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Jia X, Shao L, Quan H, Zhong Z, Dong C. Exploring vimentin's role in breast cancer via PICK1 alternative polyadenylation and the miR-615-3p-PICK1 interaction. Biofactors 2025; 51:e2147. [PMID: 39781570 PMCID: PMC11712540 DOI: 10.1002/biof.2147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 11/09/2024] [Indexed: 01/12/2025]
Abstract
Breast cancer continues to be a major health issue for women worldwide, with vimentin (VIM) identified as a crucial factor in its progression due to its role in cell migration and the epithelial-to-mesenchymal transition (EMT). This study focuses on elucidating VIM's regulatory mechanisms on the miR-615-3p/PICK1 axis. Utilizing the 4T1 breast cancer cell model, we first used RNA-seq and proteomics to investigate the changes in the APA of PICK1 following VIM knockout (KO). These high-throughput analyses aimed to uncover the underlying transcriptional and proteomic alterations associated with VIM's influence on breast cancer cells. RNA-seq and proteomic profiling revealed significant APA in PICK1 following VIM KO, suggesting a novel mechanism by which VIM regulates breast cancer progression. Validation experiments confirmed that VIM KO affects the miR-615-3p-PICK1 axis, with miR-615-3p's regulation of PICK1 being contingent upon the APA of PICK1. These findings highlight the complex interplay between VIM, miR-615-3p, and PICK1 in the regulation of breast cancer cell behavior. This study reveals that vimentin affects the miR-615-3p-PICK1 axis through APA, revealing the key role of VIM in cancer progression. Opened up new avenues for targeted cancer therapy, with a focus on regulating the interaction between APA and miR-615-3p-PICK1.
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Affiliation(s)
- Xinyan Jia
- College of Basic Medical ScienceJinzhou Medical UniversityJinzhouLiaoningChina
| | - Lujing Shao
- Department of Oncology, Shanghai East Hospital, Tongji University School of MedicineTongji UniversityShanghaiPeople's Republic of China
| | - Hong Quan
- Department of Breast Surgery, Shanghai East Hospital, Tongji University School of MedicineTongji UniversityShanghaiPeople's Republic of China
| | - Zhixian Zhong
- Department of Oncology, Shanghai East Hospital, Tongji University School of MedicineTongji UniversityShanghaiPeople's Republic of China
| | - Chunyan Dong
- Department of Oncology, Shanghai East Hospital, Tongji University School of MedicineTongji UniversityShanghaiPeople's Republic of China
- Ji'an Central People's Hospital (Ji'an Hospital of Shanghai East Hospital)Jiangxi ProvinceChina
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Yu X, Wang X, Xu F, Zhang X, Wang M, Zhou R, Sun Z, Pan X, Feng L, Zhang W, Sun Y, Zhang W, Zhou D, Jiang Y. Mir-615-3p promotes osteosarcoma progression via the SESN2/AMPK/mTOR pathway. Cancer Cell Int 2024; 24:411. [PMID: 39702297 DOI: 10.1186/s12935-024-03604-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 12/05/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Osteosarcoma (OS) is the most common primary malignant bone neoplasm. Growing researches have highlighted the tumor promoting role of miR-615-3p in various cancers. Notwithstanding, the biological function and underlying mechanisms of miR-615-3p in OS development still unclear. METHODS Quantitative Real-Time PCR analysis (qRT-PCR) and RNA fluorescence in situ hybridization (FISH) staining were performed to measure miR-615-3p expression in OS. CCK-8 assay, colony formation assay and EdU assay were applied to analyze the OS cell proliferation activity. Cell metastasis abilities were evaluated using Transwell assays. Analysis of apoptosis was performed based on flow cytometric detection. The potential mechanisms of miR-615-3p in OS progression were investigated through RNA immunoprecipitation (RIP) assays, dual-luciferase reporter assays, qRT-PCR and western blotting. In vivo experiments, mouse xenograft model was carried out to assess the tumorigenicity of miR-615-3p. RESULTS This study demonstrated a significant upregulation of miR-615-3p in OS. In addition, miR-615-3p knockdown suppressed OS proliferation, invasion, metastasis and EMT. Mechanistically, miR-615-3p regulated sestrin 2 (SESN2) expression negatively by targeting its 3'UTR. Moreover, silencing SESN2 facilitated OS progression and activated mTOR pathway. Noteworthy, the anticancer functions of miR-615-3p knockdown were partially recovered by SESN2 silencing. Taken together, the miR-615-3p/SESN2/mTOR pathway is critical for regulating OS progression. CONCLUSION Our results revealed that miR-615-3p modulated mTOR signaling, thus influencing the progression of OS. For OS treatment, molecular strategies that target the miR-615-3p/SESN2/mTOR pathway is promising.
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Affiliation(s)
- Xuecheng Yu
- Department of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Changzhou, 213003, China
| | - Xin Wang
- Department of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Changzhou, 213003, China
| | - Fan Xu
- Department of Disease Control, 987 Hospital of Joint Logistics Support Force of PLA, Baoji, Shaanxi, China
| | - Xinyi Zhang
- Wenzhou Medical University, Wenzhou, 325035, China
| | - Muyi Wang
- Department of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Changzhou, 213003, China
| | - Ruikai Zhou
- Department of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Changzhou, 213003, China
| | - Zhengyi Sun
- Department of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Changzhou, 213003, China
| | - Xiaohui Pan
- Department of Orthopedics, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu Province, China
| | - Lin Feng
- The people's hospital of WuQia county, WuQia, 845450, Xinjiang, China
| | - Wanchao Zhang
- Department of Radiology, The people's hospital of WuQia county, WuQia, 845450, Xinjiang, China
| | - Yong Sun
- Department of Orthopedics, Wuqia People's Hospital, Xinjiang, China
| | - Wenting Zhang
- Affiliated Changzhou Children's Hospital of Nantong University, Changzhou, 213003, Jiangsu, China.
| | - Dong Zhou
- Department of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Changzhou, 213003, China.
- Department of Orthopedics, Wuqia People's Hospital, Xinjiang, China.
- Affiliated Changzhou Children's Hospital of Nantong University, Changzhou, 213003, Jiangsu, China.
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China.
| | - Yuqing Jiang
- Department of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Changzhou, 213003, China.
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3
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Wilson C, Swaroop P, Kumar S, Chopra A, Sharawat SK. Molecular leveraging of HOX-embedded non-coding RNAs in the progression of acute myeloid leukemia. Hum Cell 2024; 38:24. [PMID: 39614990 DOI: 10.1007/s13577-024-01149-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Abstract
Acute myeloid leukemia (AML) is characterized by impaired differentiation of myeloid cells leading to hematopoietic failure. Despite advances, the molecular mechanisms driving AML remain incompletely understood, limiting the identification and targeting of critical vulnerabilities in leukemic cells. Homeobox (HOX) genes, encoding transcription factors essential for myeloid and lymphoid differentiation, are distributed across four clusters: HOXA (chromosome 7), HOXB (chromosome 17), HOXC (chromosome 12), and HOXD (chromosome 2). In addition to protein-coding sequences, HOX clusters encode non-coding RNAs (ncRNAs), which are functional as transcripts and do not translate into proteins. This is the first study wherein we comprehensively reviewed the literature for HOX-embedded ncRNAs, encompassing long non-coding RNAs (lncRNAs), microRNAs, circular RNAs (circRNAs), and piwiRNAs with a role in AML. To date, there is no evidence of circular RNAs and piwi RNAs encoded from the HOX gene clusters. Our review focuses on how leukemic cells harness the regulatory mechanisms of HOX-cluster-derived ncRNAs, (predominantly HOXA and HOXB) to modulate expression of HOX transcription factors facilitating leukemogenesis. HOX ncRNAs either regulate genes on the same chromosome (e.g., lncRNA HOTTIP) or influence expression of genes on different chromosomes (e.g., HOTAIR, HOX10-AS, miR-196b, and miR-10a). We discuss how specific HOX ncRNA networks are leveraged by leukemic cells, presenting an opportunity to explore targeted therapies and address the molecular heterogeneity of AML. Additionally, the aberrant expression of HOX ncRNAs such as HOXB derived ncRNAs in NPM1 mutated AML suggests their potential utility as improved biomarkers and for prognostication of patients with specific molecular aberrations.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/therapy
- Nucleophosmin/genetics
- Disease Progression
- Genes, Homeobox/genetics
- RNA, Untranslated/genetics
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/physiology
- MicroRNAs/genetics
- Homeodomain Proteins/genetics
- Multigene Family/genetics
- RNA, Circular/genetics
- RNA, Circular/physiology
- Cell Differentiation/genetics
- Transcription Factors/genetics
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Affiliation(s)
- Christine Wilson
- Department of Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, Room No. 401, 4th Floor, New Delhi, India
| | - Priyanka Swaroop
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Sachin Kumar
- Department of Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, Room No. 401, 4th Floor, New Delhi, India
| | - Anita Chopra
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Surender K Sharawat
- Department of Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, Room No. 401, 4th Floor, New Delhi, India.
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Huang HH, Chang JT, You GR, Fu YF, Shen EYL, Huang YF, Shen CR, Cheng AJ. MiRNA Profiling of Areca Nut-Induced Carcinogenesis in Head and Neck Cancer. Cancers (Basel) 2024; 16:3710. [PMID: 39518147 PMCID: PMC11545612 DOI: 10.3390/cancers16213710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/24/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND While miRNAs are increasingly recognized for their role in tumorigenesis, their involvement in head and neck cancer (HNC) remains insufficiently explored. Additionally, the carcinogenic mechanisms of areca nut, a major habitual carcinogen in Southeast Asia, are not well understood. METHODS AND RESULTS This study adopts a systematic approach to identify miRNA profiles associated with areca nut-induced HNC. Using miRNA microarray analysis, we identified 292 miRNAs dysregulated in areca nut-treated HNC cells, with 136 upregulated and 156 downregulated. Bioinformatic analysis of the TCGA-HNSC dataset uncovered a set of 692 miRNAs relevant to HNC development, comprising 449 overexpressed and 243 underexpressed in tumor tissues. Integrating these datasets, we defined a signature of 84 miRNAs, including 39 oncogenic miRNAs (OncomiRs) and 45 tumor-suppressive miRNAs (TsmiRs), highlighting their pivotal role in areca nut-induced carcinogenesis. MultiMiR analysis identified 740 genes cross-regulated by eight hub TsmiRs, significantly impacting key cancer-related pathways (p53, PI3K-AKT, MAPK, and Ras) and critical oncogenic processes. Moreover, we validated miR-499a-5p as a vital regulator, demonstrating its ability to mitigate areca nut-induced cancer progression by reducing cell migration, invasion, and chemoresistance. CONCLUSIONS Thus, this miRNA signature addresses a crucial gap in understanding the molecular underpinnings of areca nut-induced carcinogenesis and offers a promising platform for clinical applications in risk assessment, diagnosis, and prognosis of areca nut-associated malignancies.
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Affiliation(s)
- Hung-Han Huang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (H.-H.H.); (C.-R.S.)
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (G.-R.Y.); (Y.-F.F.)
| | - Joseph T. Chang
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (J.T.C.); (E.Y.-L.S.)
- School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Guo-Rung You
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (G.-R.Y.); (Y.-F.F.)
| | - Yu-Fang Fu
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (G.-R.Y.); (Y.-F.F.)
| | - Eric Yi-Liang Shen
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (J.T.C.); (E.Y.-L.S.)
| | - Yi-Fang Huang
- Department of General Dentistry, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan;
- Graduate Institute of Dental and Craniofacial Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chia-Rui Shen
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (H.-H.H.); (C.-R.S.)
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (G.-R.Y.); (Y.-F.F.)
| | - Ann-Joy Cheng
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (H.-H.H.); (C.-R.S.)
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (G.-R.Y.); (Y.-F.F.)
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (J.T.C.); (E.Y.-L.S.)
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Hong Y, Chen T, He Q, Ma Q, Chen Z. Clinical implications of serum miR-34a in breast cancer and its predictive value for the efficacy of neoadjuvant chemotherapy. Am J Transl Res 2024; 16:2711-2718. [PMID: 39006295 PMCID: PMC11236626 DOI: 10.62347/phys4309] [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: 03/25/2024] [Accepted: 06/05/2024] [Indexed: 07/16/2024]
Abstract
OBJECTIVES This study aims to explore the implications of serum miR-34a in breast cancer (BC) and its predictive value for the efficacy of neoadjuvant chemotherapy (NACT). METHODS A retrospective analysis was performed on 102 female BC patients (research group) admitted to The Second Affiliated Hospital of Anhui Medical University between January 2016 to March 2018 and 102 concurrent female health controls who underwent physical examinations (control group). Serum samples from both groups were subjected to quantitative reverse transcription polymerase chain reaction to measure miR-34a expression. The correlation of miR-34a with BC patients' clinical parameters was analyzed, and the implications of miR-34a for diagnosing BC and predicting NACT efficacy were assessed by receiver operating characteristic curves. Logistic regression analysis was employed to determine whether miR-34a independently influenced treatment effectiveness and patient outcomes. RESULTS The data showed significantly lower miR-34a levels in the research group than in the control group (P<0.05). The area under the curve (AUC) of miR-34a for differentiating BC was 0.888. In BC patients, miR-34a was strongly correlated with tumor staging and differentiation degree. Following NACT, BC patients showed an evident rise in miR-34a expression, with higher levels in patients with effective treatment compared to those with treatment failure (P<0.05). The AUC values of serum miR-34a in predicting the efficacy of neoadjuvant chemotherapy from FD to SD and from SD to TD were 0.880 and 0.861, respectively (P<0.001). Furthermore, patients with favorable prognosis exhibited markedly higher serum miR-34a expression than those with poor prognosis (P<0.05). The AUC of miR-34a expression for predicting adverse prognosis was 0.825. Decreased miR-34a was identified as an independent risk factor for treatment failure and poor prognosis. CONCLUSIONS Taken together, serum miR-34a is downregulated in BC and can predict the clinical progression of BC patients and the therapeutic efficacy of NACT.
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Affiliation(s)
- Yanyan Hong
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Tingting Chen
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Qian He
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Qiang Ma
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Zhendong Chen
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
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Gottumukkala SB, Ganesan TS, Palanisamy A. Comprehensive molecular interaction map of TGFβ induced epithelial to mesenchymal transition in breast cancer. NPJ Syst Biol Appl 2024; 10:53. [PMID: 38760412 PMCID: PMC11101644 DOI: 10.1038/s41540-024-00378-w] [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: 10/20/2023] [Accepted: 04/29/2024] [Indexed: 05/19/2024] Open
Abstract
Breast cancer is one of the prevailing cancers globally, with a high mortality rate. Metastatic breast cancer (MBC) is an advanced stage of cancer, characterised by a highly nonlinear, heterogeneous process involving numerous singling pathways and regulatory interactions. Epithelial-mesenchymal transition (EMT) emerges as a key mechanism exploited by cancer cells. Transforming Growth Factor-β (TGFβ)-dependent signalling is attributed to promote EMT in advanced stages of breast cancer. A comprehensive regulatory map of TGFβ induced EMT was developed through an extensive literature survey. The network assembled comprises of 312 distinct species (proteins, genes, RNAs, complexes), and 426 reactions (state transitions, nuclear translocations, complex associations, and dissociations). The map was developed by following Systems Biology Graphical Notation (SBGN) using Cell Designer and made publicly available using MINERVA ( http://35.174.227.105:8080/minerva/?id=Metastatic_Breast_Cancer_1 ). While the complete molecular mechanism of MBC is still not known, the map captures the elaborate signalling interplay of TGFβ induced EMT-promoting MBC. Subsequently, the disease map assembled was translated into a Boolean model utilising CaSQ and analysed using Cell Collective. Simulations of these have captured the known experimental outcomes of TGFβ induced EMT in MBC. Hub regulators of the assembled map were identified, and their transcriptome-based analysis confirmed their role in cancer metastasis. Elaborate analysis of this map may help in gaining additional insights into the development and progression of metastatic breast cancer.
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Affiliation(s)
| | - Trivadi Sundaram Ganesan
- Department of Medical Oncology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | - Anbumathi Palanisamy
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, India.
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Cao Y, Wang H, Hu S, Xu Q, Ma J, Wang H, Xiong X, Wang W, Wang L. PICK1 modulates glycolysis and angiogenesis of hypoxic endothelial cells by regulating iron homeostasis. Mol Cell Biochem 2024; 479:1297-1312. [PMID: 37368155 DOI: 10.1007/s11010-023-04795-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 06/18/2023] [Indexed: 06/28/2023]
Abstract
Iron accumulation, which is controlled by transferrin receptor 1 (TfR1), modulates hypoxia-inducible factor-1α (HIF-1α) activation and angiogenesis of hypoxic endothelial cells. The study examined the role of protein interacting with C-kinase 1 (PICK1), a scaffold protein containing PDZ domain, in regulating glycolysis and angiogenesis of hypoxic vascular endothelial cells through its potential effect on TfR1, which features a supersecondary structure that interacts with the PDZ domain. Iron chelator deferoxamine and TfR1 siRNA were employed to assess the impact of iron accumulation on angiogenesis, while the effects of PICK1 siRNA and overexpressing lentivirus on TfR1-mediated iron accumulation were also investigated in hypoxic human umbilical vein vascular endothelial cells (HUVECs). The study found that 72-h hypoxia impaired the proliferation, migration, and tube formation of HUVECs, and reduced the upregulation of vascular endothelial growth factor, HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, and PICK1, while increasing the expression of TfR1 as compared to 24-h hypoxia. Administration of deferoxamine or TfR1 siRNA reversed these effects and led to increased glycolysis, ATP content, and phosphofructokinase activity, along with increased PICK1 expression. PICK1 overexpression improved glycolysis, enhanced angiogenic capacity, and attenuated TfR1 protein upregulation in hypoxic HUVECs, with higher expression of angiogenic markers, which could be significantly reversed by the PDZ domain inhibitor. PICK1 knockdown exerted opposite effects. The study concluded that PICK1 modulated intracellular iron homeostasis, thereby promoting glycolysis and angiogenesis of HUVECs in response to prolonged hypoxia, at least in part, by regulating TfR1 expression.
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Affiliation(s)
- Yu Cao
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Hongbo Wang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Ouhai, Wenzhou, 325000, Zhejiang, China
| | - Shuyu Hu
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Ouhai, Wenzhou, 325000, Zhejiang, China
| | - Qiaomin Xu
- Department of Anesthesiology, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, 321400, Zhejiang, China
| | - Jun Ma
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Huile Wang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xiangqing Xiong
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Ouhai, Wenzhou, 325000, Zhejiang, China
| | - Wantie Wang
- Institute of Ischemia-Reperfusion Injury, Wenzhou, 325035, Zhejian, China
| | - Liangrong Wang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Ouhai, Wenzhou, 325000, Zhejiang, China.
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Hasanlu M, Amiri-Dashatan N, Farahani M, Koushki M, Ahmadi H, Parsamanesh N, Ahmadi NA. Comprehensive Analysis of the Expression, Prognosis, and Immune Infiltrates for Chromodomain-Helicase-DNA-Binding Proteins in Breast Tumor. Asian Pac J Cancer Prev 2024; 25:1547-1558. [PMID: 38809626 PMCID: PMC11318824 DOI: 10.31557/apjcp.2024.25.5.1547] [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: 09/01/2023] [Accepted: 05/04/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Several recent studies suggest that chromodomain-helicase -DNA-binding domains (CHDs) are linked with cancers. We explored the association between chromodomain-Helicase-DNA-binding domain proteins and breast cancer (BrCa) and introduced potential prognostic markers using various databases. MATERIALS AND METHODS We analyzed the expression of the CHD family and their prognostic value in BrCa by mining UALCAN, TIMER, and Kaplan-Meier plotter databases. The association of CHD expression and immune infiltrating abundance was studied via the TIMER database. In addition, microRNAs related to the CHD family were identified by using the MirTarBase online database. RESULTS The present study indicated that compared to normal tissues, BrCa tissues showed increased mRNA levels of CHD3/4/7 but decreased CHD2/5/9 expression. Interestingly, We also found a positive correlation between CHD gene expression and the infiltration of macrophage, neutrophil, and dendritic cells in BrCa, except CHD3/5. The Kaplan-Meier Plotter analysis suggested that high expression levels of CHD1/2/3/4/6/8/9 were significantly related to shorter relapse-free survival (RFS), while higher mRNA expression of CHD1, CHD2, CHD8, and CHD9 was significantly associated with longer overall survival of BrCa patients. The miRNAs of hsa-miR-615-3p and hsa-let-7b-5p were identified as being more correlated with the CHD family. CONCLUSION The altered expression of some CHD members was significantly related to clinical cancer outcomes, and CHD1/2/8/9 could serve as potential prognostic biomarkers to improve the survival of BrCa patients. However, to evaluate the studied CHD members in detail are needed further investigations including experimental validation.
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Affiliation(s)
- Masoumeh Hasanlu
- Department of Internal Medicine, Vali-e-Asr Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Nasrin Amiri-Dashatan
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Masoumeh Farahani
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mehdi Koushki
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Hesameddin Ahmadi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Micro Nano System Laboratory (MNSL), Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran.
| | - Negin Parsamanesh
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Nayeb Ali Ahmadi
- Proteomics Research Center, Department of Medical Laboratory Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Ou X, Zhang Y, Xu Y, Liu Y, Tu W, Hu C, Liu Y. PICK1 inhibits the malignancy of nasopharyngeal carcinoma and serves as a novel prognostic marker. Cell Death Dis 2024; 15:294. [PMID: 38664379 PMCID: PMC11045752 DOI: 10.1038/s41419-024-06687-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 04/13/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024]
Abstract
Although many important advances have been made in the treatment of nasopharyngeal carcinoma (NPC) in recent years, local recurrence and distant metastasis remain the main factors affecting NPC prognosis. Biomarkers for predicting the prognosis of NPC need to be urgently identified. Here, we used whole-exon sequencing (WES) to determine whether PICK1 mutations are associated with the prognosis of NPC. Functionally, PICK1 inhibits the proliferation and metastasis of NPC cells both in vivo and in vitro. Mechanistically, PICK1 inhibited the expression of proteins related to the Wnt/β-catenin signaling pathway. PICK1 restrained the nuclear accumulation of β-catenin and accelerated the degradation of β-catenin through the ubiquitin-proteasome pathway. The reduced PICK1 levels were significantly associated with poor patient prognosis. Hence, our study findings reveal the mechanism by which PICK1 inactivates the Wnt/β-catenin signaling pathway, thereby inhibiting the progression of NPC. They support PICK1 as a potential tumor suppressor and prognostic marker for NPC.
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Affiliation(s)
- Xiaomin Ou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Yingzi Zhang
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Yiqing Xu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Yi Liu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Wenzhi Tu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
| | - Chaosu Hu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China.
| | - Yong Liu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
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Zhang HL, Doblin S, Zhang ZW, Song ZJ, Dinesh B, Tabana Y, Saad DS, Adam Ahmed Adam M, Wang Y, Wang W, Zhang HL, Wu S, Zhao R, Khaled B. Elucidating the molecular basis of ATP-induced cell death in breast cancer: Construction of a robust prognostic model. World J Clin Oncol 2024; 15:208-242. [PMID: 38455130 PMCID: PMC10915939 DOI: 10.5306/wjco.v15.i2.208] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/10/2023] [Accepted: 01/12/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Breast cancer is a multifaceted and formidable disease with profound public health implications. Cell demise mechanisms play a pivotal role in breast cancer pathogenesis, with ATP-triggered cell death attracting mounting interest for its unique specificity and potential therapeutic pertinence. AIM To investigate the impact of ATP-induced cell death (AICD) on breast cancer, enhancing our understanding of its mechanism. METHODS The foundational genes orchestrating AICD mechanisms were extracted from the literature, underpinning the establishment of a prognostic model. Simultaneously, a microRNA (miRNA) prognostic model was constructed that mirrored the gene-based prognostic model. Distinctions between high- and low-risk cohorts within mRNA and miRNA characteristic models were scrutinized, with the aim of delineating common influence mechanisms, substantiated through enrichment analysis and immune infiltration assessment. RESULTS The mRNA prognostic model in this study encompassed four specific mRNAs: P2X purinoceptor 4, pannexin 1, caspase 7, and cyclin 2. The miRNA prognostic model integrated four pivotal miRNAs: hsa-miR-615-3p, hsa-miR-519b-3p, hsa-miR-342-3p, and hsa-miR-324-3p. B cells, CD4+ T cells, CD8+ T cells, endothelial cells, and macrophages exhibited inverse correlations with risk scores across all breast cancer subtypes. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis revealed that genes differentially expressed in response to mRNA risk scores significantly enriched 25 signaling pathways, while miRNA risk scores significantly enriched 29 signaling pathways, with 16 pathways being jointly enriched. CONCLUSION Of paramount significance, distinct mRNA and miRNA signature models were devised tailored to AICD, both potentially autonomous prognostic factors. This study's elucidation of the molecular underpinnings of AICD in breast cancer enhances the arsenal of potential therapeutic tools, offering an unparalleled window for innovative interventions. Essentially, this paper reveals the hitherto enigmatic link between AICD and breast cancer, potentially leading to revolutionary progress in personalized oncology.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Sandai Doblin
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Babu Dinesh
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Dahham Sabbar Saad
- Department of Science, University of Technology and Applied Sciences Rustaq, Rustaq 10 P.C. 329, Oman
| | - Mowaffaq Adam Ahmed Adam
- Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States
| | - Yong Wang
- Department of Pathology Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Wei Wang
- College of Acupuncture-moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Long Zhang
- Universiti Sains Malaysia, Advanced Medical and Dental Institute, Penang 13200, Malaysia
| | - Sen Wu
- Department of Biomedical Science, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Barakat Khaled
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
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11
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Guo L, Kong D, Liu J, Luo L, Zheng W, Chen C, Sun S. Searching for Essential Genes and Targeted Drugs Common to Breast Cancer and Osteoarthritis. Comb Chem High Throughput Screen 2024; 27:238-255. [PMID: 37157194 DOI: 10.2174/1386207326666230508113036] [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: 08/29/2022] [Revised: 03/07/2023] [Accepted: 03/17/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND It is documented that osteoarthritis can promote the progression of breast cancer (BC). OBJECTIVE This study aims to search for the essential genes associated with breast cancer (BC) and osteoarthritis (OA), explore the relationship between epithelial-mesenchymal transition (EMT)- related genes and the two diseases, and identify the candidate drugs. METHODS The genes related to both BC and OA were determined by text mining. Protein-protein Interaction (PPI) analysis was carried out, and as a result, the exported genes were found to be related to EMT. PPI and the correlation of mRNA of these genes were also analyzed. Different kinds of enrichment analyses were performed on these genes. A prognostic analysis was performed on these genes for examining their expression levels at different pathological stages, in different tissues, and in different immune cells. Drug-gene interaction database was employed for potential drug discovery. RESULTS A total number of 1422 genes were identified as common to BC and OA and 58 genes were found to be related to EMT. We found that HDAC2 and TGFBR1 were significantly poor in overall survival. High expression of HDAC2 plays a vital role in the increase of pathological stages. Four immune cells might play a role in this process. Fifty-seven drugs were identified that could potentially have therapeutic effects. CONCLUSION EMT may be one of the mechanisms by which OA affects BC. Using the drugs can have potential therapeutic effects, which may benefit patients with both diseases and broaden the indications for drug use.
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Affiliation(s)
- Liantao Guo
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei 430060, People's Republic of China
| | - Deguang Kong
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei 430060, People's Republic of China
| | - Jianhua Liu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei 430060, People's Republic of China
| | - Lan Luo
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei 430060, People's Republic of China
| | - Weijie Zheng
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei 430060, People's Republic of China
| | - Chuang Chen
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei 430060, People's Republic of China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei 430060, People's Republic of China
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12
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Wang J, Tao Y, Zhao F, Liu T, Shen X, Zhou L. Expression of urinary exosomal miRNA-615-3p and miRNA-3147 in diabetic kidney disease and their association with inflammation and fibrosis. Ren Fail 2023; 45:2121929. [PMID: 36695327 PMCID: PMC9879181 DOI: 10.1080/0886022x.2022.2121929] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is one of the most common chronic complications of type 2 diabetes mellitus (T2DM), and it is particularly important to identify a high-quality method for evaluating disease progression. Urinary exosomes contain microRNA that might promise early diagnostic and monitoring markers of DKD. The present study aimed to identify novel exosome-related markers associated with inflammation and fibrosis to assess the progression of DKD. METHOD Exosomes were extracted from the urine of 83 participants to determine the expression levels of miRNA-615-3p and miRNA-3147 in 20 healthy people, 21 patients with T2DM and 42 patients with DKD, as determined by RT-qPCR. The circulating expression level of TGF-β1 was detected by ELISA. Serum Cystatin C was measured by a latex-enhanced immunoturbidimetric method. The correlation analyses were performed for all clinical and laboratory parameters. RESULT The expression level of urinary exosomal miRNA-615-3p in DKD patients was significantly higher than that in the control group and the T2DM group by RT-qPCR. The expression of miRNA-3147 showed an upward trend in the three groups of subjects, but it was not statistically significant. The urinary exosomal miRNA-615-3p was positively correlated with serum Cystatin C, plasma TGF-β1, creatinine, BUN, PCR and 24-h urine protein, and negatively correlated with eGFR and albumin. The diagnostic efficacy of urinary exosomal miRNA-615-3p combined with the ACR was higher than that of ACR alone. CONCLUSIONS Urinary exosomal miRNA-615-3p may be used as a novel biomarker for evaluating the progression of DKD, and may be involved in the process of inflammation and fibrosis in DKD. The combined diagnosis of urinary exosomal miRNA-615-3p and ACR may be used as more stable and sensitive diagnostic criteria for DKD.
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Affiliation(s)
- Jiaxin Wang
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yiying Tao
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fan Zhao
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Tong Liu
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiahong Shen
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ling Zhou
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China,CONTACT Ling Zhou Department of Nephrology, The First Affiliated Hospital of Soochow University, 889 Pinghai Rd, Suzhou, 215000, People’s Republic of China
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Krishnamoorthy S, Muruganantham B, Yu JR, Park WY, Muthusami S. Exploring the utility of FTS as a bonafide binding partner for EGFR: A potential drug target for cervical cancer. Comput Biol Med 2023; 167:107592. [PMID: 37976824 DOI: 10.1016/j.compbiomed.2023.107592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/25/2023] [Accepted: 10/17/2023] [Indexed: 11/19/2023]
Abstract
Establishment of human papilloma virus (HPV) infection and its progression to cervical cancer (CC) requires the participation of epidermal growth factor (EGF) receptor (EGFR) and fused toes homolog (FTS). This review is an attempt to understand the structure-function relationship between FTS and EGFR as a tool for the development of newer CC drugs. Motif analysis was performed using national center for biotechnology information (NCBI), kyoto encyclopedia of genes and genomes (KEGG), simple modular architecture research tool (SMART) and multiple expectation maximizations for motif elicitation (MEME) database. The secondary and tertiary structure prediction of FTS was performed using DISOPRED3 and threading assembly, respectively. A positive correlation was found between the transcript levels of FTS and EGFR. Amino acids responsible for interaction between EGFR and FTS were determined. The nine micro-RNAs (miRNAs) that regulates the expression of FTS were predicted using Network Analyst 3.0 database. hsa-miR-629-5p and hsa-miR-615-3p are identified as significant positive and negative regulators of FTS gene expression. This review opens up new avenues for the development of CC drugs which interfere with the interaction between FTS and EGFR.
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Affiliation(s)
- Sneha Krishnamoorthy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, 641021, Tamil Nadu, India
| | - Bharathi Muruganantham
- Centre for Cancer Research, Karpagam Academy of Higher Education, Coimbatore, 641021, Tamil Nadu, India
| | - Jae-Ran Yu
- Department of Environmental and Tropical Medicine, Konkuk University College of Medicine, Chungju, South Korea
| | - Woo-Yoon Park
- Department of Radiation Oncology Hospital, College of Medicine, Chungbuk National University, Cheongju, South Korea.
| | - Sridhar Muthusami
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, 641021, Tamil Nadu, India; Centre for Cancer Research, Karpagam Academy of Higher Education, Coimbatore, 641021, Tamil Nadu, India.
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14
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Wang Z, Yang H, Han Y, Teng J, Kong X, Qi X. Screening and identification of key biomarkers associated with amyotrophic lateral sclerosis and depression using bioinformatics. Medicine (Baltimore) 2023; 102:e36265. [PMID: 38013317 PMCID: PMC10681454 DOI: 10.1097/md.0000000000036265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 11/01/2023] [Indexed: 11/29/2023] Open
Abstract
This study aims to identify common molecular biomarkers between amyotrophic lateral sclerosis (ALS) and depression using bioinformatics methods, in order to provide potential targets and new ideas and methods for the diagnosis and treatment of these diseases. Microarray datasets GSE139384, GSE35978 and GSE87610 were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between ALS and depression were identified. After screening for overlapping DEGs, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software, and hub genes were identified. Finally, a network between miRNAs and hub genes was constructed using the NetworkAnalyst tool, and possible key miRNAs were predicted. A total of 357 genes have been identified as common DEGs between ALS and depression. GO and KEGG enrichment analyses of the 357 DEGs showed that they were mainly involved in cytoplasmic translation. Further analysis of the PPI network using Cytoscape and MCODE plugins identified 6 hub genes, including mitochondrial ribosomal protein S12 (MRPS12), poly(rC) binding protein 1 (PARP1), SNRNP200, PCBP1, small G protein signaling modulator 1 (SGSM1), and DNA methyltransferase 1 (DNMT1). Five possible target miRNAs, including miR-221-5p, miR-21-5p, miR-100-5p, miR-30b-5p, and miR-615-3p, were predicted by constructing a miRNA-gene network. This study used bioinformatics techniques to explore the potential association between ALS and depression, and identified potential biomarkers. These biomarkers may provide new ideas and methods for the early diagnosis, treatment, and monitoring of ALS and depression.
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Affiliation(s)
- Ziyue Wang
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Hao Yang
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Yu Han
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Jing Teng
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Xinru Kong
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Xianghua Qi
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
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15
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Telkoparan-Akillilar P, Cevik D. Identification of differentially expressed miRNAs and mRNAs associated with the regulation of breast cancer via in silico and in vitro methods. Cytotechnology 2023; 75:363-379. [PMID: 37655273 PMCID: PMC10465466 DOI: 10.1007/s10616-023-00583-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 06/20/2023] [Indexed: 09/02/2023] Open
Abstract
miRNA expressions are altered during development of breast cancer (BC). The aim of this study is to identify novel cancer-related miRNAs and pathways to understand the mechanisms of BC subtypes. GSE59247 dataset was downloaded from gene expression omnibus (GEO) database and analyzed with GEO2R software. The differential miRNA expressions in BC cells were evaluated by miRNome PCR array. Venn diagram was used to reveal co-differentially expressed miRNAs between GSE59247 dataset and miRNome array. Clinical prognostic significance of selected miRNAs was evaluated via Kaplan Meier curve. KEGG pathway enrichment analysis was performed to find miRNA targets and results were validated by TNM plot analysis and q-RT-PCR. TargetScan database was used to predict the association of miRNAs and 3'-untranslated regions of target genes and their expressions were visualized by human protein atlas database. Venn diagram analysis showed overlap of 11 miRNAs from in silico and in vitro analysis. KEGG analysis revealed 'Lysine Degradation Pathway' as the most significantly enriched targeted pathway. q-RT-PCR results confirmed that Lysine degradation pathway related genes SETD7, SETDB2, EHHADH, SETMAR, KMT2A and SUV39H2 were differentially expressed in BC cells. Target prediction analysis identified binding sites between miR-1323-5p and 3'-UTR of SETD7, miR-129-5p and 3'-UTR of EHHADH and miR-628-5p and 3'-UTR of SETDB2 mRNA. Notably, miR-1323-5p, miR-129-5p, and miR-628-5p are differentially expressed in BC and they bind to 3'UTR of critical genes of Lysine degradation pathway, namely SETD7, SETDB2 and EHHADH. These miRNAs might serve as potential diagnostic and prognostic biomarkers for progression.
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Affiliation(s)
- Pelin Telkoparan-Akillilar
- Department of Medical Biology, Faculty of Medicine, Yuksek Ihtisas University, No.18A, 1505. Street, Ankara, 06530 Turkey
| | - Dilek Cevik
- Department of Medical Biology, Faculty of Medicine, Yuksek Ihtisas University, No.18A, 1505. Street, Ankara, 06530 Turkey
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16
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Tabrizi-Nezhadi P, MotieGhader H, Maleki M, Sahin S, Nematzadeh S, Torkamanian-Afshar M. Application of Protein-Protein Interaction Network Analysis in Order to Identify Cervical Cancer miRNA and mRNA Biomarkers. ScientificWorldJournal 2023; 2023:6626279. [PMID: 37746664 PMCID: PMC10513823 DOI: 10.1155/2023/6626279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/28/2023] [Accepted: 09/04/2023] [Indexed: 09/26/2023] Open
Abstract
Cervical cancer (CC) is one of the world's most common and severe cancers. This cancer includes two histological types: squamous cell carcinoma (SCC) and adenocarcinoma (ADC). The current study aims at identifying novel potential candidate mRNA and miRNA biomarkers for SCC based on a protein-protein interaction (PPI) and miRNA-mRNA network analysis. The current project utilized a transcriptome profile for normal and SCC samples. First, the PPI network was constructed for the 1335 DEGs, and then, a significant gene module was extracted from the PPI network. Next, a list of miRNAs targeting module's genes was collected from the experimentally validated databases, and a miRNA-mRNA regulatory network was formed. After network analysis, four driver genes were selected from the module's genes including MCM2, MCM10, POLA1, and TONSL and introduced as potential candidate biomarkers for SCC. In addition, two hub miRNAs, including miR-193b-3p and miR-615-3p, were selected from the miRNA-mRNA regulatory network and reported as possible candidate biomarkers. In summary, six potential candidate RNA-based biomarkers consist of four genes containing MCM2, MCM10, POLA1, and TONSL, and two miRNAs containing miR-193b-3p and miR-615-3p are opposed as potential candidate biomarkers for CC.
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Affiliation(s)
| | - Habib MotieGhader
- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
- Department of Health Ecosystem, Medical Faculty, Nisantasi University, Istanbul, Turkey
| | - Masoud Maleki
- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Soner Sahin
- Department of Health Ecosystem, Medical Faculty, Nisantasi University, Istanbul, Turkey
| | - Sajjad Nematzadeh
- Software Engineering Department, Engineering Faculty, Topkapi University, Istanbul, Turkey
| | - Mahsa Torkamanian-Afshar
- Department of Computer Engineering, Faculty of Engineering and Architecture, Nisantasi University, Istanbul, Turkey
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17
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Ye Q, Raese RA, Luo D, Feng J, Xin W, Dong C, Qian Y, Guo NL. MicroRNA-Based Discovery of Biomarkers, Therapeutic Targets, and Repositioning Drugs for Breast Cancer. Cells 2023; 12:1917. [PMID: 37508580 PMCID: PMC10378316 DOI: 10.3390/cells12141917] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/14/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Breast cancer treatment can be improved with biomarkers for early detection and individualized therapy. A set of 86 microRNAs (miRNAs) were identified to separate breast cancer tumors from normal breast tissues (n = 52) with an overall accuracy of 90.4%. Six miRNAs had concordant expression in both tumors and breast cancer patient blood samples compared with the normal control samples. Twelve miRNAs showed concordant expression in tumors vs. normal breast tissues and patient survival (n = 1093), with seven as potential tumor suppressors and five as potential oncomiRs. From experimentally validated target genes of these 86 miRNAs, pan-sensitive and pan-resistant genes with concordant mRNA and protein expression associated with in-vitro drug response to 19 NCCN-recommended breast cancer drugs were selected. Combined with in-vitro proliferation assays using CRISPR-Cas9/RNAi and patient survival analysis, MEK inhibitors PD19830 and BRD-K12244279, pilocarpine, and tremorine were discovered as potential new drug options for treating breast cancer. Multi-omics biomarkers of response to the discovered drugs were identified using human breast cancer cell lines. This study presented an artificial intelligence pipeline of miRNA-based discovery of biomarkers, therapeutic targets, and repositioning drugs that can be applied to many cancer types.
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Affiliation(s)
- Qing Ye
- West Virginia University Cancer Institute/Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA; (Q.Y.); (R.A.R.); (D.L.); (J.F.); (W.X.); (C.D.)
| | - Rebecca A. Raese
- West Virginia University Cancer Institute/Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA; (Q.Y.); (R.A.R.); (D.L.); (J.F.); (W.X.); (C.D.)
| | - Dajie Luo
- West Virginia University Cancer Institute/Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA; (Q.Y.); (R.A.R.); (D.L.); (J.F.); (W.X.); (C.D.)
| | - Juan Feng
- West Virginia University Cancer Institute/Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA; (Q.Y.); (R.A.R.); (D.L.); (J.F.); (W.X.); (C.D.)
| | - Wenjun Xin
- West Virginia University Cancer Institute/Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA; (Q.Y.); (R.A.R.); (D.L.); (J.F.); (W.X.); (C.D.)
| | - Chunlin Dong
- West Virginia University Cancer Institute/Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA; (Q.Y.); (R.A.R.); (D.L.); (J.F.); (W.X.); (C.D.)
| | - Yong Qian
- Health Effects Laboratory Division, National Institute for Occupational and Safety & Health, Morgantown, WV 26505, USA;
| | - Nancy Lan Guo
- West Virginia University Cancer Institute/Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA; (Q.Y.); (R.A.R.); (D.L.); (J.F.); (W.X.); (C.D.)
- Department of Occupational and Environmental Health Sciences, School of Public Health, West Virginia University, Morgantown, WV 26506, USA
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Hao H, Wang B, Yang L, Sang Y, Xu W, Liu W, Zhang L, Jiang D. miRNA-186-5p inhibits migration, invasion and proliferation of breast cancer cells by targeting SBEM. Aging (Albany NY) 2023; 15:6993-7007. [PMID: 37477531 PMCID: PMC10415540 DOI: 10.18632/aging.204887] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 06/22/2023] [Indexed: 07/22/2023]
Abstract
The paper aimed to investigate the effect of miR186-5p on invasion and migration of breast cancer cells and its molecular mechanism. MicroRNA-186-5p was found to be low expressed in breast cancer and highly expressed in SBEM by bioinformatics analysis. After transfecting MDA-MB-231 cells with miR-186-5p inhibitor NC, miR-186-5p inhibitor, miR-186-5p mimic NC and miR-186-5p mimic, respectively. The migration and invasive ability of breast cancer cells were detected by cell scratch test and Transwell test. Moreover, after adding 740 Y-P to the miR-186-5p mimic NC group and miR-186-5p mimic group cells, SBEM and PI3K pathway-related proteins were detected by Western blotting and proliferation of the cancer cells was evaluated by monoclonal cell experiment. Meanwhile, exogenous miR-186-5p mimic in MDA-MB-231 cells significantly inhibited the expression of SBEM, p-PI3K, p-AKT and their downstream pathways, MMP1, MMP3, MMP9, CyclinD1, PCNA and CyclinB1 proteins and reduced proliferation of breast cancer cells. Furthermore, the expression of SBEM protein in the miR-186-5p mimic + 740Y-P group was significantly lower than the miR-186-5p mimic NC + 740Y-P group after adding 740 Y-P. However, there were no significant changes in the protein's levels associated with PI3K pathway and the cancer cells proliferation. These results suggest that low expression of miR-186-5p in breast cancer results in an abnormally high expression of SBEM, activation of PI3K/AKT signaling pathway, promoting migration and invasion of human breast cancer cells.
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Affiliation(s)
- Hui Hao
- Department of Medical Oncology, The Forth Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Bingsheng Wang
- Department of Medical Oncology, Hebei Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Lin Yang
- Graduate School, Chengde Medical University and Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Yinzhou Sang
- Department of Pathology, Hebei Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Wei Xu
- Department of Medical Oncology, Hebei Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Wei Liu
- Department of Medical Oncology, Hebei Cangzhou People’s Hospital, Cangzhou 061001, China
| | - Lili Zhang
- Department of Medicine, Cangzhou Medical College, Cangzhou 061011, China
| | - Da Jiang
- Department of Medical Oncology, The Forth Hospital of Hebei Medical University, Shijiazhuang 050000, China
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Wei SL, Ye JJ, Sun L, Hu L, Wei YY, Zhang DW, Xu MM, Fei GH. Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer. Cancer Cell Int 2023; 23:129. [PMID: 37394466 DOI: 10.1186/s12935-023-02974-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 06/22/2023] [Indexed: 07/04/2023] Open
Abstract
BACKGROUND The gefitinib resistance mechanism in non-small cell lung cancer (NSCLC) remains unclear, albeit exosomal circular RNA (circRNA) is known to possibly play a vital role in it. METHODS We employed high-throughput sequencing techniques to detect the expressions of exosomal circRNA both in gefitinib-resistant and gefitinib-sensitive cells in this study. The circKIF20B expression was determined in serum exosomes and tissues of patients by qRT-PCR. The structure, stability, and intracellular localization of circKIF20B were verified by Sanger sequencing, Ribonuclease R (RNase R)/actinomycin D (ACTD) treatments, and Fluorescence in situ hybridization (FISH). The functions of circKIF20B were investigated by 5-Ethynyl-20-deoxyuridine (EdU), flow cytometry, Cell Counting Kit-8 (CCK-8), oxygen consumption rate (OCR), and xenograft model. Co-culture experiments were performed to explore the potential ability of exosomal circKIF20B in treating gefitinib resistance. The downstream targets of circKIF20B were determined by luciferase assay, RNA pulldown, and RNA immunoprecipitation (RIP). RESULTS We found that circKIF20B was poorly expressed in the serum exosomes of gefitinib-resistant patients (n = 24) and the tumor tissues of patients with NSCLC (n = 85). CircKIF20B was negatively correlated with tumor size and tumor stage. Decreasing circKIF20B was found to promote gefitinib resistance by accelerating the cell cycle, inhibiting apoptosis, and enhancing mitochondrial oxidative phosphorylation (OXPHOS), whereas increasing circKIF20B was found to restore gefitinib sensitivity. Mechanistically, circKIF20B is bound to miR-615-3p for regulating the MEF2A and then altering the cell cycle, apoptosis, and mitochondrial OXPHOS. Overexpressing circKIF20B parental cells can restore sensitivity to gefitinib in the recipient cells by upregulating the exosomal circKIF20B expression. CONCLUSIONS This study revealed a novel mechanism of circKIF20B/miR-615-3p/MEF2A signaling axis involving progression of gefitinib resistance in NSCLC. Exosomal circKIF20B is expected to be an easily accessible and alternative liquid biopsy candidate and potential therapeutic target in gefitinib-resistant NSCLC. The schematic diagram of mechanism in this study. Exosomal circKIF20B inhibits gefitinib resistance and cell proliferation by arresting the cell cycle, promoting apoptosis, and reducing OXPHOS via circKIF20B/miR-615-3p/MEF2A axis in NSCLC.
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Affiliation(s)
- Si-Liang Wei
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui, China
| | - Jing-Jing Ye
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui, China
| | - Li Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui, China
| | - Lei Hu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui, China
| | - Yuan-Yuan Wei
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui, China
| | - Da-Wei Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui, China
| | - Meng-Meng Xu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui, China
| | - Guang-He Fei
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
- Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui, China.
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20
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Zhang Y, Lu Y, Xu Y, Le Z, Liu Y, Tu W, Liu Y. Hypoxia-induced degradation of PICK1 by RBCK1 promotes the proliferation of nasopharyngeal carcinoma cells. Life Sci 2023; 321:121594. [PMID: 36934971 DOI: 10.1016/j.lfs.2023.121594] [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: 01/23/2023] [Revised: 03/03/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023]
Abstract
AIMS Hypoxia is an important feature of nasopharyngeal carcinoma (NPC). "Protein interacting with PRKCA 1" (PICK1) is commonly downregulated in human malignancies and is functionally related to poor prognosis. However, there is a limited understanding of the upstream mechanisms regulating PICK1 currently. MAIN METHODS PICK1 and HIF-1α expression levels were analyzed by Immunohistochemistry (IHC), western blotting, and quantitative real-time PCR assay. Protein stability and ubiquitin assays were used to investigate PICK1 protein degradation. Immunofluorescence and co-immunoprecipitation assays were used to demonstrate the interaction between RBCK1 and PICK1. Gene knockdown by siRNA transfection was used to investigate the role of HIF-1α and RBCK1 in hypoxia-induced PICK1 degradation. Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) assays and subcutaneous xenograft nude models were used to explore the roles of RBCK1 and PICK1 in NPC cell proliferation. KEY FINDINGS PICK1 expression in NPC tissue was negatively relative to that of HIF-1α. HIF-1α downregulated PICK1 expression by facilitating its ubiquitination by the E3 ligases RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1), thereby enhancing proteasome-mediated PICK1 degradation. RBCK1 knockdown inhibited NPC cell proliferation, which was ameliorated by double knockdown of RBCK1/PICK1. SIGNIFICANCE These data provide evidence for an NPC cell adaptation mechanism to hypoxia, where HIF-1α regulates RBCK1, which targets PICK1 for degradation to promote cell proliferation.
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Affiliation(s)
- Yingzi Zhang
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Yue Lu
- Department of Radiotherapy, Huangpu Branch of the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yiqing Xu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Ziyu Le
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Yi Liu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Wenzhi Tu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
| | - Yong Liu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
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21
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He Q, Huo R, Wang J, Xu H, Zhao S, Zhang J, Sun Y, Jiao Y, Weng J, Zhao J, Cao Y. Exosomal miR-3131 derived from endothelial cells with KRAS mutation promotes EndMT by targeting PICK1 in brain arteriovenous malformations. CNS Neurosci Ther 2023; 29:1312-1324. [PMID: 36718590 PMCID: PMC10068464 DOI: 10.1111/cns.14103] [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: 08/25/2022] [Revised: 01/04/2023] [Accepted: 01/13/2023] [Indexed: 02/01/2023] Open
Abstract
AIMS To explore the underlying mechanism by which low-frequency KRAS mutations result in extensive EndMT occurrence. METHODS Exosomes derived from primarily cultured brain arteriovenous malformation (bAVMs) and human umbilical vein endothelial cells (HUVECs) transfected with KRASG12D , KRASWT , or KRASNC lentiviruses were isolated, and their effects on HUVECs were identified by western blotting and immunofluorescence staining. The expression levels of exosomal microRNAs (miRNAs) were evaluated by miRNA microarray, followed by functional experiments on miR-3131 and detection of its downstream target, and miR-3131 inhibitor in reversing the EndMT process induced by KRASG12D -transfected HUVECs and bAVM endothelial cells (ECs) were explored. RESULTS Exosomes derived from KRASG12D bAVM ECs and KRASG12D -transfected HUVECs promoted EndMT in HUVECs. MiR-3131 levels were highest in the exosomes of KRASG12D -transfected HUVECs, and HUVECs transfected with the miR-3131 mimic acquired mesenchymal phenotypes. RNA-seq and dual-luciferase reporter assays revealed that PICK1 is the direct downstream target of miR-3131. Exosomal miR-3131 was highly expressed in KRASG12D bAVMexos compared with non-KRAS-mutant bAVMexos or HUVECexos . Finally, a miR-3131 inhibitor reversed EndMT in HUVECs treated with exosomes or the supernatant of KRASG12D -transfected HUVECs and KRASG12D bAVM ECs. CONCLUSION Exosomal miR-3131 promotes EndMT in KRAS-mutant bAVMs, and miR-3131 might be a potential biomarker and therapeutic target in KRASG12D -mutant bAVMs.
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Affiliation(s)
- Qiheng He
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Ran Huo
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Jie Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Hongyuan Xu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Shaozhi Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Junze Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yingfan Sun
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yuming Jiao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Jiancong Weng
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Jizong Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yong Cao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Beijing Institute of Brain Disorders, Beijing, China
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22
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Lee SH, Ng CX, Wong SR, Chong PP. MiRNAs Overexpression and Their Role in Breast Cancer: Implications for Cancer Therapeutics. Curr Drug Targets 2023; 24:484-508. [PMID: 36999414 DOI: 10.2174/1389450124666230329123409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/20/2022] [Accepted: 01/30/2023] [Indexed: 04/01/2023]
Abstract
MicroRNAs have a plethora of roles in various biological processes in the cells and most human cancers have been shown to be associated with dysregulation of the expression of miRNA genes. MiRNA biogenesis involves two alternative pathways, the canonical pathway which requires the successful cooperation of various proteins forming the miRNA-inducing silencing complex (miRISC), and the non-canonical pathway, such as the mirtrons, simtrons, or agotrons pathway, which bypasses and deviates from specific steps in the canonical pathway. Mature miRNAs are secreted from cells and circulated in the body bound to argonaute 2 (AGO2) and miRISC or transported in vesicles. These miRNAs may regulate their downstream target genes via positive or negative regulation through different molecular mechanisms. This review focuses on the role and mechanisms of miRNAs in different stages of breast cancer progression, including breast cancer stem cell formation, breast cancer initiation, invasion, and metastasis as well as angiogenesis. The design, chemical modifications, and therapeutic applications of synthetic anti-sense miRNA oligonucleotides and RNA mimics are also discussed in detail. The strategies for systemic delivery and local targeted delivery of the antisense miRNAs encompass the use of polymeric and liposomal nanoparticles, inorganic nanoparticles, extracellular vesicles, as well as viral vectors and viruslike particles (VLPs). Although several miRNAs have been identified as good candidates for the design of antisense and other synthetic modified oligonucleotides in targeting breast cancer, further efforts are still needed to study the most optimal delivery method in order to drive the research beyond preclinical studies.
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Affiliation(s)
- Sau Har Lee
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
| | - Chu Xin Ng
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
| | - Sharon Rachel Wong
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
| | - Pei Pei Chong
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
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23
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Li J, Lv F, Jin T. Structuring and validating a prognostic model for low-grade gliomas based on the genes for plasma membrane tension. Front Neurol 2022; 13:1024869. [PMID: 36408514 PMCID: PMC9668894 DOI: 10.3389/fneur.2022.1024869] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
Background Recent studies indicate that cell mechanics are associated with malignancy through its impact on cell migration and adhesion. Gliomas are the most common primary malignant brain tumors. Low-grade gliomas (LGGs) include diffuse LGGs (WHO grade II) and intermediate-grade gliomas (WHO grade III). Few studies have focused on membrane tension in LGGs. Herein, we assessed the prognostic value of plasma membrane tension-related genes (MTRGs) in LGGs. Methods We selected plasma MTRGs identified in previous studies for analysis. Based on LGG RNA sequencing (RNA-seq) data in The Cancer Genome Atlas, a prognostic signature containing four genes was constructed via log-rank testing, LASSO regression and stepwise multivariate Cox regression and was validated with other datasets. Additionally, functional annotation, pathway enrichment and immune and molecular characteristics of the prognostic model defined subgroups were analyzed. Thereafter, a predictive nomogram that integrated baseline characteristics was constructed to determine the 3, 5, and 10-year overall survival (OS) of patients with LGG. Differentially expressed genes were confirmed via quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Results Our MTRG prognostic signature was based on ARFIP2, PICK1, SH3GL2, and SRGAP3 expression levels. The high-risk group was more positively associated with apoptosis and cell adhesion pathways and exhibited a low IDH1 mutation rate, high TP53 mutation rate and a low 1p19q co-deletion rate. The high-risk group also exhibited incremental infiltration of immune cells, more forceful immune activities and high expression of immune checkpoints as well as benefited less from immune therapy compared with the low-risk group. Our prognostic model had better forecasting ability than other scoring systems. We found that the nomogram was a better tool for predicting outcomes for patients with LGG. Finally, qRT-PCR confirmed that SH3GL2 and SRGAP3 expression levels in glioma tissues were significantly lower than those in normal brain tissues. The results of IHC analysis confirmed that SH3GL2 protein expression was higher in patients with longer survival. Conclusion Our plasma membrane tension-related gene prognostic signature is a prospective tool that can differentiate between prognosis, gene mutation landscape, immune microenvironment, immune infiltration and immunotherapeutic efficacy in LGG.
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Affiliation(s)
- Jia Li
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fangfang Lv
- Department of Pediatric Pulmonology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ting Jin
- Operating Room, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Ting Jin
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24
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Construction of a ferroptosis-associated circRNA-miRNA-mRNA network in age-related macular degeneration. Exp Eye Res 2022; 224:109234. [PMID: 36044964 DOI: 10.1016/j.exer.2022.109234] [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: 05/30/2022] [Revised: 08/14/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022]
Abstract
Age-related macular degeneration (AMD) is a leading cause of severe vision impairment in the aging population. However, the underlying molecular mechanism remains unclear. Ferroptosis is a novel non-apoptotic programmed cell death pathway, that contributes to AMD. In addition, non-coding RNA-led epigenetic profile was identified in the regulation of AMD progression. Considering that non-coding RNAs are vital regulators of ferroptosis-related genes in various pathological events, we explored and constructed a ferroptosis-associated circRNA-miRNA-mRNA network in AMD. Differential expression of fourteen ferroptosis-associated genes were identified based on our microarray analysis and the FerrDb tool at the threshold of P < 0.05 and log2|fold change| ≥ 1, which were subsequently validated by the public datasets. We further screened eight miRNAs via public datasets and the miRNet database. Based on these eight miRNAs, 23 circRNAs were mined using the Starbase tool. Taking all these together, we obtained a ferroptosis-related network with 414 pairs of circRNA-miRNA-mRNA, which are potential targets in future AMD treatments.
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25
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Xu Z, Li Y, Li P, Sun Y, Lv S, Wang Y, He X, Xu J, Xu Z, Li L, Li Y. Soft substrates promote direct chemical reprogramming of fibroblasts into neurons. Acta Biomater 2022; 152:255-272. [PMID: 36041647 DOI: 10.1016/j.actbio.2022.08.049] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 08/13/2022] [Accepted: 08/23/2022] [Indexed: 11/01/2022]
Abstract
Fibroblasts can be directly reprogrammed via a combination of small molecules to generate induced neurons (iNs), bypassing intermediate stages. This method holds great promise for regenerative medicine; however, it remains inefficient. Recently, studies have suggested that physical cues may improve the direct reprogramming of fibroblasts into neurons, but the underlying mechanisms remain to be further explored, and the physical factors reported to date do not exhibit the full properties of the extracellular matrix (ECM). Previous in vitro studies mainly used rigid polystyrene dishes, while one of the characteristics of the native in-vivo environment of neurons is the soft nature of brain ECM. The reported stiffness of brain tissue is very soft ranging between 100 Pa and 3 kPa, and the effect of substrate stiffness on direct neuronal reprogramming has not been explored. Here, we show for the first time that soft substrates substantially improved the production efficiency and quality of iNs, without needing to co-culture with glial cells during reprogramming, producing more glutamatergic neurons with electrophysiological functions in a shorter time. Transcriptome sequencing indicated that soft substrates might promote glutamatergic neuron reprogramming through integrins, actin cytoskeleton, Hippo signalling pathway, and regulation of mesenchymal-to-epithelial transition, and competing endogenous RNA network analysis provided new targets for neuronal reprogramming. We demonstrated that soft substrates may promote neuronal reprogramming by inhibiting microRNA-615-3p-targeting integrin subunit beta 4. Our findings can aid the development of regenerative therapies and help improve our understanding of neuronal reprogramming. STATEMENT OF SIGNIFICANCE: : First, we have shown that low stiffness promotes direct reprogramming on the basis of small molecule combinations. To the best of our knowledge, this is the first report on this type of method, which may greatly promote the progress of neural reprogramming. Second, we found that miR-615-3p may interact with ITGB4, and the soft substrates may promote neural reprogramming by inhibiting microRNA (miR)-615-3p targeting integrin subunit beta 4 (ITGB4). We are the first to report on this mechanism. Our findings will provide more functional neurons for subsequent basic and clinical research in neurological regenerative medicine, and will help to improve the overall understanding of neural reprogramming. This work also provides new ideas for the design of medical biomaterials for nerve regeneration.
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Affiliation(s)
- Ziran Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yan Li
- Division of Orthopedics and Biotechnology, Department for Clinical Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.
| | - Pengdong Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, Guangdong, China.
| | - Yingying Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Stomatology, The First Hospital of Jilin University, Changchun 130021, China.
| | - Shuang Lv
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yin Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Xia He
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Pathology, Shanxi Bethune Hospital, Taiyuan 030032, China.
| | - Jinying Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Burns Surgery, The First Hospital of Jilin University, Changchun 130000, China.
| | - Zhixiang Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Lisha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
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Javdani H, Mollaei H, Karimi F, Mahmoudi S, Farahi A, Mirzaei-Parsa MJ, Shahabi A. Review article epithelial to mesenchymal transition‑associated microRNAs in breast cancer. Mol Biol Rep 2022; 49:9963-9973. [PMID: 35716288 DOI: 10.1007/s11033-022-07553-4] [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: 08/06/2021] [Revised: 04/27/2022] [Accepted: 05/03/2022] [Indexed: 10/18/2022]
Abstract
Despite major advances, breast cancer (BC) is the most commonly diagnosed carcinoma and remains a deadly disease among women worldwide. Many researchers point toward an important role of an epithelial to mesenchymal transition (EMT) in BC development and promoting metastasis. Here, will be discussed that how functional changes of transcription factors, signaling pathways, and microRNAs (miRNA) in BC promote EMT. A thorough understanding the EMT biology can be important to determine reversing the process and design treatment approaches. There are frequent debates as to whether EMT is really relevant to BC in vivo, in which due to the intrinsic heterogeneity and tumor microenvironment. Nevertheless, given the importance of EMT in cancer progression and metastasis, the implementation of therapies against cancer-associated EMT will continue to help us develop and test potential treatments.
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Affiliation(s)
- Hossein Javdani
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Homa Mollaei
- Department of Biology, Faculty of Sciences, University of Birjand, Birjand, Iran
| | - Farzaneh Karimi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Shiva Mahmoudi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Farahi
- Student Research Committee, Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohamad Javad Mirzaei-Parsa
- Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Arman Shahabi
- Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran. .,Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, P. O. Box: 7618747653, Kerman, Iran.
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27
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Three-Dimensional Organotypic Cultures Reshape the microRNAs Transcriptional Program in Breast Cancer Cells. Cancers (Basel) 2022; 14:cancers14102490. [PMID: 35626094 PMCID: PMC9139376 DOI: 10.3390/cancers14102490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/03/2022] [Accepted: 05/10/2022] [Indexed: 02/04/2023] Open
Abstract
The 3D organotypic cultures, which depend on the growth of cells over the extracellular matrix (ECM) used as a scaffold, can better mimic several characteristics of solid cancers that influence tumor biology and the response to drug therapies. Most of our current knowledge on cancer is derived from studies in 2D cultures, which lack the ECM-mediated microenvironment. Moreover, the role of miRNAs that is critical for fine-tuning of gene expression is poorly understood in 3D cultures. The aim of this study was to compare the miRNA expression profiles of breast cancer cells grown in 2D and 3D conditions. On an on-top 3D cell culture model using a basement membrane matrix enriched with laminin, collagen IV, entactin, and heparin-sulfate proteoglycans, the basal B (Hs578T) and luminal (T47D) breast cancer cells formed 3D spheroid-like stellate and rounded mass structures, respectively. Morphological changes in 3D cultures were observed as cell stretching, cell–cell, and cell–ECM interactions associated with a loss of polarity and reorganization on bulk structures. Interestingly, we found prolongations of the cytoplasmic membrane of Hs578T cells similar to tunneled nanotubes contacting between neighboring cells, suggesting the existence of cellular intercommunication processes and the possibility of fusion between spheroids. Expression profiling data revealed that 354 miRNAs were differentially expressed in 3D relative to 2D cultures in Hs578T cells. Downregulated miRNAs may contribute to a positive regulation of genes involved in hypoxia, catabolic processes, and focal adhesion, whereas overexpressed miRNAs modulate genes involved in negative regulation of the cell cycle. Target genes of the top ten modulated miRNAs were selected to construct miRNA/mRNA coregulation networks. Around 502 interactions were identified for downregulated miRNAs, including miR-935/HIF1A and miR-5189-3p/AKT that could contribute to cell migration and the response to hypoxia. Furthermore, the expression levels of miR-935 and its target HIF1A correlated with the expression found in clinical tumors and predicted poor outcomes. On the other hand, 416 interactions were identified for overexpressed miRNAs, including miR-6780b-5p/ANKRD45 and miR-7641/CDK4 that may result in cell proliferation inhibition and cell cycle arrest in quiescent layers of 3D cultures. In conclusion, 3D cultures could represent a suitable model that better resembles the miRNA transcriptional programs operating in tumors, with implications not only in the understanding of basic cancer biology in 3D microenvironments, but also in the identification of novel biomarkers of disease and potential targets for personalized therapies in cancer.
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Sørensen AT, Rombach J, Gether U, Madsen KL. The Scaffold Protein PICK1 as a Target in Chronic Pain. Cells 2022; 11:1255. [PMID: 35455935 PMCID: PMC9031029 DOI: 10.3390/cells11081255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/23/2022] [Accepted: 03/30/2022] [Indexed: 02/05/2023] Open
Abstract
Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients' quality of life, but also constitute an enormous burden on society. It is therefore of great interest to explore new potent targets for effective pain treatment with fewer side effects and without addiction liability. A critical component of chronic pain conditions is central sensitization, which involves the reorganization and strengthening of synaptic transmission within nociceptive pathways. Such changes are considered as maladaptive and depend on changes in the surface expression and signaling of AMPA-type glutamate receptors (AMPARs). The PDZ-domain scaffold protein PICK1 binds the AMPARs and has been suggested to play a key role in these maladaptive changes. In the present paper, we review the regulation of AMPARs by PICK1 and its relation to pain pathology. Moreover, we highlight other pain-relevant PICK1 interactions, and we evaluate various compounds that target PICK1 and have been successfully tested in pain models. Finally, we evaluate the potential on-target side effects of interfering with the action of PICK1 action in CNS and beyond. We conclude that PICK1 constitutes a valid drug target for the treatment of inflammatory and neuropathic pain conditions without the side effects and abuse liability associated with current pain medication.
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Affiliation(s)
| | | | | | - Kenneth Lindegaard Madsen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; (A.T.S.); (J.R.); (U.G.)
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Santos-Álvarez JC, Velázquez-Enríquez JM, García-Carrillo R, Rodríguez-Beas C, Ramírez-Hernández AA, Reyes-Jiménez E, González-García K, López-Martínez A, Pérez-Campos Mayoral L, Aguilar-Ruiz SR, Romero-Tlalolini MDLÁ, Torres-Aguilar H, Castro-Sánchez L, Arellanes-Robledo J, Vásquez-Garzón VR, Baltiérrez-Hoyos R. miRNAs Contained in Extracellular Vesicles Cargo Contribute to the Progression of Idiopathic Pulmonary Fibrosis: An In Vitro Aproach. Cells 2022; 11:cells11071112. [PMID: 35406675 PMCID: PMC8997737 DOI: 10.3390/cells11071112] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/17/2022] [Accepted: 03/22/2022] [Indexed: 12/24/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease. Lesions in the lung epithelium cause alterations in the microenvironment that promote fibroblast accumulation. Extracellular vesicles (EVs) transport proteins, lipids, and nucleic acids, such as microRNAs (miRNAs). The aim of this study was to characterize the differentially expressed miRNAs in the cargo of EVs obtained from the LL97 and LL29 fibroblast cell lines isolated from IPF lungs versus those derived from the CCD19 fibroblast cell line isolated from a healthy donors. We characterized EVs by ultracentrifugation, Western blotting, and dynamic light scattering. We identified miRNAs by small RNA-seq, a total of 1144 miRNAs, of which 1027 were known miRNAs; interestingly, 117 miRNAs were novel. Differential expression analysis showed that 77 miRNAs were upregulated and 68 were downregulated. In addition, pathway enrichment analyses from the Gene Ontology and Kyoto Encyclopedia of Genomes identified several miRNA target genes in the categories, cell proliferation, regulation of apoptosis, pathways in cancer, and proteoglycans in cancer. Our data reveal that miRNAs contained in EVs cargo could be helpful as biomarkers for fibrogenesis, diagnosis, and therapeutic intervention of IPF.
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Affiliation(s)
- Jovito Cesar Santos-Álvarez
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (J.C.S.-Á.); (J.M.V.-E.); (A.A.R.-H.); (E.R.-J.); (K.G.-G.); (A.L.-M.); (S.R.A.-R.)
| | - Juan Manuel Velázquez-Enríquez
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (J.C.S.-Á.); (J.M.V.-E.); (A.A.R.-H.); (E.R.-J.); (K.G.-G.); (A.L.-M.); (S.R.A.-R.)
| | - Rosendo García-Carrillo
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Mexico;
| | | | - Alma Aurora Ramírez-Hernández
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (J.C.S.-Á.); (J.M.V.-E.); (A.A.R.-H.); (E.R.-J.); (K.G.-G.); (A.L.-M.); (S.R.A.-R.)
| | - Edilburga Reyes-Jiménez
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (J.C.S.-Á.); (J.M.V.-E.); (A.A.R.-H.); (E.R.-J.); (K.G.-G.); (A.L.-M.); (S.R.A.-R.)
| | - Karina González-García
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (J.C.S.-Á.); (J.M.V.-E.); (A.A.R.-H.); (E.R.-J.); (K.G.-G.); (A.L.-M.); (S.R.A.-R.)
| | - Armando López-Martínez
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (J.C.S.-Á.); (J.M.V.-E.); (A.A.R.-H.); (E.R.-J.); (K.G.-G.); (A.L.-M.); (S.R.A.-R.)
| | - Laura Pérez-Campos Mayoral
- Centro de Investigación, Facultad de Medicina, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca 68120, Mexico;
| | - Sergio Roberto Aguilar-Ruiz
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (J.C.S.-Á.); (J.M.V.-E.); (A.A.R.-H.); (E.R.-J.); (K.G.-G.); (A.L.-M.); (S.R.A.-R.)
| | | | - Honorio Torres-Aguilar
- Facultad de Ciencias Químicas, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico;
| | - Luis Castro-Sánchez
- Centro Universitario de Investigaciones Biomédicas, CONACYT-Universidad de Colima, Universidad de Colima, Colima 28045, Mexico;
| | | | - Verónica Rocío Vásquez-Garzón
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (M.d.l.Á.R.-T.); (V.R.V.-G.)
| | - Rafael Baltiérrez-Hoyos
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico; (M.d.l.Á.R.-T.); (V.R.V.-G.)
- Correspondence:
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Dong C, Wu K, Gu S, Wang W, Xie S, Zhou Y. PTBP3 mediates TGF-β-induced EMT and metastasis of lung adenocarcinoma. Cell Cycle 2022; 21:1406-1421. [PMID: 35323096 PMCID: PMC9345618 DOI: 10.1080/15384101.2022.2052530] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is associated with a poor prognosis due to early metastasis to distant organs. TGF-β potently induces epithelial-to-mesenchymal transition (EMT) and promotes invasion and metastasis of cancers. However, the mechanisms underlying this alteration are largely unknown. PTBP3 plays a critical role in RNA splicing and transcriptional regulation. Although accumulating evidence has revealed that PTBP3 exhibits a pro-oncogenic role in several cancers, whether and how PTBP3 mediates TGF-β-induced EMT and metastasis in LUAD remains unknown. The expression levels and prognostic value of PTBP3 were analyzed in human LUAD tissues and matched normal tissues. siRNAs and lentivirus-mediated vectors were used to transfect LUAD cell lines. Various in vitro experiments including western blot, qRT-PCR, a luciferase reporter assay, chromatin immunoprecipitation (ChIP), transwell migration and invasion assay and in vivo metastasis experiment were performed to determine the roles of PTBP3 in TGF-β-induced EMT and metastasis. PTBP3 expression was significantly upregulated in patients with LUAD, and high expression of PTBP3 indicated a poor prognosis. Intriguingly, we found that PTBP3 expression level in LUAD cell lines was significantly increased by exogenous TGF-β1 in a Smad-dependent manner. Mechanistically, p-Smad3 was recruited to the PTBP3 promoter and activated its transcription. In turn, PTBP3 knockdown abolished TGF-β1-mediated EMT through the inhibition of Smad2/3 expression. Furthermore, PTBP3 overexpression increased lung and liver metastasis of LUAD cells in vivo. PTBP3 is indispensable to TGF-β-induced EMT and metastasis of LUAD cells and is a novel potential therapeutic target for the treatment of LUAD.
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Affiliation(s)
- Chenglai Dong
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Kaiqin Wu
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shaorui Gu
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wenli Wang
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shiliang Xie
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yongxin Zhou
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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Deng S, Hu Q, Chen X, Lei Q, Lu W. GM130 protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by regulating autophagy formation. Exp Gerontol 2022; 163:111772. [PMID: 35331826 DOI: 10.1016/j.exger.2022.111772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/02/2022] [Accepted: 03/18/2022] [Indexed: 11/18/2022]
Abstract
Blood-brain barrier (BBB) disruption following intracerebral hemorrhage (ICH) significantly contributes to neurological deficits. Tight junction (TJ) protein loss in brain endothelial cells leads to BBB disruption. We previously revealed the importance of the Golgi apparatus (GA) in maintaining TJ integrity in mouse brain endothelial (bEnd.3) cells, but the specific mechanisms remain unknown. Herein, we investigated the potential role of the GA in BBB damage and neurological dysfunction after ICH using bEnd.3 cells and hemin to mimic hemorrhage in vitro. We used a rat hemorrhage stroke model to evaluate the role of the GA in BBB disruption during ICH. GM130 levels decreased with ICH length in vivo and in vitro. TJ protein destruction further increased following GM130 silencing. GM130 overexpression alleviated TJ protein impairment and improved BBB integrity. bEnd.3 cells treated with an autophagy inhibitor showed reduced TJ protein damage following GM130 silencing. The intracerebroventricular injection of an autophagy inhibitor rescued GM130 silencing-induced BBB leakage. Thus, TJ proteins were destroyed by excessive autophagic pathway activation following ICH, whereas GM130 protected against TJ damage by maintaining proper autophagy. We suggest that GM130-regulated selective autophagy modulates BBB integrity and GM130 upregulation suppresses the autophagy-lysosome pathway, which might maintain BBB function. Therefore, GA protection is beneficial for ICH, and GM130 is a potential therapeutic target for its treatment.
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Affiliation(s)
- Shuwen Deng
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Qing Hu
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xiqian Chen
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Qiang Lei
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Wei Lu
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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Hu Y, Tang J, Xu F, Chen J, Zeng Z, Han S, Wang F, Wang D, Huang M, Zhao Y, Huang Y, Zhuo W, Zhao G. A reciprocal feedback between N6-methyladenosine reader YTHDF3 and lncRNA DICER1-AS1 promotes glycolysis of pancreatic cancer through inhibiting maturation of miR-5586-5p. J Exp Clin Cancer Res 2022; 41:69. [PMID: 35183226 PMCID: PMC8857805 DOI: 10.1186/s13046-022-02285-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/10/2022] [Indexed: 11/23/2022] Open
Abstract
Background Glycolysis is a pivotal process in metabolic reprogramming of tumorigenesis. Previous research has indicated that lncRNAs might play crucial roles in glycolysis of various tumors. However, the function of lncRNAs in glycolysis of pancreatic cancer has not been fully elucidated. Methods Bio-information analyses were applied to reveal the potential glycolysis-associated lncRNA. RT-PCR and fluorescence in situ hybridization (FISH) assays were applied to detect the expression of antisense RNA1 of DICER1 (DICER1-AS1) in pancreatic cancer tissues and cell lines. Gain- and loss-of-function experiments were performed to evaluate the roles of DICER1-AS1 in glycolysis and tumorigenesis of PC. Mechanistic experiments including luciferase reporter assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) were employed to uncover the downstream targets and regulatory mechanism of DICER1-AS1 in glycolysis of PC. Results Bio-information analysis indicated that DICER1-AS1 was downregulated in PC and negatively correlated with glycolytic genes expression. Meanwhile, overexpression of DICER1-AS1 inhibited glycolysis, proliferation, and metastasis of PC cells both in vitro and in vivo. Mechanistically, DICER1-AS1 promoted transcription of its sense gene DICER1 by recruiting transcriptional factor YY1 to the DICER1 promoter. Meanwhile, DICER1 promoted maturation of miR-5586-5p which consequently inhibited glycolytic gene expression including LDHA, HK2, PGK1, and SLC2A1. Notably, enhanced interaction between N6-methyladenosine (m6A) reader YTHDF3 and DICER1-AS1 led to degradation of DICER1-AS1 in response to glucose depletion. Moreover, our data revealed that YTHDF3 was a critical target for miR-5586-5p, by which forming a negative feedback with DICER1-AS1 to regulate glycolysis of PC. Conclusion Our results implicate a negative feedback of m6A reader YTHDF3 and glycolytic lncRNA DICER1-AS1 is involved in glycolysis and tumorigenesis of PC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02285-6.
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Liu Y, Li H, Zhao Y, Li D, Zhang Q, Fu J, Fan S. Knockdown of ADORA2A antisense RNA 1 inhibits cell proliferation and enhances imatinib sensitivity in chronic myeloid leukemia. Bioengineered 2022; 13:2296-2307. [PMID: 35034552 PMCID: PMC8973732 DOI: 10.1080/21655979.2021.2024389] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Long non-coding RNAs (LncRNAs) exert important regulatory roles in chronic myeloid leukemia (CML). In this study, we aimed to investigate the potential role and molecular mechanism of lncRNA ADORA2A antisense RNA 1 (ADORA2A-AS1) in CML. We found that the expression of ADORA2A-AS1 was upregulated in CML. Further, knockdown of ADORA2A-AS1 inhibited the proliferation, induced apoptosis, arrested cell cycle, and enhanced imatinib sensitivity in CML cells. Besides, ADORA2A-AS1 promoted the expression of transforming growth factor-beta receptor 1 (TGFBR1) and ATP binding cassette subfamily C member 2 (ABCC2) via sponging miR-665, thereby exerting a tumor-promoting activity. Collectively, our results confirmed the oncogenic effect of ADORA2A-AS1 in CML, indicating that ADORA2A-AS1 is a promosing therapeutic target for CML.
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Affiliation(s)
- Yabo Liu
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Huibo Li
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yanqiu Zhao
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Dandan Li
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Qian Zhang
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jinyue Fu
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shengjin Fan
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Du Y, Miao Z, Qiu L, Lv Y, Wang K, Guo L. Clinical Potential of miR-451 and miR-506 as a Prognostic Biomarker in Patients with Breast Cancer. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:9578788. [PMID: 35070246 PMCID: PMC8767372 DOI: 10.1155/2022/9578788] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 12/29/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND The incidence and mortality of breast cancer in the world remain high. The function and important role of miR-451 and miR-506 in a series of cancers have been proved. The purpose of this research was to explore the clinical diagnosis and prognostic significance of miR-451 and miR-506 expression in breast cancer. METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to detect miR-451 and miR-506 expression in serum and tissues. The relationship of miR-451 and miR-506 with clinical parameters was determined by the chi-square test. Receiver operating characteristics (ROC) analysis was conducted to evaluate the diagnostic accuracy of miR-451 and miR-506 in breast cancer. In addition, we determined the prognostic performance of miR-451 and miR-506 using Kaplan-Meier survival assay. RESULTS The expression of miR-451 and miR-506 in breast cancer patients was significantly lower than that in healthy people. miR-451 and miR-506 expression decreased in breast cancer tissues compared with paracancerous tissue. High expression of miR-451 and miR-506 was associated with positive lymph node metastasis and late tumor node metastasis stage. Breast cancer patients with high miR-451 and miR-506 expression had lower five-year survival rate. The level of miR-451 and miR-506 expression showed high diagnostic accuracy for distinguishing breast cancer patients and healthy people. CONCLUSION miR-451 and miR-506 could be used as biomarker for the diagnosis and prognosis of breast cancer.
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Affiliation(s)
- Yu Du
- Department of Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing City 100050, China
| | - Zhuang Miao
- Department of Laboratory, Affiliated Hospital of Jilin Medical College, Jilin City 132013, Jilin Province, China
| | - Lijuan Qiu
- Department of Blood Transfusion, Beijing Children's Hospital, Capital Medical University, Beijing City 100045, China
| | - Yan Lv
- Department of Laboratory, Beijing Public Security Hospital, Beijing City 100050, China
| | - Kedi Wang
- Department of Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing City 100050, China
| | - Lusheng Guo
- Department of Laboratory, Affiliated Hospital of Jilin Medical College, Jilin City 132013, Jilin Province, China
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Yu J, Zhang H, Zhao C, Li G, Zhang Y, Sun Y. CircRNA circ_0008037 facilitates tumor growth and the Warburg effect via upregulating NUCKS1 by binding to miR-433-3p in non-small cell lung cancer. Thorac Cancer 2021; 13:162-172. [PMID: 34850570 PMCID: PMC8758425 DOI: 10.1111/1759-7714.14235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) participate in the genesis and progression of tumors, including non-small cell lung cancer (NSCLC). At present, the role and regulatory mechanisms of circRNAs in NSCLC have not been fully elucidated. The aim of this study was to explore the role and regulatory mechanism of circRNA hsa_circ_0008037 (circ_0008037) in NSCLC. METHODS Expression of circ_0008037 in NSCLC tissues and cells was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Loss-of-function experiments were performed to analyze the influence of circ_0008037 knockdown on proliferation, migration, invasion, and the Warburg effect of NSCLC cells. Western blotting was utilized for protein analysis. The regulatory mechanism of circ_0008037 was surveyed by bioinformatics analysis, RNA pulldown assay, and dual-luciferase reporter assay. Xenograft assay was used to validate the oncogenicity of circ_0008037 in NSCLC in vivo. RESULTS Circ_0008037 was upregulated in NSCLC tissues and cells. Circ_0008037 downregulation reduced tumor growth in vivo and repressed proliferation, migration, invasion, and decreased the Warburg effect of NSCLC cells in vitro. Mechanically, circ_0008037 regulated nuclear ubiquitous casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) expression via sponging miR-433-3p. Furthermore, MiR-433-3p inhibitor reversed the inhibiting influence of circ_0008037 silencing on proliferation, migration, invasion, and the Warburg effect of NSCLC cells. Also, NUCKS1 elevation overturned the repressive influence of miR-433-3p mimic on proliferation, migration, invasion, and the Warburg effect of NSCLC cells. CONCLUSION Circ_0008037 accelerated tumor growth and elevated the Warburg effect via regulating NUCKS1 expression by adsorbing miR-433-3p, providing an underlying target for NSCLC treatment.
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Affiliation(s)
- Jia Yu
- Department of Respiratory, Dongying People's Hospital, Dongying, China
| | - Haining Zhang
- Department of Respiratory, Dongying People's Hospital, Dongying, China
| | - Chunsheng Zhao
- Department of Respiratory, Dongying People's Hospital, Dongying, China
| | - Guanghui Li
- Department of Respiratory, Dongying People's Hospital, Dongying, China
| | - Yingying Zhang
- Department of Respiratory, Dongying People's Hospital, Dongying, China
| | - Yang Sun
- Department of Respiratory, Dongying People's Hospital, Dongying, China
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Du P, Luo K, Li G, Zhu J, Xiao Q, Li Y, Zhang X. Long non-coding RNA VCAN-AS1 promotes the malignant behaviors of breast cancer by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway. Bioengineered 2021; 12:5028-5044. [PMID: 34365889 PMCID: PMC8806652 DOI: 10.1080/21655979.2021.1960774] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
An accumulating number of studies have found that long noncoding RNAs (lncRNAs) participate in breast cancer (BC) development. LncRNA VCAN-AS1, a novel lncRNA, has been confirmed to regulate the progression of gastric cancer, while its role in BC is elusive. Here, our results illustrate that VCAN-AS1 is overexpressed in BC tissues and cells, while miR-106a-5p was downregulated and negatively correlated with VCAN-AS1. In addition, high VCAN-AS1 expression and low miR-106a-5p expression were closely correlated with poor overall survival in BC patients. Functional experiments confirmed that VCAN-AS1 overexpression notably accelerated BC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) and enhanced tumor cell growth while also suppressing cell apoptosis. However, overexpression of miR-106a-5p had the opposite effects. In addition, rescue experiments confirmed that overexpression of VCAN-AS1 inhibited the tumor-suppressive effects mediated by miR-106a-5p. Mechanistically, through bioinformatics analysis, we found that VCAN-AS1 functions as a competitive endogenous RNA (ceRNA) of miR-106a-5p, which targets the 3ʹ untranslated region (UTR) of signal transducer and activator of transcription 3 (STAT3). Further experiments indicated that miR-106a-5p downregulated the STAT3/hypoxia-inducible factor-1alpha (HIF-1α) pathway, while activating the STAT3 pathway reversed miR-106a-5p-mediated antitumor effects. Collectively, our data suggest that VCAN-AS1 is upregulated in breast cancer and promotes its progression by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway. This study provides a new target for BC therapy.
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Affiliation(s)
- Peng Du
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kaifeng Luo
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Guoyong Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jisheng Zhu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qi Xiao
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yong Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xingjian Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Yu YZ, Mu Q, Ren Q, Xie LJ, Wang QT, Wang CP. miR-381-3p suppresses breast cancer progression by inhibition of epithelial-mesenchymal transition. World J Surg Oncol 2021; 19:230. [PMID: 34362391 PMCID: PMC8348871 DOI: 10.1186/s12957-021-02344-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
Background Accumulating evidence indicates that miRNAs are involved in multiple cellular functions and participate in various cancer development and progression, including breast cancer. Methods We aimed to investigate the role of miR-381-3p in breast cancer. The expression level of miR-381-3p and EMT transcription factors was examined by quantitative real-time PCR (qRT-PCR). The effects of miR-381-3p on breast cancer proliferation and invasion were determined by Cell Counting Kit-8 (CCK-8), colony formation, and transwell assays. The regulation of miR-381-3p on its targets was determined by dual-luciferase analysis, qRT-PCR, and western blot. Results We found that the expression of miR-381-3p was significantly decreased in breast cancer tissues and cell lines. Overexpression of miR-381-3p inhibited breast cancer proliferation and invasion, whereas knockdown of miR-381-3p promoted cell proliferation and invasion in MDA-MB-231 and SKBR3 cells. Mechanistically, overexpression of miR-381-3p inhibited breast cancer epithelial–mesenchymal transition (EMT). Both Sox4 and Twist1 were confirmed as targets of miR-381-3p. Moreover, transforming growth factor-β (TGF-β) could reverse the effects of miR-381-3p on breast cancer progression. Conclusions Our observation suggests that miR-381-3p inhibits breast cancer progression and EMT by regulating the TGF-β signaling via targeting Sox4 and Twist1.
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Affiliation(s)
- Yong-Zheng Yu
- The First Department of Breast Surgery, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, 266042, China
| | - Qiang Mu
- The First Department of Breast Surgery, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, 266042, China
| | - Qian Ren
- The First Department of Breast Surgery, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, 266042, China
| | - Li-Juan Xie
- Department of Ophthalmology, Qingdao Women and Children's Hospital, Qingdao University, Qingdao, 266034, China
| | - Qi-Tang Wang
- The First Department of Breast Surgery, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, 266042, China
| | - Cui-Ping Wang
- The First Department of Breast Surgery, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, 266042, China.
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Semina EV, Rysenkova KD, Troyanovskiy KE, Shmakova AA, Rubina KA. MicroRNAs in Cancer: From Gene Expression Regulation to the Metastatic Niche Reprogramming. BIOCHEMISTRY (MOSCOW) 2021; 86:785-799. [PMID: 34284705 DOI: 10.1134/s0006297921070014] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
By 2003, the Human Genome project had been completed; however, it turned out that 97% of genome sequences did not encode proteins. The explanation came later when it was found the untranslated DNA contain sequences for short microRNAs (miRNAs) and long noncoding RNAs that did not produce any mRNAs or tRNAs, but instead were involved in the regulation of gene expression. Initially identified in the cytoplasm, miRNAs have been found in all cell compartments, where their functions are not limited to the degradation of target mRNAs. miRNAs that are secreted into the extracellular space as components of exosomes or as complexes with proteins, participate in morphogenesis, regeneration, oncogenesis, metastasis, and chemoresistance of tumor cells. miRNAs play a dual role in oncogenesis: on one hand, they act as oncogene suppressors; on the other hand, they function as oncogenes themselves and inactivate oncosuppressors, stimulate tumor neoangiogenesis, and mediate immunosuppressive processes in the tumors, The review presents current concepts of the miRNA biogenesis and their functions in the cytoplasm and nucleus with special focus on the noncanonical mechanisms of gene regulation by miRNAs and involvement of miRNAs in oncogenesis, as well as the authors' opinion on the role of miRNAs in metastasis and formation of the premetastatic niche.
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Affiliation(s)
- Ekaterina V Semina
- National Cardiology Research Center, Ministry of Health of the Russian Federation, Moscow, 121552, Russia. .,Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
| | - Karina D Rysenkova
- National Cardiology Research Center, Ministry of Health of the Russian Federation, Moscow, 121552, Russia.,Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
| | | | - Anna A Shmakova
- National Cardiology Research Center, Ministry of Health of the Russian Federation, Moscow, 121552, Russia
| | - Kseniya A Rubina
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
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MicroRNAs in Epithelial-Mesenchymal Transition Process of Cancer: Potential Targets for Chemotherapy. Int J Mol Sci 2021; 22:ijms22147526. [PMID: 34299149 PMCID: PMC8305963 DOI: 10.3390/ijms22147526] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/07/2021] [Accepted: 07/10/2021] [Indexed: 12/12/2022] Open
Abstract
In the last decades, a kind of small non-coding RNA molecules, called as microRNAs, has been applied as negative regulators in various types of cancer treatment through down-regulation of their targets. More recent studies exert that microRNAs play a critical role in the EMT process of cancer, promoting or inhibiting EMT progression. Interestingly, accumulating evidence suggests that pure compounds from natural plants could modulate deregulated microRNAs to inhibit EMT, resulting in the inhibition of cancer development. This small essay is on the purpose of demonstrating the significance and function of microRNAs in the EMT process as oncogenes and tumor suppressor genes according to studies mainly conducted in the last four years, providing evidence of efficient target therapy. The review also summarizes the drug candidates with the ability to restrain EMT in cancer through microRNA regulation.
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Li Q, Qiu Y, Jin T, Liu M, Hou Y. [MiR- 4719 inhibits migration and invasion of human breast cancer cells via targeting ARHGAP36]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:854-861. [PMID: 34238737 DOI: 10.12122/j.issn.1673-4254.2021.06.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To detect the expression of miR-4719 in breast cancer tissues and cells and explore its role in regulating invasion and migration of breast cancer cells. OBJECTIVE qRT-PCR was used to detect the expression of miR-4719 and ARHGAP36 in 30 pairs of human breast cancer tissues and adjacent tissues, two breast cancer cell lines (BT549 and MDA-MB- 231) and normal breast cells (MCF-10A). Bioinformatic methods were utilized to analyze the relationship between miR-4719 expression and overall survival of breast cancer patients and predict the potential target gene miR- 4719. miR-4719 mimics, ARHGAP36 shRNA and ARHGAP36 plasmids were transfected into breast cancer cells to test the effects of miR-4719 overexpression, ARHGAP36 knockdown and ARHGAP36 overexpression on cell migration and invasion using wound healing assay and Transwell assay. A dual-luciferase reporter assay was used to verify the direct binding between miR-4719 and 3'-UTR of ARHGAP36. OBJECTIVE Compared with those in adjacent tissues or normal breast cells, the expressions of miR-4719 were significantly decreased and the expression of ARHGAP36 was increased in breast cancer tissues (P < 0.001) and breast cancer cell lines (P < 0.01). A low expression of miR-4719 was correlated with a poorer overall survival of breast cancer patients (P < 0.05). Overexpression of miR-4719 and ARHGAP36 knockdown both significantly attenuated the invasion and migration abilities of breast cancer cells (P < 0.05). The expression of miR-4719 was inversely correlated to that of ARHGAP36 in breast cancer tissues (P < 0.01). Dual-luciferase reporter assay confirmed that ARHGAP36 was the target gene of miR-4719 (P < 0.01), and exogenous miR-4719 could significantly lower the expression of ARHGAP36 (P < 0.05). ARHGAP36 overexpression significantly reversed the inhibitory effects of miR-4719 mimics on migration and invasion of breast cancer cells (P < 0.05). OBJECTIVE The expression of miR-4719 is aberrantly decreased in breast cancer tissues to promote migration and invasion of breast cancer cells by up-regulating ARHGAP36 expression.
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Affiliation(s)
- Q Li
- Key Laboratory of Laboratory Medical Diagnostics of Ministry of Education Chongqing Medical University, Chongqing 400016, China
| | - Y Qiu
- Key Laboratory of Laboratory Medical Diagnostics of Ministry of Education Chongqing Medical University, Chongqing 400016, China
| | - T Jin
- Key Laboratory of Laboratory Medical Diagnostics of Ministry of Education Chongqing Medical University, Chongqing 400016, China
| | - M Liu
- Key Laboratory of Laboratory Medical Diagnostics of Ministry of Education Chongqing Medical University, Chongqing 400016, China
| | - Y Hou
- Experimental Teaching Center of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
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41
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Dou Q, Tong H, Yang Y, Zhang H, Gan H. PICK1 Deficiency Exacerbates Sepsis-Associated Acute Kidney Injury. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9884297. [PMID: 34307672 PMCID: PMC8285178 DOI: 10.1155/2021/9884297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/19/2021] [Accepted: 06/24/2021] [Indexed: 12/19/2022]
Abstract
We performed in vitro and in vivo experiments to explore the role of protein kinase C-binding protein 1 (PICK1), an intracellular transporter involved in oxidative stress-related neuronal diseases, in sepsis-related acute kidney injury (AKI). Firstly, PCR, western blotting, and immunohistochemistry were used to observe the expression of PICK1 after lipopolysaccharide- (LPS-) induced AKI. Secondly, by inhibiting PICK1 in vivo and silencing PICK1 in vitro, we further explored the effect of PICK1 on AKI. Finally, the relationship between PICK1 and oxidative stress and the related mechanisms were explored. We found that the expression of PICK1 was increased in LPS-induced AKI models both in vitro and in vivo. PICK1 silencing significantly aggravated LPS-induced apoptosis, accompanied by ROS production in renal tubular epithelial cells. FSC231, a PICK1-specific inhibitor, aggravated LPS-induced kidney injury. Besides, NAC (N-acetylcysteine), a potent ROS scavenger, significantly inhibited the PICK1-silencing-induced apoptosis. In conclusion, PICK1 might protect renal tubular epithelial cells from LPS-induced apoptosis by reducing excessive ROS, making PICK1 a promising preventive target in LPS-induced AKI.
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Affiliation(s)
- Qian Dou
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Hang Tong
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yichun Yang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Han Zhang
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Hua Gan
- Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Nie G, Cao X, Mao Y, Lv Z, Lv M, Wang Y, Wang H, Liu C. Tumor-associated macrophages-mediated CXCL8 infiltration enhances breast cancer metastasis: Suppression by Danirixin. Int Immunopharmacol 2021; 95:107153. [PMID: 33677254 DOI: 10.1016/j.intimp.2020.107153] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 10/07/2020] [Accepted: 10/21/2020] [Indexed: 01/11/2023]
Abstract
Breast cancer is the most frequent cancer among females and the second most common cause of cancer deaths worldwide. Tumor-associated macrophages (TAMs) are the most abundant immune cell population in the tumor microenvironment, including breast cancer. Breast cancer stem cells (BCSCs) play an important role in regulating breast cancer growth and metastasis, which still remains an obstacle for successful treatment of breast cancer and requires further investigation, as well as the potential therapeutic strategies. Cytokine array validated that C-X-C motif chemokine ligand 8 (CXCL8) is a pivotal chemokine secreted by TAMs, and CXCL8 could enhance breast cancer migration, invasion ability, and epithelial-mesenchymal transition (EMT) in both animal and human breast cancer. In this study, the clinical data firstly indicated that high CXCL8 expression was significantly associated with metastasis and tumor growth in breast cancer patients. Then, we showed that TAMs-released CXCL8 could markedly elevate the migration, invasion and EMT events in breast cancer cells, as well as the self-renewal of BCSCs in vitro. These processes were markedly abrogated by the treatment of Danirixin, a reversible and selective antagonist of CXC chemokine receptor 2 (CXCR2). Consistently, the in vivo analysis confirmed that CXCL8 suppression using Danirixin effectively reduced the tumor growth, lung metastasis and repressed the self-renewal of BCSCs. Collectively, TAMs/CXCL8 could enhance BCSCs self-renewal and breast cancer metastasis, and these effects could be markedly abolished by Danirixin treatment, suppressing breast cancer progression consequently. Therefore, Danirixin could be considered as a novel and effective therapeutic strategy for breast cancer treatment without obvious toxicity to major organs.
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Affiliation(s)
- Gang Nie
- Department of Breast Center, The Affiliated Hospital of Qingdao University, Shandong 266000, China
| | - Xiangbo Cao
- The Affiliated Hospital of Qingdao University, Library, Shandong 266000, China
| | - Yan Mao
- Department of Breast Center, The Affiliated Hospital of Qingdao University, Shandong 266000, China
| | - Zhidong Lv
- Department of Breast Center, The Affiliated Hospital of Qingdao University, Shandong 266000, China
| | - Meng Lv
- Department of Breast Center, The Affiliated Hospital of Qingdao University, Shandong 266000, China
| | - Yongmei Wang
- Department of Breast Center, The Affiliated Hospital of Qingdao University, Shandong 266000, China
| | - Haibo Wang
- Department of Breast Center, The Affiliated Hospital of Qingdao University, Shandong 266000, China
| | - Chen Liu
- Department of Breast Center, The Affiliated Hospital of Qingdao University, Shandong 266000, China.
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Abdelaleem OO, Shaker OG, AbdelHafez MN, Abdelghaffar NK, Eid HM, Zaidan M, Khalefa AA, Ahmed NA, Hemeda NF, Zaki OM, Awaji AAA, Mohammed SR. The Influence of rs1859168 Polymorphism on Serum Expression of HOTTIP and Its Target miR-615-3p in Egyptian Patients with Breast Cancer. Biomolecules 2021; 11:733. [PMID: 34069089 PMCID: PMC8156858 DOI: 10.3390/biom11050733] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/02/2021] [Accepted: 05/07/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Polymorphisms of long noncoding RNAs are lately documented as hazardous factors for the development of numerous tumors. Furthermore, the evaluation of noncoding RNAs has emerged as a novel detector of breast cancer patients. We aimed to genotype the HOXA transcript at the distal tip (HOTTIP) rs1859168 and assess its relationship with the levels of the serum HOTTIP and its target miR-615-3p in patients with breast cancer (BC). METHODS One hundred and fifty-one patients with BC, 139 patients with fibroadenoma (FA), and 143 healthy participants were incorporated into the current study. The genotyping of rs1859168 and the measurements of the HOTTIP and miR-615-3p levels were assessed using quantitative real-time PCR. RESULTS We revealed a significant association between each of the CC genotypes, C allele, dominant and recessive models, and the increased risk of BC (p = 0.013, p < 0.001, p < 0.001, and p < 0.001, respectively) relative to the healthy controls. Similarly, the CC genotype, C allele, and recessive model were observed to be related to the increased incidence of BC with respect to FA (p < 0.001 for all). A significant upregulation of HOTTIP and a marked decrease of miR-615-3p were verified in patients with BC compared to each of the healthy individuals, patients with FA, and the non-BC group (healthy subjects + FA) (p < 0.001 for all). A significant negative correlation was demonstrated between the expression of HOTTIP and miR-615-3p in the serum of patients with BC. The HOTTIP expression was upregulated, while that of miR-615-3p was downregulated in patients with BC who carried the CC genotype with respect to those who carried the AA or AC genotypes (p < 0.05 for all). CONCLUSIONS The genetic variants of rs1859168 are linked to an increased susceptibility to BC. Moreover, HOTTIP and miR-615-3p may be used as novel indicators and targets for the treatment of patients with BC.
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Affiliation(s)
- Omayma O. Abdelaleem
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum 63511, Egypt; (O.O.A.); (S.R.M.)
| | - Olfat G. Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11511, Egypt;
| | - Marwa N. AbdelHafez
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo 11511, Egypt;
| | - Noha K. Abdelghaffar
- Department of Clinical pathology, Faculty of Medicine, Fayoum University, Fayoum 63511, Egypt;
| | - Hanaa M. Eid
- Department of Microbiology and Immunology, Faculty of Medicine, Fayoum University, Fayoum 63511, Egypt
| | - Mohamed Zaidan
- Department of General Surgery, Faculty of Medicine, Fayoum University, Fayoum 63511, Egypt;
| | - Abeer A. Khalefa
- Department of Physiology, Faculty of Medicine, Zagazig University, Zagazig 44523, Egypt; (A.A.K.); (N.A.A.)
| | - Naglaa A. Ahmed
- Department of Physiology, Faculty of Medicine, Zagazig University, Zagazig 44523, Egypt; (A.A.K.); (N.A.A.)
| | - Nada F. Hemeda
- Department of Genetics, Faculty of Agriculture, Fayoum University, Fayoum 63511, Egypt;
| | - Othman M. Zaki
- Department of Clinical Pathology, Faculty of Medicine, Damietta University, Damietta 34511, Egypt;
| | - Aeshah Ali A. Awaji
- Department of Biology, Faculty of Science, University College of Taymaa, Tabuk University, Tabuk 47711, Saudi Arabia;
| | - Shereen R. Mohammed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum 63511, Egypt; (O.O.A.); (S.R.M.)
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Yuan L, Li JX, Yang Y, Chen Y, Ma TT, Liang S, Bu Y, Yu L, Nan Y. Depletion of MRPL35 inhibits gastric carcinoma cell proliferation by regulating downstream signaling proteins. World J Gastroenterol 2021; 27:1785-1804. [PMID: 33967557 PMCID: PMC8072187 DOI: 10.3748/wjg.v27.i16.1785] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/04/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric carcinoma (GC) is a digestive system disease with high morbidity and mortality. However, early clinical detection is difficult, and the therapeutic effect for advanced disease is not satisfactory. Thus, finding new tumor markers and therapeutic targets conducive to the treatment of GC is imperative. MRPL35 is a member of the large subunit family of mitochondrial ribosomal protein. MRPL35 shows the characteristic of oncogene in colorectal cancer and esophageal cancer, which promotes the exploration of the correlation between MRPL35 and GC. We proposed that the expression of MRPL35 might be critical in GC.
AIM To study the effect of MRPL35 knockdown on GC cell proliferation.
METHODS The expression of MRPL35 in GC was evaluated based on data from the public tumor database UALCAN (http://www.ualcan.path.uab.edu). The effect of the expression of MRPL35 on the prognosis was evaluated with KMplot (http://www.kmplot.com). The expression of MRPL35 was assessed on the tissue microarray by immunohistochemistry and the level of MRPL35 mRNA in 25 pairs of clinical GC tissues and matched adjacent tissues was detected by quantitative reverse transcription-polymerase chain reaction. Celigo cell count assay, colony formation assay, and flow cytometry were used to assess the role of MRPL35 in GC cell proliferation and apoptosis in vitro. Additionally, tumor formation experiment in BALB/c nude mice was utilized to determine the effect of MRPL35 on GC cell proliferation. After knockdown of MRPL35, related proteins were identified by isobaric tags for relative and absolute quantification analysis, and the expression of related proteins was detected by Western blot.
RESULTS The expression of MRPL35 was up-regulated in GC (P = 1.77 × 10-4). The Kaplan-Meier plots of the overall survival indicated that high expression of MRPL35 was associated with a poor survival in GC. Compared with adjacent tissues, the expression of MRPL35 in GC tissues was increased, which was related to age (P = 0.03), lymph node metastasis (P = 0.007), and pathological tumor-node-metastasis stage (P = 0.024). Knockdown of MRPL35 inhibited GC cell proliferation and colony formation and induced apoptosis. Animal experiment results showed that knockdown of MRPL35 inhibited tumor formation in BALB/c nude mice. Western blotting analysis showed that after knockdown of MRPL35, the expression of PICK1 and BCL-XL proteins decreased, and that of AGR2 protein increased.
CONCLUSION Collectively, our findings demonstrate that knockdown of MRPL35 inhibits GC cell proliferation through related proteins including PICK1, BCL-XL, and AGR2.
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Affiliation(s)
- Ling Yuan
- Pharmacy College of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jia-Xin Li
- Pharmacy College of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Yang
- Pharmacy College of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yan Chen
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Ting-Ting Ma
- Pharmacy College of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Shuang Liang
- Department of Oncology and Endocrinology, Yinchuan Hospital of Traditional Chinese Medicine Affiliated to Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yang Bu
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Lei Yu
- Department of Infectious Diseases, The Fourth Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yi Nan
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
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Zhou Y, Li K, Du Y, Wu Z, Wang H, Zhang X, Yang Y, Chen L, Hao K, Wang Z, Lyu J. Protein interacting with C-kinase 1 is involved in epithelial-mesenchymal transformation and suppresses progress of gastric cancer. Med Oncol 2021; 38:34. [PMID: 33660148 DOI: 10.1007/s12032-021-01483-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 02/17/2021] [Indexed: 01/06/2023]
Abstract
Protein interacting with C-kinase 1 (PICK1) is a 415-aa multidomain scaffold protein encoded by the PICK1 gene. Accumulating evidence suggests that PICK1 is involved in the progression of cancer. However, the role of PICK1 in gastric cancer (GC) remains largely unknown. Using integrated analysis of publicly available GC transcriptome data from the Gene Expression Omnibus (GEO) database and immunohistochemistry analysis of samples obtained from clinical GC patients, we found that PICK1 expression was significantly down-regulated in gastric tumor tissues in comparison with adjacent normal tissues. Our analyses also revealed that decreased expression of PICK1 conferred a disadvantage on overall survival time in GC patients. Additionally, PICK1 expression showed a strong association with the epithelial-mesenchymal transition (EMT) pathway, and PICK1 might represent a functional bridge for EMT. Moreover, PICK1 expression was significantly decreased in the EMT subtype of GC and was negatively correlated with the expression of fibronectin 1 (FN1) and myosin light chain 9 (MYL9) mRNAs. Thus, our study provides evidence that PICK1 is a promising biomarker for the molecular etiology of GC.
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Affiliation(s)
- Ying Zhou
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Kaiqiang Li
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China.,Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China
| | - Yaoqiang Du
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China.,Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China
| | - Zhaoyu Wu
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Hao Wang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Xin Zhang
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China
| | - Yexiaoqing Yang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Linjie Chen
- School of Laboratory Medicine, Hangzhou Medical College, Hangzhou, 310053, China
| | - Ke Hao
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China.,Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China
| | - Zhen Wang
- Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China. .,Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China.
| | - Jianxin Lyu
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China. .,Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China. .,School of Laboratory Medicine, Hangzhou Medical College, Hangzhou, 310053, China.
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Wu H, Chu Y, Sun S, Li G, Xu S, Zhang X, Jiang Y, Gao S, Wang Q, Zhang J, Pang D. Hypoxia-Mediated Complement 1q Binding Protein Regulates Metastasis and Chemoresistance in Triple-Negative Breast Cancer and Modulates the PKC-NF-κB-VCAM-1 Signaling Pathway. Front Cell Dev Biol 2021; 9:607142. [PMID: 33708767 PMCID: PMC7940382 DOI: 10.3389/fcell.2021.607142] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 01/29/2021] [Indexed: 12/24/2022] Open
Abstract
Objectives Complement 1q binding protein (C1QBP/HABP1/p32/gC1qR) has been found to be overexpressed in triple-negative breast cancer (TNBC). However, the underlying mechanisms of high C1QBP expression and its role in TNBC remain largely unclear. Hypoxia is a tumor-associated microenvironment that promotes metastasis and paclitaxel (PTX) chemoresistance in tumor cells. In this study, we aimed to assess C1QBP expression and explore its role in hypoxia-related metastasis and chemoresistance in TNBC. Materials and Methods RNA-sequencing of TNBC cells under hypoxia was performed to identify C1QBP. The effect of hypoxia inducible factor 1 subunit alpha (HIF-1α) on C1QBP expression was investigated using chromatin immunoprecipitation (ChIP) assay. The role of C1QBP in mediating metastasis, chemoresistance to PTX, and regulation of metastasis-linked vascular cell adhesion molecule 1 (VCAM-1) expression were studied using in vitro and in vivo experiments. Clinical tissue microarrays were used to verify the correlation of C1QBP with the expression of HIF-1α, VCAM-1, and RELA proto-oncogene nuclear factor-kappa B subunit (P65). Results We found that hypoxia-induced HIF-1α upregulated C1QBP. The inhibition of C1QBP notably blocked metastasis of TNBC cells and increased their sensitivity to PTX under hypoxic conditions. Depletion of C1QBP decreased VCAM-1 expression by reducing the amount of P65 in the nucleus and suppressed the activation of hypoxia-induced protein kinase C-nuclear factor-kappa B (PKC-NF-κB) signaling.immunohistochemistry (IHC) staining of the tissue microarray showed positive correlations between the C1QBP level and those of HIF-1α, P65, and VCAM-1. Conclusion Targeting C1QBP along with PTX treatment might be a potential treatment for TNBC patients.
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Affiliation(s)
- Hao Wu
- Sino-Russian Medical Research Center, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yijun Chu
- Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shanshan Sun
- Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Guozheng Li
- Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shouping Xu
- Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xianyu Zhang
- Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yongdong Jiang
- Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Song Gao
- Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qin Wang
- Sino-Russian Medical Research Center, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Jian Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Da Pang
- Sino-Russian Medical Research Center, Harbin Medical University Cancer Hospital, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
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47
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Wu M, Zhao Y, Peng N, Tao Z, Chen B. Identification of chemoresistance-associated microRNAs and hub genes in breast cancer using bioinformatics analysis. Invest New Drugs 2021; 39:705-712. [PMID: 33394259 DOI: 10.1007/s10637-020-01059-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 12/25/2020] [Indexed: 10/22/2022]
Abstract
Breast cancer threatens women's health. Although there are a lot of methods to treat breast cancer, chemotherapy resistance still hinders the effectiveness of treatment. This study attempts to explore the mechanism of chemotherapy resistance from the perspective of miRNA and look for several new targets for developing new drugs. Three datasets (GSE73736, GSE71142 and GSE6434) from Gene Expression Omnibus (GEO) were used for the bioinformatics analysis. Differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DE-genes) were obtained by using R package "limma". DAVID tool was used to perform gene ontology annotation analysis (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the overlapping genes. Protein-protein interaction (PPI) network was established by STRING database and visualized by software Cytoscape. Hub genes were identified by software Cytoscape. The prognostic value of hub genes was assessed through Kaplan-Meier plotter website. In total, 22 DE-miRNAs, 1932 DE-genes and top 10 hub genes were obtained. The genes were mainly enriched in cell signaling pathways like ErbB signaling pathway and PI3K / AKT/mTOR pathway. These pathways have a significant impact on the proliferation, invasion and drug resistance in cancer. MiRNA-Gene interaction may provide new insight for exploring the mechanism of chemotherapy resistance in breast cancer. Our study ultimately identified effective biomarkers and potential drug targets, which may enhance the effect of chemotherapy in patients with breast cancer.
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Affiliation(s)
- Ming Wu
- Departments of Breast Surgery, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Yujie Zhao
- Departments of Breast Surgery, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Nanxi Peng
- Departments of Breast Surgery, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Zuo Tao
- Departments of Breast Surgery, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Bo Chen
- Departments of Breast Surgery, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.
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48
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Abdi E, Latifi-Navid S, Zahri S, Kholghi-Oskooei V, Mostafaiy B, Yazdanbod A, Pourfarzi F. SNP-SNP interactions of oncogenic long non-coding RNAs HOTAIR and HOTTIP on gastric cancer susceptibility. Sci Rep 2020; 10:16763. [PMID: 33028884 PMCID: PMC7541458 DOI: 10.1038/s41598-020-73682-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Genetic variants within oncogenic long non-coding RNAs HOTAIR and HOTTIP may affect their gene expression levels, thereby modifying genetic susceptibility to gastric cancer (GC). In a hospital-based study in Ardabil-a very high-risk area in North-West Iran, 600 blood samples from 300 GC patients and 300 healthy controls were recruited for genotyping. Seven HOTAIR (i.e., rs17720428, rs7958904, rs1899663, and rs4759314) and HOTTIP (i.e., rs3807598, rs17501292, and rs1859168) 'tag' single nucleotide polymorphisms (SNPs) were genotyped by the Infinium HTS platform. The rs17720428, rs7958904, and rs1899663 tagSNPs significantly increased GC risk under dominant models by 1.5-, 1.57-, and 1.5-fold, respectively. The G-C-T-A haplotype of HOTAIR tagSNPs increased the risk of GC by 1.31-fold. No significant association was found between HOTTIP SNPs and the risk of GC. HOTAIR and HOTTIP variants were also not associated with any clinicopathologic characteristics. The SNP-SNP interaction of HOTAIR rs17720428/rs7958904 with HOTTIP rs1859168 was associated with an increased risk of GC (rs17720428 TG-rs1859168 CC, OR = 1.76; rs7958904 GC-rs1859168 CC, OR = 1.85; rs7958904 CC-rs1859168 CC, OR = 1.86). Interestingly, the SNP-SNP interaction of HOTAIR rs1899663 with HOTTIP rs1859168 strongly increased the risk of GC (rs1899663 GT-rs1859168 CC, OR = 4.3; rs1899663 TT-rs1859168 CC, OR = 9.37; rs1899663 TT-rs1859168 CA, OR = 6.59). We showed that the HOTAIR rs17720428, rs7958904, and rs1899663 tagSNPs and their interactions with the HOTTIP rs1859168 polymorphism significantly increased the risk of GC. Specifically, novel SNP-SNP interactions between HOTAIR and HOTTIP tagSNPs have a larger impact than individual SNP effects on GC risk, thereby providing us with valuable information to reveal potential biological mechanisms for developing GC.
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Affiliation(s)
- Esmat Abdi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, 5619911367, Ardabil, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, 5619911367, Ardabil, Iran.
| | - Saber Zahri
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, 5619911367, Ardabil, Iran
| | - Vahid Kholghi-Oskooei
- Department of Laboratory Sciences, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, 9516915169, Torbat Heydariyeh, Iran.,Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, 9516915169, Torbat Heydariyeh, Iran
| | - Behdad Mostafaiy
- Department of Statistics, Faculty of Sciences, University of Mohaghegh Ardabili, 5619911367, Ardabil, Iran
| | - Abbas Yazdanbod
- Digestive Disease Research Center, Ardabil University of Medical Sciences, 5618953141, Ardabil, Iran
| | - Farhad Pourfarzi
- Digestive Disease Research Center, Ardabil University of Medical Sciences, 5618953141, Ardabil, Iran
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49
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Liu J, Du F, Chen C, Li D, Chen Y, Xiao X, Hou X. CircRNA ITCH increases bortezomib sensitivity through regulating the miR-615-3p/PRKCD axis in multiple myeloma. Life Sci 2020; 262:118506. [PMID: 33031827 DOI: 10.1016/j.lfs.2020.118506] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/09/2020] [Accepted: 09/23/2020] [Indexed: 12/18/2022]
Abstract
AIMS Bortezomib (BTZ) is described as the first-line agent for multiple myeloma (MM) chemotherapy, but the emergence of BTZ resistance usually results in the failure of chemotherapy in MM. Circular RNA (circRNA) itchy E3 ubiquitin protein ligase (circITCH) is a novel identified circRNA that plays a vital role in the development of human cancers. However, the role of circITCH in the development of BTZ resistance in MM remains elusive. MATERIALS AND METHODS The expression of circITCH, miR-615-3p, and protein kinase C, delta (PRKCD) was detected with quantitative reverse transcription PCR and western blot. The effects of circITCH on the sensitivity of MM cells to BTZ were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, flow cytometry, and xenograft tumor assay. The interaction of circITCH, microRNA-615-3p, and PRKCD was explored using luciferase reporter assay and RNA immunoprecipitation assay. KEY FINDINGS circITCH was downregulated in MM bone marrow specimens and cell lines, as well as BTZ-resistant MM cells. Reduced expression of circITCH was indicative of poor prognosis in MM patients. Upregulation of circITCH enhanced the sensitivity of BTZ-resistant MM cells to BTZ in vitro and in vivo. Furthermore, circITCH was identified as a sponge for miR-615-3p, and PRKCD is confirmed as a direct target of miR-615-3p. Besides, circITCH overexpression enhanced the sensitivity of MM cells to BTZ through miR-615-3p/PRKCD axis. SIGNIFICANCE circITCH overexpression enhanced the sensitivity of MM cells to BTZ through miR-615-3p/PRKCD axis, providing a novel potential target for combating BTZ resistance in patients with MM.
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Affiliation(s)
- Jianhua Liu
- Orthopaedics Department, The First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Fang Du
- Department of Hematology and Oncology, No. 988 Hospital of Joint Logistic Support Force of the Chinese People's Liberation Army, Zhengzhou, Henan Province, China
| | - Chaohui Chen
- Orthopaedics Department, The First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Donghui Li
- Orthopaedics Department, The First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Yong Chen
- Orthopaedics Department, The First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Xia Xiao
- Orthopaedics Department, The First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Xiaodong Hou
- Ultrasound Department, The First Affiliated Hospital of Henan University, Kaifeng, Henan, China.
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50
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Sang K, Yi T, Huang X, Pan C, Zhou J, Yu L. MiR-370-5p inhibits the progression of breast cancer via targeting LUC7L3. J Recept Signal Transduct Res 2020; 41:442-450. [PMID: 32972267 DOI: 10.1080/10799893.2020.1819319] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Breast cancer is one of the most common malignancies and one of the leading causes of cancer-induced mortality among women. Over the past decades, the occurrence of breast cancer has been a significant increase. As documented in numerous researches, microRNAs (miRNAs) play vital roles in a wide range of biological processes associated with the occurrence and development of breast cancer. Nevertheless, the role of miR-370-5p in breast cancer remains obscure, and the possible molecular regulatory mechanism needs to be further explored. In this study, our results delineated that miR-370-5p was downregulated in breast cancer tissues and cell lines. Besides, miR-370-5p overexpression suppressed cell proliferation and invasion in breast cancer. MiR-370-5p downregulation exerted an opposite result. In addition, LUC7L3 was identified as a target gene for miR-370-5p. Similar with the results induced by miR-370-5p overexpression, LUC7L3 knockdown attenuated the proliferation and invasion ability of breast cancer cells. Moreover, the alternation of LUC7L3 expression reversed the regulatory effects of miR-370-5p on cell phenotypes in breast cancer. Overall, miR-370-5p may exert antitumor effect on breast cancer. Hence, miR-370-5p may serve as a novel therapeutic marker for the treatment of patients with breast cancer.
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Affiliation(s)
- Kai Sang
- Department of Breast Surgery, Jiangsu Taizhou People's Hospital, Taizhou, China
| | - Tongbo Yi
- Department of Breast Surgery, Jiangsu Taizhou People's Hospital, Taizhou, China
| | - Xinxin Huang
- Department of Pediatrics, Taizhou Fourth People's Hospital, Taizhou, China
| | - Chi Pan
- Department of Breast Surgery, Jiangsu Taizhou People's Hospital, Taizhou, China
| | - Jian Zhou
- Department of Breast Surgery, Jiangsu Taizhou People's Hospital, Taizhou, China
| | - Lei Yu
- Department of Oncology, Jiangsu Taizhou People's Hospital, Taizhou, China
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