Research Center of IRI, FDA, Tehran, Iran
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Xie C, Li SY, Fang JH, Zhu Y, Yang JE. Functional long non-coding RNAs in hepatocellular carcinoma. Cancer Lett 2020; 500:281-291. [PMID: 33129957 DOI: 10.1016/j.canlet.2020.10.042] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/21/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent human malignancy with high morbidity worldwide. Hepatocarcinogenesis is a complex multistep process, and its underlying molecular mechanisms remain largely unknown. Recently, long non-coding RNAs (lncRNAs), a class of newly discovered molecules, have been revealed as essential regulators in the development of HCC. HCC-associated lncRNAs affect multiple malignant phenotypes by modulating gene expression or protein activity. Moreover, the dysregulation of lncRNAs in the liver is also associated with diseases predisposing to HCC, such as chronic viral infection, nonalcoholic steatohepatitis, and liver fibrosis/cirrhosis. A deeper understanding of the lncRNA regulatory network in the multistep processes of HCC development will provide new insights into the diagnosis and treatment of HCC. In this review, we introduce the biogenesis and function of lncRNAs and summarize recent knowledge on how lncRNAs regulate the malignant hallmarks of HCC, such as uncontrolled cell proliferation, resistance to cell death, metabolic reprogramming, immune escape, angiogenesis, and metastasis. We also review emerging insights into the role of lncRNAs in HCC-associated liver diseases. Finally, we discuss the potential applications of lncRNAs as early diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Chen Xie
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou 510275, PR China
| | - Song-Yang Li
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou 510275, PR China
| | - Jian-Hong Fang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou 510275, PR China
| | - Ying Zhu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou 510275, PR China
| | - Jin-E Yang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou 510275, PR China.
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Han S, Zhang T, Kusumanchi P, Huda N, Jiang Y, Liangpunsakul S, Yang Z. Role of microRNA-7 in liver diseases: a comprehensive review of the mechanisms and therapeutic applications. J Investig Med 2020; 68:1208-1216. [PMID: 32843369 PMCID: PMC9303053 DOI: 10.1136/jim-2020-001420] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/21/2020] [Indexed: 12/14/2022]
Abstract
MicroRNA-7 (miR-7) is a small non-coding RNA, which plays critical roles in regulating gene expression of multiple key cellular processes. MiR-7 exhibits a tissue-specific pattern of expression, with abundant levels found in the brain, spleen, and pancreas. Although it is expressed at lower levels in other tissues, including the liver, miR-7 is involved in both the development of organs and biological functions of cells. In this review, we focus on the mechanisms by which miR-7 controls cell growth, proliferation, invasion, metastasis, metabolism, and inflammation. We also summarize the specific roles of miR-7 in liver diseases. MiR-7 is considered as a tumor suppressor miRNA in hepatocellular carcinoma and is involved in the pathogenesis of hepatic steatosis and hepatitis. Future studies to further define miR-7 functions and its mechanism in association with other types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting miR-7 for the treatment of liver diseases.
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Affiliation(s)
- Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing, China
| | - Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nazmul Huda
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Our emerging understanding of the roles of long non-coding RNAs in normal liver function, disease, and malignancy. JHEP Rep 2020; 3:100177. [PMID: 33294829 PMCID: PMC7689550 DOI: 10.1016/j.jhepr.2020.100177] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 08/06/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are important biological mediators that regulate numerous cellular processes. New experimental evidence suggests that lncRNAs play essential roles in liver development, normal liver physiology, fibrosis, and malignancy, including hepatocellular carcinoma and cholangiocarcinoma. In this review, we summarise our current understanding of the function of lncRNAs in the liver in both health and disease, as well as discuss approaches that could be used to target these non-coding transcripts for therapeutic purposes.
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Key Words
- ABCA1, ATP-binding cassette transporter A1
- ACTA2/ɑ-SMA, α-smooth muscle actin
- APO, apolipoprotein
- ASO, antisense oligonucleotides
- BDL, bile duct ligation
- CCA, cholangiocarcinoma
- CCl4, carbon tetrachloride
- COL1A1, collagen type I α 1
- CYP, cytochrome P450
- Cholangiocarcinoma
- DANCR, differentiation antagonising non-protein coding RNA
- DE, definitive endoderm
- DEANR1, definitive endoderm-associated lncRNA1
- DIGIT, divergent to goosecoid, induced by TGF-β family signalling
- DILC, downregulated in liver cancer stem cells
- EST, expression sequence tag
- EpCAM, epithelial cell adhesion molecule
- FBP1, fructose-bisphosphatase 1
- FENDRR, foetal-lethal non-coding developmental regulatory RNA
- FXR, farnesoid X receptor
- GAS5, growth arrest-specific transcript 5
- H3K18ac, histone 3 lysine 18 acetylation
- H3K36me3, histone 3 lysine 36 trimethylation
- H3K4me3, histone 3 lysine 4 trimethylation
- HCC, hepatocellular carcinoma
- HEIH, high expression In HCC
- HNRNPA1, heterogenous nuclear protein ribonucleoprotein A1
- HOTAIR, HOX transcript antisense RNA
- HOTTIP, HOXA transcript at the distal tip
- HSC, hepatic stellate cells
- HULC, highly upregulated in liver cancer
- Hepatocellular carcinoma
- HuR, human antigen R
- LCSC, liver cancer stem cell
- LSD1, lysine-specific demethylase 1
- LXR, liver X receptors
- LeXis, liver-expressed LXR-induced sequence
- Liver cancer
- Liver fibrosis
- Liver metabolism
- Liver-specific lncRNAs
- LncLSTR, lncRNA liver-specific triglyceride regulator
- MALAT1, metastasis-associated lung adenocarcinoma transcript 1
- MEG3, maternally expressed gene 3
- NAT, natural antisense transcript
- NEAT1, nuclear enriched abundant transcript 1
- ORF, open reading frame
- PKM2, pyruvate kinase muscle isozyme M2
- PPAR-α, peroxisome proliferator-activated receptor-α
- PRC, polycomb repressive complex
- RACE, rapid amplification of cDNA ends
- RNA Pol, RNA polymerase
- S6K1, S6 kinase 1
- SHP, small heterodimer partner
- SREBPs, steroid response binding proteins
- SREs, sterol response elements
- TGF-β, transforming growth factor-β
- TTR, transthyretin
- XIST, X-inactive specific transcript
- ZEB1, zinc finger E-box-binding homeobox 1
- ceRNA, competing endogenous RNA
- eRNA, enhancer RNAs
- lincRNA, long intervening non-coding RNA
- lncRNA
- lncRNA, long non-coding RNA
- mTOR, mammalian target of rapamycin
- siRNA, small interfering RNA
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Shen ZJ, Han YC, Wang YN, Xie HZ. LncRNA and mRNA expression profiles and functional networks of hyposalivation of the submandibular gland in hypertension. Sci Rep 2020; 10:13972. [PMID: 32811845 PMCID: PMC7434885 DOI: 10.1038/s41598-020-70853-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/30/2020] [Indexed: 11/09/2022] Open
Abstract
Hyposalivation is a complication of hypertension. However, little is known about the role of long non-coding RNAs (lncRNAs) in salivary glands in hypertension. This study aimed to compare the lncRNA and mRNA expression profiles between spontaneous hypertension rats (SHRs) and Wistar-Kyoto (WKY) rats through microarray analysis and apple bioinformatics methods to analyse their potential roles in hyposalivation. The differentially expressed (DE) lncRNAs and mRNAs were confirmed by quantitative real-time PCR (qRT-PCR). Compared with WKY rats, 225 DE lncRNAs and 473 DE mRNAs were identified in the SMG of SHRs. The pathway analyses of DE mRNAs showed that inflammatory mediator regulation of transient receptor potential channels was involved in hyposalivation in SHRs. Ten DE lncRNAs were chosen for further research. A coding-non-coding gene co-expression (CNC) network and competing endogenous RNA (ceRNA) network analysis revealed that the potential functions of these 10 DE lncRNAs were closely connected with the processes of the immune response. This study showed abundant DE lncRNAs and mRNAs in hypertensive SMGs. Furthermore, our results indicated strong associations between the immune response and hyposalivation and showed the potential of immune-related genes as novel and therapeutic targets for hyposalivation.
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Affiliation(s)
- Zhu-Jun Shen
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 1000730, China
| | - Ye-Chen Han
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 1000730, China
| | - Yi-Ning Wang
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 1000730, China
| | - Hong-Zhi Xie
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 1000730, China.
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