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Alimohammadi M, Abolghasemi H, Cho WC, Reiter RJ, Mafi A, Aghagolzadeh M, Hushmandi K. Interplay between LncRNAs and autophagy-related pathways in leukemia: mechanisms and clinical implications. Med Oncol 2025; 42:154. [PMID: 40202565 DOI: 10.1007/s12032-025-02710-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 03/30/2025] [Indexed: 04/10/2025]
Abstract
Autophagy is a conserved catabolic process that removes protein clumps and defective organelles, thereby promoting cell equilibrium. Growing data suggest that dysregulation of the autophagic pathway is linked to several cancer hallmarks. Long non-coding RNAs (lncRNAs), which are key parts of gene transcription, are increasingly recognized for their significant roles in various biological processes. Recent studies have uncovered a strong connection between the mutational landscape and altered expression of lncRNAs in the tumor formation and development, including leukemia. Research over the past few years has emphasized the role of lncRNAs as important regulators of autophagy-related gene expression. These RNAs can influence key leukemia characteristics, such as apoptosis, proliferation, epithelial-mesenchymal transition (EMT), migration, and angiogenesis, by modulating autophagy-associated signaling pathways. With altered lncRNA expression observed in leukemia cells and tissues, they hold promise as diagnostic biomarkers and therapeutic targets. The current review focuses on the regulatory function of lncRNAs in autophagy and their involvement in leukemia, potentially uncovering valuable therapeutic targets for leukemia treatment.
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Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Abolghasemi
- Department of Pediatrics, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio, TX, USA
| | - Alireza Mafi
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahboobeh Aghagolzadeh
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Liang Y, Zhao J, Dai T, Li X, Chen L, He Z, Guo M, Zhao J, Xu L. A review of KLF4 and inflammatory disease: Current status and future perspective. Pharmacol Res 2024; 207:107345. [PMID: 39134187 DOI: 10.1016/j.phrs.2024.107345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 08/03/2024] [Accepted: 08/07/2024] [Indexed: 08/15/2024]
Abstract
Inflammation is the response of the human body to injury, infection, or other abnormal states, which is involved in the development of many diseases. As a member of the Krüppel-like transcription factors (KLFs) family, KLF4 plays a crucial regulatory role in physiological and pathological processes due to its unique dual domain of transcriptional activation and inhibition. A growing body of evidence has demonstrated that KLF4 plays a pivotal role in the pathogenesis of various inflammatory disorders, including inflammatory bowel disease, osteoarthritis, renal inflammation, pneumonia, neuroinflammation, and so on. Consequently, KLF4 has emerged as a promising new therapeutic target for inflammatory diseases. This review systematically generalizes the molecular regulatory network, specific functions, and mechanisms of KLF4 to elucidate its complex roles in inflammatory diseases. An in-depth study on the biological function of KLF4 is anticipated to offer a novel research perspective and potential intervention strategies for inflammatory diseases.
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Affiliation(s)
- Yidan Liang
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Jiamin Zhao
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Tengkun Dai
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Xin Li
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Longqin Chen
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Zhixu He
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Mengmeng Guo
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Juanjuan Zhao
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Lin Xu
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou 563000, China.
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Zeng ZL, Zhu Q, Zhao Z, Zu X, Liu J. Magic and mystery of microRNA-32. J Cell Mol Med 2021; 25:8588-8601. [PMID: 34405957 PMCID: PMC8435424 DOI: 10.1111/jcmm.16861] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/25/2021] [Accepted: 08/02/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are a group of endogenous, small (∼22 nts in length) noncoding RNA molecules that function specifically by base pairing with the mRNA of genes and regulate gene expression at the post-transcriptional level. Alterations in miR-32 expression have been found in numerous diseases and shown to play a vital role in cell proliferation, apoptosis, oncogenesis, invasion, metastasis and drug resistance. MiR-32 has been documented as an oncomiR in the majority of related studies but has been also verified as a tumour suppressor miRNA in conflicting reports. Moreover, it has a crucial role in metabolic and cardiovascular disorders. This review provides an in-depth look into the most recent finding regarding miR-32, which is involved in the expression, regulation and functions in different diseases, especially tumours. Additionally, this review outlines novel findings suggesting that miR-32 may be useful as a noninvasive biomarker and as a targeted therapeutic in several diseases.
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Affiliation(s)
- ZL Zeng
- The First Affiliated HospitalDepartment of Metabolism and EndocrinologyHengyang Medical SchoolUniversity of South ChinaHengyangChina
- The First Affiliated HospitalDepartment of Clinical MedicineHengyang Medical SchoolUniversity of South ChinaHengyangChina
- Key Laboratory for Arteriosclerology of Hunan ProvinceDepartment of Cardiovascular DiseaseHengyang Medical SchoolUniversity of South ChinaHengyangChina
| | - Qingyun Zhu
- The First Affiliated HospitalDepartment of Metabolism and EndocrinologyHengyang Medical SchoolUniversity of South ChinaHengyangChina
- The First Affiliated HospitalDepartment of Clinical MedicineHengyang Medical SchoolUniversity of South ChinaHengyangChina
| | - Zhibo Zhao
- The First Affiliated HospitalDepartment of Metabolism and EndocrinologyHengyang Medical SchoolUniversity of South ChinaHengyangChina
- The First Affiliated HospitalDepartment of Clinical MedicineHengyang Medical SchoolUniversity of South ChinaHengyangChina
| | - Xuyu Zu
- The First Affiliated HospitalDepartment of Metabolism and EndocrinologyHengyang Medical SchoolUniversity of South ChinaHengyangChina
- The First Affiliated HospitalDepartment of Clinical MedicineHengyang Medical SchoolUniversity of South ChinaHengyangChina
| | - Jianghua Liu
- The First Affiliated HospitalDepartment of Metabolism and EndocrinologyHengyang Medical SchoolUniversity of South ChinaHengyangChina
- The First Affiliated HospitalDepartment of Clinical MedicineHengyang Medical SchoolUniversity of South ChinaHengyangChina
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Aberrant expression profile of miR-32, miR-98 and miR-374 in chronic lymphocytic leukemia. Leuk Res 2021; 111:106691. [PMID: 34455196 DOI: 10.1016/j.leukres.2021.106691] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/12/2021] [Accepted: 08/19/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Leukemia is a malignant and progressive disease of hematopoiesis. The disease arises due to abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Chronic lymphoblastic leukemia (CLL) is a subtype of blood cancers, with the origin of B lymphocytes and the involvement of bone marrow, blood and lymph nodes. MicroRNAs (miRNAs) are small non-coding RNAs with pivotal roles in cellular and molecular processes related to different malignancies, including CLL. In this way, we aimed to evaluate the expression of miR-32-5p, miR-98-5p, and miR-374b-5p in CLL patients. We also investigated the signaling pathways regulated by the studied miRs and also frequently disturbed miRs in CLL. METHODS Blood samples were collected from 32 CLL patients from Kermanshah province, Iran and 34 age and sex-matched healthy individuals. RNA was extracted from PBMCs and then was subjected to cDNA synthesis. Using specifically designed primers and Real-Time PCR method the expression of miRNAs was detected and was statistically analyzed. Using mirPath v.3, systematic pathway enrichment analysis was performed for the three studied miRNAs here along with the frequently disturbed miRNAs in CLL. RESULTS The experiments indicated a significant reduction in the expression of all three miRs (p-value<0.0001) in CLL patients compared with healthy individuals. ROC analysis suggested that the three studied miRs can serve as potential biomarkers for early diagnosis of CLL. The in silico analysis suggested proteoglycans in cancer as a pathway regulated by the studied miRs and frequently dysregulated miRs in CLL. CONCLUSION The observed reduction in expression of miR-32-5p, miR-98-5p, and miR-374b-5p in treatment naïve CLL patients here might be suggestive of their modulatory protective role in CLL progression. Moreover, the candidate peripheral miRNAs could potentially serve as diagnostic biomarkers which warrant further investigation in a larger sample size.
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Abdi E, Latifi-Navid S, Abdi F, Taherian-Esfahani Z. Emerging circulating MiRNAs and LncRNAs in upper gastrointestinal cancers. Expert Rev Mol Diagn 2020; 20:1121-1138. [DOI: 10.1080/14737159.2020.1842199] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/22/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Esmat Abdi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Fatemeh Abdi
- Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran
| | - Zahra Taherian-Esfahani
- Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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Challenges in Cancer Biomarker Discovery Exemplified by the Identification of Diagnostic MicroRNAs in Prostate Tissues. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9086829. [PMID: 32462034 PMCID: PMC7225851 DOI: 10.1155/2020/9086829] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/20/2020] [Accepted: 04/25/2020] [Indexed: 12/23/2022]
Abstract
Identification and clinical translation of routinely tested biomarkers require a complex and multistep workflow. Here, we described a confirmatory process estimating the utility of previously identified candidate tissue miRNAs for diagnosis of prostate cancer (PCa). RNA was isolated from formalin-fixed paraffin-embedded (FFPE) prostate tissue surgically resected from 44 patients with PCa and 24 patients with benign prostate hyperplasia (BPH). Of the 92 RNA samples obtained, 68 represented 42 malignant (PCa) areas and 26 represented nonmalignant (PCa 0%) areas of the prostate tissue sections. The levels of miR-32-5p, miR-183-5p, miR-141-5p, miR-187-3p, miR-375, miR-663b, miR-615-3p, miR-205-5p, miR-221-3p, and miR-222-3p were evaluated using Exiqon chemistry. Five (miR-32-5p, miR-141-5p, miR-187-3p, miR-375, and miR-615-3p), one (miR-32-5p), and two (miR-32-5p and miR-141-5p) miRNAs discriminated between BPH and areas of cancer-bearing prostate tissue harboring different numbers of cancer cells (PCa 15–70%, PCa 2–10%, and PCA 0%, respectively), with an area under the receiver operating characteristics curve (AUC-ROC) > 0.9. Only miRNA 32-5p discriminated BPH specimens from sections of cancer-bearing prostate tissue with a low percentage, a high percentage, or no dysplastic cells. miR-32-5p could be considered as potential diagnostic biomarker discriminating BPH from noncancerous areas within cancer-bearing prostate tissue. However, further clinical studies are warranted to confirm its diagnostic utility.
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Yoon JH, Min K, Lee SK. Epstein-Barr Virus miR-BART17-5p Promotes Migration and Anchorage-Independent Growth by Targeting Kruppel-Like Factor 2 in Gastric Cancer. Microorganisms 2020; 8:microorganisms8020258. [PMID: 32075248 PMCID: PMC7074886 DOI: 10.3390/microorganisms8020258] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/12/2020] [Accepted: 02/13/2020] [Indexed: 12/24/2022] Open
Abstract
Epstein-Barr virus (EBV) infects more than 90% of the global population and is associated with a variety of tumors including nasopharyngeal carcinoma, Hodgkin lymphoma, natural killer/T lymphoma, and gastric carcinoma. In EBV-associated gastric cancer (EBVaGC), highly expressed EBV BamHI A rightward transcripts (BART) miRNAs may contribute to tumorigenesis with limited viral antigens. Despite previous studies on the targets of BART miRNAs, the functions of all 44 BART miRNAs have not been fully clarified. Here, we used RNA sequencing data from the Cancer Genome Atlas to find genes with decreased expression in EBVaGC. Furthermore, we used AGS cells infected with EBV to determine whether expression was reduced by BART miRNA. We showed that the expression of Kruppel-like factor 2 (KLF2) is lower in AGS-EBV cells than in the AGS control. Using bioinformatics analysis, four BART miRNAs were selected to check whether they suppress KLF2 expression. We found that only miR-BART17-5p directly down-regulated KLF2 and promoted gastric carcinoma cell migration and anchorage-independent growth. Our data suggest that KLF2 functions as a tumor suppressor in EBVaGC and that miR-BART17-5p may be a valuable target for effective EBVaGC treatment.
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Affiliation(s)
| | | | - Suk Kyeong Lee
- Correspondence: ; Tel.: +82-2-2258-7480; Fax: +82-504-201-2396
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Wang D, Zeng T, Lin Z, Yan L, Wang F, Tang L, Wang L, Tang D, Chen P, Yang M. Long non-coding RNA SNHG5 regulates chemotherapy resistance through the miR-32/DNAJB9 axis in acute myeloid leukemia. Biomed Pharmacother 2019; 123:109802. [PMID: 31884339 DOI: 10.1016/j.biopha.2019.109802] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/10/2019] [Accepted: 12/15/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a common hematopoietic malignancy with invasive activity. Drug resistance greatly contributes to the poor efficacy of chemotherapy in AML treatment. Recent research indicates that long non-coding RNAs (LncRNAs) regulates chemotherapy resistance in malignancy. METHODS Microarray analysis was used to screen out AML related genes, and interaction between small nucleolar RNA host gene 5(SNHG5) and miR-32, as well as that between miR-32 and DNAJB9. Quantitative real-time PCR (qRT-PCR) and In situ hybridization(ISH) were used to determine the expression levels of SNHG5, miR-32 and DNAJB9 mRNA in AML cell lines and clinic samples. Western blot was performed to detect protein expression levels. After being treated with varying concentrations of Adriamycin(ADM), cell viability was evaluated using a cell counting kit-8(CCK8). RESULTS We carried out a genome-wide LncRNA expression study and found SNHG5 aberrantly overexpressed in AML comparing to the donors. Knock-down of SNHG5 promoted sensitivity of AML cells to chemotherapy. In addition, miR-32 was identified as the downstream target of SNHG5 and miR-32 inhibitor abrogated the inhibiting effects of downregulated SNHG5 on AML cell viability. Furthermore, inhibited SNHG5 decreased DNAJB9 expression levels by sponging miR-32. The SNHG5/miR-32/DNAJB9 axis targeted autophagy to regulate chemotherapy resistance. CONCLUSION SHNG5 regulates chemotherapy resistance by targeting the miR-32/DNAJB9 axis in acute myeloid leukemia, which provided a novel potential target for AML and revealed an important mechanism of chemotherapy resistance.
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Affiliation(s)
- Dan Wang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ting Zeng
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zhi Lin
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Lu Yan
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Fenglin Wang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Lanlan Tang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Leyuan Wang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Pan Chen
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
| | - Minghua Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
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Shukla V, Varghese VK, Kabekkodu SP, Mallya S, Chakrabarty S, Jayaram P, Pandey D, Banerjee S, Sharan K, Satyamoorthy K. Enumeration of deregulated miRNAs in liquid and tissue biopsies of cervical cancer. Gynecol Oncol 2019; 155:135-143. [PMID: 31434614 DOI: 10.1016/j.ygyno.2019.08.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/18/2019] [Accepted: 08/11/2019] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The altered miRNAs expression in cervical cancer tissue can be a critical player during tumorigenesis, may contribute to tumor cell heterogeneity and may determine distinct phenotypes within the tumor. Recent studies have highlighted the role of circulating miRNAs as a minimally-invasive biomarker and its potential as biosignature to complement routine tissue-based procedures. METHODS In order to determine whether miRNAs in serum can indicate changes in cervical tissue specimens, we performed small RNA sequencing and selected miRNAs were validated using qRT-PCR in serum and tissue specimens (n = 115). Further, luciferase assay were performed to investigate the interactions between hsa-miR-409-3p and hsa-miR-454-3p binding sites on 3'UTR region of MTF2 and ST18 respectively. RESULTS We have identified a total of 14 differentially expressed miRNAs common in serum and tissue specimens. Among them, hsa-miR-17-5p, hsa-miR-32-5p and hsa-miR-454-3p were upregulated while, hsa-miR-409-3p was downregulated in serum and tissue of cervical cancer subjects. Our in-silico small RNA sequencing data analysis identified isomiRs and classified miRNA into clusters and subtypes (exonic, intronic and intergenic) with respect to the expression status in serum and tissue specimens. Expression level of hsa-miR-409-3p and hsa-miR-454-3p were inversely correlated with their target genes MTF2 and ST18 levels respectively in human cervical cancer specimens. Luciferase assay demonstrated that hsa-miR-409-3p and hsa-miR-454-3p functionally interacts with 3'-UTR of MTF2 and ST18 respectively to decrease their activity. CONCLUSION Our results support the significant role of circulating miRNAs in disease dissemination and their potential utility as biosignatures of clinical relevance.
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Affiliation(s)
- Vaibhav Shukla
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Vinay Koshy Varghese
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Sandeep Mallya
- Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Pradyumna Jayaram
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Deeksha Pandey
- Department of Obstetrics and Gynecology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Sourjya Banerjee
- Department of Radiotherapy and Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Mangalore, India
| | - Krishna Sharan
- Department of Radiotherapy and Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India.
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MicroRNA-32 targeting PTEN enhances M2 macrophage polarization in the glioma microenvironment and further promotes the progression of glioma. Mol Cell Biochem 2019; 460:67-79. [PMID: 31218569 DOI: 10.1007/s11010-019-03571-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/04/2019] [Indexed: 12/25/2022]
Abstract
This study was aimed to explore the molecular mechanism of macrophage polarization and its effect on glioma progression. THP1 cells were cocultured in conditioned medium from U87 human glioblastoma cells to simulate the glioma microenvironment. The expression of miR-32 and PTEN in THP1 cells was detected by real-time PCR. A luciferase reporter assay was conducted to confirm the target relation between miR-32 and PTEN. Western blot assays and ELISA were performed to detect PTEN, M2 macrophage-specific markers, PI3K/AKT signaling proteins, and apoptosis-related proteins. U87 cell proliferation was evaluated by CCK-8 and colony forming assays, and the migration ability of the cells was evaluated by Transwell and wound healing assays. The U87 culture supernatant promoted the M2 phenotype of THP1 cells. miR-32 was upregulated and PTEN was downregulated in THP1 cells with the M2 phenotype in the glioma microenvironment. Luciferase assays confirmed that PTEN expression was suppressed by miR-32 through interaction with the 3'UTR of PTEN. Overexpression of miR-32 suppressed PTEN expression in THP1 cells. Overexpression of miR-32 or downregulation of PTEN promoted the expression of M2 macrophage-specific markers, thereby enhancing M2 macrophage polarization. Additionally, miR-32 inhibited THP1 cell apoptosis via suppressing the PI3K/AKT signaling pathway. Most importantly, the proliferation and migration capacities of U87 cells treated with the THP1 culture supernatant after miR-32 overexpression were enhanced, and these effects could be reversed by cotransfection with pcDNA3.1-PTEN. miR-32 negatively modulates PTEN, thereby promoting M2 macrophage transformation through PI3K/AKT signaling, enhancing glioma proliferation and migration abilities.
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Isoliquiritigenin suppresses the proliferation and induced apoptosis via miR-32/LATS2/Wnt in nasopharyngeal carcinoma. Eur J Pharmacol 2019; 856:172352. [PMID: 31004603 DOI: 10.1016/j.ejphar.2019.04.033] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 04/11/2019] [Accepted: 04/16/2019] [Indexed: 12/17/2022]
Abstract
Nasopharyngeal Carcinoma is limited by the various severe side-effects and surgery is rarely performed. Iosliquiritigenin has a series of biological activities, such as antiviral, anti-free radical and antitumor. However, the role and underlying mechanism of isoliquiritigenin in nasopharyngeal carcinoma have not been understood yet. Herein, the results revealed that isoliquiritigenin could inhibit cell proliferation in nasopharyngeal carcinoma cell lines, including C666-1 and CNE2, in both Cell Counting Kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assay. In addition, isoliquiritigenin promoted nasopharyngeal carcinoma cell apoptosis, with the up-regulations of Bax, Caspase-3 and Caspase-9 and the down-regulation of Bcl-2. Meanwhile, isoliquiritigenin suppressed nasopharyngeal carcinoma cells migration and invasion with the down-regulation of matrix metalloproteinases (MMP)-2 and MMP-9. Furthermore, the expression of miR-32 was up-regulated in the nasopharyngeal carcinoma tissues, while isoliquiritigenin could significantly down-regulate the expression of miR-32. And over-expression of miR-32 promoted the nasopharyngeal carcinoma cells growth, migration and invasion, and suppressed apoptosis. However, isoliquiritigenin treatment dramatically inhibited the effect of miR-32. Besides, luciferase reporter assay confirmed that large tumor suppressor 2 (LATS2) was a direct target of miR-32. And isoliquiritigenin increased the expression of LATS2, while silencing of LATS2 promoted the nasopharyngeal carcinoma cells growth. Moreover, western blotting discovered that isoliquiritigenin inhibited nasopharyngeal carcinoma cells growth via Wnt signaling pathway. Finally, CNE2 cells transplanted xenografts tumor model in nude mice were performed and it suggested that isoliquiritigenin could inhibit the development of xenografts nude mice, along with the decrease of tumor volume and the expression of miR-32 and LATS2. Overall, isoliquiritigenin was confirmed to be a potent anti-nasopharyngeal carcinoma compound both in vitro and in vivo, and accomplished by regulation of miR-32/LATS2/Wnt.
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Jiao Y, Yang H, Qian J, Gong Y, Liu H, Wu S, Cao L, Tang L. miR‑3664‑5P suppresses the proliferation and metastasis of gastric cancer by attenuating the NF‑κB signaling pathway through targeting MTDH. Int J Oncol 2019; 54:845-858. [PMID: 30628643 PMCID: PMC6365029 DOI: 10.3892/ijo.2019.4680] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common and fatal types of cancers worldwide and the specific mechanism has not been completely elucidated. microRNA (miR)‑3664‑5P has rarely been studied and the aim of the present study was to assess an association between miR‑3664‑5P and GC. Differences in miR‑3664‑5P expression in 100 GC (0.1846±0.08276) and paired normal tissues (0.4382±0.1595) were detected using reverse transcription‑quantitative polymerase chain reaction assays (P<0.001). 5‑Ethynyl‑2‑deoxyuridine, Cell Counting Kit‑8, transwell and flow cytometry assays were performed in vitro and the results were further verified using a mouse xenotransplantation and a lung metastasis model in vivo. miR‑3664‑5P was significantly downregulated in GC tissues when compared with normal tissues and positively associated with the prognosis of patients with GC (P<0.001). Overexpression of miR‑3664‑5P suppressed and miR‑3664‑5P knockdown promoted the proliferation and metastasis of GC cells in vitro and in vivo. Following the application of bioinformatic algorithms and luciferase reporter assays, metadherin (MTDH) was confirmed as the target gene of miR‑3664‑5P. miR‑3664‑5P reduced MTDH expression and downregulated the nuclear factor (NF)‑κB signaling pathway. Rescue experiments demonstrated that suppression of MTDH restored the effect of miR‑3664‑5P inhibitors on GC cell lines. The results suggested that miR‑3664‑5P suppressed the proliferation and metastasis of GC cells by attenuating the NF‑κB signaling pathway via MTDH targeting. Consequently, miR‑3664‑5P may have potential to be an independent prognostic factor and biomarker in GC.
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Affiliation(s)
- Yuwen Jiao
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Haojun Yang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Jun Qian
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Yu Gong
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Hanyang Liu
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Siyuan Wu
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Liang Cao
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Liming Tang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
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13
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Identification of small molecule inhibitors for differentially expressed miRNAs in gastric cancer. Comput Biol Chem 2018; 77:442-454. [DOI: 10.1016/j.compbiolchem.2018.07.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/26/2018] [Accepted: 07/16/2018] [Indexed: 12/19/2022]
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14
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Liu YT, Zong D, Jiang XS, Yin L, Wang LJ, Wang TT, Zhu J, He X. miR-32 promotes esophageal squamous cell carcinoma metastasis by targeting CXXC5. J Cell Biochem 2018; 120:6250-6263. [PMID: 30362164 DOI: 10.1002/jcb.27912] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 09/25/2018] [Indexed: 12/11/2022]
Abstract
MicroRNA-32 (miR-32) functioned as a tumor oncogene in some cancer, which control genes involved in important biological and pathological functions and facilitate the tumor growth and metastasis. However, the role of miR-32 modulates esophageal squamous cell carcinoma (ESCC) malignant transformation has not been clarified. Here, we focused on the function and the underlying molecular mechanism of miR-32 in ESCC. Results discovered a significant increased expression of miR-32 in ESCC tissues and cells. Downregulation of miR-32 inhibited the migration, invasion, adhesion of ESCC cell lines (EC9706 and KYSE450), and the levels of EMT protein in vitro. In vivo, miR-32 inhibitors decrease tumor size, tumor weight, and the number of metastatic nodules. Hematoxylin and eosin (H&E) results revealed that inhibition of miR-32 attenuate lung metastasis. Immunohistochemistry and immunofluorescence assay showed increased level of E-cadherin and decreased level of N-cadherin and Vimentin with treatment of miR-32 inhibitors. Furthermore, miR-32 targeted the 3'-untranslated region (3'-UTR) of CXXC5, and inhibited the level of mRNA and protein of CXXC5. There is a negative correlation between the expressions of CXXC5 and miR-32. Then, after EC9706 and KYSE450 cells cotransfected with si-CXXC5 and miR-32 inhibitors, the ability of cell migration, invasion, and adhesion was significantly reduced. In addition, the protein expression of EMT and TGF-β signaling was also depressed. Collectively, these data supply an insight into the positive role of miR-32 in ESCC progression and metastasis, and its biological effects may attribute the inhibition of TGF-β signaling mediated by CXXC5.
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Affiliation(s)
- Ya-Tian Liu
- Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Dan Zong
- Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xue-Song Jiang
- Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Li Yin
- Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Li-Jun Wang
- Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Ting-Ting Wang
- Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jun Zhu
- Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xia He
- Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
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15
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Chen E, Li Q, Wang H, Zhang P, Zhao X, Yang F, Yang J. MiR-32 promotes tumorigenesis of colorectal cancer by targeting BMP5. Biomed Pharmacother 2018; 106:1046-1051. [DOI: 10.1016/j.biopha.2018.07.050] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/28/2018] [Accepted: 07/08/2018] [Indexed: 12/18/2022] Open
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16
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Baicalin, the major component of traditional Chinese medicine Scutellaria baicalensis induces colon cancer cell apoptosis through inhibition of oncomiRNAs. Sci Rep 2018; 8:14477. [PMID: 30262902 PMCID: PMC6160418 DOI: 10.1038/s41598-018-32734-2] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 08/30/2018] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is among the most frequently occurring cancers worldwide. Baicalin is isolated from the roots of Scutellaria baicalensis and is its dominant flavonoid. Anticancer activity of baicalin has been evaluated in different types of cancers, especially in CRC. However, the molecular mechanisms underlying the contribution of baicalin to the treatment of CRC are still unknown. Here, we confirmed that baicalin can effectively induce and enhance apoptosis in HT-29 cells in a dose-dependent manner and suppress tumour growth in xenografted nude mice. We further performed a miRNA microarray analysis of baicalin-treated and untreated HT-29 cells. The results showed that a large number of oncomiRs, including miR-10a, miR-23a, miR-30c, miR-31, miR-151a and miR-205, were significantly suppressed in baicalin-treated HT-29 cells. Furthermore, our in vitro and in vivo studies showed that baicalin suppressed oncomiRs by reducing the expression of c-Myc. Taken together, our study shows a novel mechanism for anti-cancer action of baicalin, that it induces apoptosis in colon cancer cells and suppresses tumour growth by reducing the expression of c-Myc and oncomiRs.
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17
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Link A, Kupcinskas J. MicroRNAs as non-invasive diagnostic biomarkers for gastric cancer: Current insights and future perspectives. World J Gastroenterol 2018; 24:3313-3329. [PMID: 30122873 PMCID: PMC6092583 DOI: 10.3748/wjg.v24.i30.3313] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/10/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Non-invasive diagnostic biomarkers may contribute to an early identification of gastric cancer (GC) and improve the clinical management. Unfortunately, no sensitive and specific screening biomarkers are available yet and the currently available approaches are limited by the nature of the disease. GC is a heterogenic disease with various distinct genetic and epigenetic events that occur during the multifactorial cascade of carcinogenesis. MicroRNAs (miRNAs) are commonly deregulated in gastric mucosa during the Helicobacter pylori infection and in stepwise manner from chronic gastritis, through preneoplastic conditions such as atrophic gastritis and intestinal metaplasia, to early dysplasia and invasive cancer. Identification of miRNAs in blood in 2008 led to a great interest on miRNA-based diagnostic, prognostic biomarkers in GC. In this review, we provide the most recent systematic review on the existing studies related to miRNAs as diagnostic biomarkers for GC. Here, we systematically evaluate 75 studies related to differential expression of circulating miRNAs in GC patients and provide novel view on various heterogenic aspects of the existing data and summarize the methodological differences. Finally, we highlight several important aspects crucial to improve the future translational and clinical research in the field.
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Affiliation(s)
- Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg 39120, Germany
| | - Juozas Kupcinskas
- Institute for Digestive Research and Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas LT-44307, Lithuania
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18
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Shao L, Chen Z, Soutto M, Zhu S, Lu H, Romero-Gallo J, Peek R, Zhang S, El-Rifai W. Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer. FASEB J 2018; 33:264-274. [PMID: 29985646 DOI: 10.1096/fj.201701456rr] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori infection is a major risk factor for the development of gastric cancer. Aberrant expression of microRNAs is strongly implicated in gastric tumorigenesis; however, their contribution in response to H. pylori infection has not been fully elucidated. In this study, we evaluated the expression of miR-135b-5p and its role in gastric cancer. We describe the overexpression of miR-135b-5p in human gastric cancer tissue samples compared with normal tissue samples. Furthermore, we found that miR-135b-5p is also up-regulated in gastric tumors from the trefoil factor 1-knockout mouse model. Infection with H. pylori induced the expression of miR-135b-5p in the in vitro and in vivo models. miR-135b-5p induction was mediated by NF-κB. Treatment of gastric cancer cells with TNF-α induced miR-135b-5p in a NF-κB-dependent manner. Mechanistically, we found that miR-135b-5p targets Krüppel-like factor 4 (KLF4) and binds to its 3' UTR, leading to reduced KLF4 expression. Functionally, high levels of miR-135b-5p suppress apoptosis and induce cisplatin resistance. Our results uncovered a mechanistic link between H. pylori infection and miR-135b-5p-KLF4, suggesting that targeting miR-135b-5p could be a potential therapeutic approach to circumvent resistance to cisplatin.-Shao, L., Chen, Z., Soutto, M., Zhu, S., Lu, H., Romero-Gallo, J., Peek, R., Zhang, S., El-Rifai, W. Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer.
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Affiliation(s)
- Linlin Shao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA
| | - Zheng Chen
- Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA.,Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA; and
| | - Mohammed Soutto
- Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA
| | - Shoumin Zhu
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA; and
| | - Heng Lu
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA; and
| | - Judith Romero-Gallo
- Division of Gastroenterology, Hematology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard Peek
- Division of Gastroenterology, Hematology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wael El-Rifai
- Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA.,Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA; and
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Fu X, Liu M, Qu S, Ma J, Zhang Y, Shi T, Wen H, Yang Y, Wang S, Wang J, Nan K, Yao Y, Tian T. Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018. [PMID: 29530052 PMCID: PMC5846230 DOI: 10.1186/s13046-018-0677-7] [Citation(s) in RCA: 193] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Multidrug resistance is the main obstacle for hepatocellular carcinoma (HCC) treatment. miR-32-5p is involved in HCC progression but its function in multidrug resistance is still unclear. Here we aim to find out the function of miR-32-5p in inducing multidrug resistance and its underlying mechanisms of transforming sensitive cell to resistant cell. METHODS We detected the expression of miR-32-5p and PTEN in the multidrug-resistant cell line (Bel/5-FU) and the sensitive cell line (Bel7402), HCC and para-carcinoma liver tissues through real-time PCR. Dual-luciferase reporter assay verified PTEN is the target of miR-32-5p. Exosomes from sensitive and multidrug resistant cell line were obtained and confirmed through ultracentrifuge and Nano Analyzer. Gain- and loss-of-function experiments, rescue experiments, a PI3K/Akt pathway inhibitor, an exosome biogenesis inhibitor, and nude mice xenograft models were used to determine the underlying mechanisms of miR-32-5p and PTEN, as well as exosomal miR-32-5p in inducing multidrug resistance in vitro and in vivo. RESULTS miR-32-5p was significantly elevated but PTEN was reduced in Bel/5-FU. An inverse correlation between miR-32-5p and PTEN was confirmed in HCC cell lines and patients; moreover, high expression of miR-32-5p and low expression of PTEN were positively associated with poor prognosis. Over-expression of miR-32-5p activated the PI3K/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition (EMT). CONCLUSIONS Our study demonstrated that the multidrug-resistant cell, Bel/5-FU delivers miR-32-5p to sensitive cell, Bel7402 by exosomes and activates the PI3K/Akt pathway to further induce multidrug resistance by modulating angiogenesis and EMT.
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Affiliation(s)
- Xiao Fu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Mengjie Liu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Shengyang Qu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Jiequn Ma
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yamin Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Tingting Shi
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Hongqing Wen
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China.,Department of Respiratory, Third Hospital of Xi'an, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Yujuan Yang
- The Third Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi province, 710068, People's Republic of China
| | - Shuhong Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Jing Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Kejun Nan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yu Yao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China.
| | - Tao Tian
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, People's Republic of China.
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20
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Zhu HY, Bai WD, Ye XM, Yang AG, Jia LT. Long non-coding RNA UCA1 desensitizes breast cancer cells to trastuzumab by impeding miR-18a repression of Yes-associated protein 1. Biochem Biophys Res Commun 2018; 496:1308-1313. [PMID: 29408336 DOI: 10.1016/j.bbrc.2018.02.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/01/2018] [Indexed: 11/30/2022]
Abstract
Breast cancer resistance to the monoclonal erbB2/HER2 antibody trastuzumab (or herceptin) has become a significant obstacle in clinical targeted therapy of HER2-positive breast cancer. Previous research demonstrated that such drug resistance may be related to dysregulation of miRNA expression. Here, we found that knockdown of the long non-coding RNA, urothelial cancer associated 1 (UCA1), can promote the sensitivity of human breast cancer cells to trastuzumab. Mechanistically, UCA1 knockdown upregulated miR-18a and promoted miR-18a repression of Yes-associated protein 1 (YAP1). A luciferase reporter assay confirmed the association of miR-18a with wild-type UCA1 but not with UCA1 mutated at the predicted miR-18a-binding site. The direct targeting of YAP1 by miR-18a was verified by the observation that miR-18a mimic suppressed luciferase expression from a construct containing the YAP1 3' untranslated region. Meanwhile, reciprocal repression of UCA1 and miR-18a were found to be Argonaute 2-dependent. Knockdown of YAP1 recapitulated the effect of UCA1 silencing by reducing the viability of trastuzumab-treated breast cancer cells, whereas inhibition of miR-18a abrogated UCA1 knockdown-induced improvement of trastuzumab sensitivity in breast cancer cells. These findings demonstrate that the UCA1/miR-18a/YAP1 axis plays an important role in regulating the sensitivity of breast cancer cells to trastuzumab, which has implications for the development of novel approaches to improving breast cancer responses to targeted therapy.
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Affiliation(s)
- Hua-Yu Zhu
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wen-Dong Bai
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Clinical Laboratory Center, Xinjiang Command General Hospital of Chinese People's Liberation Army, Urumqi, Xinjiang, China
| | - Xing-Ming Ye
- Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China; State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - An-Gang Yang
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Lin-Tao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular, Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
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Yu X, Ma C, Fu L, Dong J, Ying J. MicroRNA-139 inhibits the proliferation, migration and invasion of gastric cancer cells by directly targeting ρ-associated protein kinase 1. Oncol Lett 2018; 15:5977-5982. [PMID: 29552227 DOI: 10.3892/ol.2018.8038] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 10/24/2017] [Indexed: 12/18/2022] Open
Abstract
The expression, function and underlying mechanisms of microRNA-139 (miR-139) in gastric cancer were investigated in the present study. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-139 expression in gastric cancer tissues and cell lines. The effects of miR-139 overexpression on gastric cancer cell proliferation, migration and invasion were evaluated. ρ-associated protein kinase 1 (ROCK1) was predicted as a downstream target of miR-139 and its role in gastric cancer was assessed by bioinformatics analysis, luciferase reporter assay, RT-qPCR and western blot analysis. ROCK1 overexpression was established to investigate if the effects of miR-139 on gastric cancer cells may be attenuated. The results indicated that miR-139 was aberrantly downregulated in gastric cancer tissues and cell lines. Increased miR-139 expression reduced gastric cancer cell proliferation, migration and invasion. ROCK1 was demonstrated to be a direct target of miR-139 in gastric cancer and ROCK1 overexpression reversed the suppressive effects on gastric cancer cell proliferation, migration and invasion induced by miR-139 overexpression. The present study provides clear evidence demonstrating the anti-oncogenic activity of miR-139 in human gastric cancer, as mediated by the targeted downregulation of ROCK1.
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Affiliation(s)
- Xuechun Yu
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Chaojian Ma
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Ling Fu
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Jingwu Dong
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Jie Ying
- Department of Infectious Diseases, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
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22
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Yang D, Ma M, Zhou W, Yang B, Xiao C. Inhibition of miR-32 activity promoted EMT induced by PM2.5 exposure through the modulation of the Smad1-mediated signaling pathways in lung cancer cells. CHEMOSPHERE 2017; 184:289-298. [PMID: 28601662 DOI: 10.1016/j.chemosphere.2017.05.152] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/21/2017] [Accepted: 05/27/2017] [Indexed: 05/20/2023]
Abstract
Epithelial mesenchymal transition (EMT) is a crucial morphological event during tumor progression. The present study reported that EMT could be triggered by airborne fine particulate matter (PM) with a mean diameter of less than 2.5 μm (PM2.5) in human lung cancer cells. We also aimed to elucidate the possible mechanisms of these processes. The results showed that treatment with PM2.5 promoted the activity of the SMAD family member 1 (Smad1)-mediated signaling pathway and downregulated the expression of the inhibitory Smad proteins Smad6 and Smad7 in lung cancer cells. Moreover, the knockdown of Smad1 suppressed the EMT process induced by PM2.5 exposure. Our data further revealed that miR-32 has a negative effect on PM2.5-induced EMT. The results showed that the expression level of miR-32 was significantly upregulated in the PM2.5-induced EMT process. The knockdown of miR-32 enhances the activity of the Smad1-mediated signaling pathway, which promotes the EMT process induced by PM2.5. Thus, these findings indicate that PM2.5 can induce the EMT process through the Smad1-mediated signaling pathway, and miR-32 may act as an EMT inhibitor in lung cancer cells.
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Affiliation(s)
- Dan Yang
- Key Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No. 146, North Huanghe Street, Huanggu District, Shenyang City, 110034, PR China; Department of Pharmacology, Shenyang Medical College, No. 146, North Huanghe Street, Huanggu District, Shenyang City, 110034, PR China
| | - Mingyue Ma
- Key Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No. 146, North Huanghe Street, Huanggu District, Shenyang City, 110034, PR China; Department of Toxicology, School of Public Health, Shenyang Medical College, No. 146, North Huanghe Street, Huanggu District, Shenyang City, 110034, PR China
| | - Weiqiang Zhou
- Key Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No. 146, North Huanghe Street, Huanggu District, Shenyang City, 110034, PR China
| | - Biao Yang
- Key Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No. 146, North Huanghe Street, Huanggu District, Shenyang City, 110034, PR China
| | - Chunling Xiao
- Key Laboratory of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No. 146, North Huanghe Street, Huanggu District, Shenyang City, 110034, PR China.
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Long noncoding RNA LINC00673 epigenetically suppresses KLF4 by interacting with EZH2 and DNMT1 in gastric cancer. Oncotarget 2017; 8:95542-95553. [PMID: 29221147 PMCID: PMC5707041 DOI: 10.18632/oncotarget.20980] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 08/04/2017] [Indexed: 01/01/2023] Open
Abstract
Long non-coding RNAs (lncRNAs), a variety of transcripts without protein coding ability, have recently been reported to play vital roles in gastric cancer (GC) development and progression. However, the biological role of long non-coding RNA LINC00673 in GC is not fully known. In the study, we found that LINC00673 expression was dramatically higher in gastric cancer tissues compared with adjacent normal tissues, and positively associated with lymph node metastasis, distant metastasis and TNM stage in patients. Higher LINC00673 expression predicted poor disease-free survival (DFS) and overall survival (OS) in GC patients. By univariate and multivariate Cox analysis, the results confirmed that higher LINC00673 expression was an independent risk factor of prognosis in patients. Knockdown of endogenous LINC00673 significantly inhibited cell proliferation, colony formation number, cell migration and invasion in GC. Furthermore, knockdown of endogenous LINC00673 reduced the expression levels of PCNA, CyclinD1 and CDK2 in GC cells. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) proved that LINC00673 suppressed KLF4 expression by interacting with EZH2 and DNMT1 in GC cells. Moreover, we confirmed that LINC00673 promoted cell proliferation and invasion by partly repressing KLF4 expression in GC. Taken together, these results indicated that LINC00673 may be a prognostic biomarker and therapeutic target for GC patients.
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Zhang X, Liu F, Wang Q, Geng Y. Overexpressed microRNA-506 and microRNA-124 alleviate H2O2-induced human cardiomyocyte dysfunction by targeting krüppel-like factor 4/5. Mol Med Rep 2017; 16:5363-5369. [PMID: 28849090 PMCID: PMC5647069 DOI: 10.3892/mmr.2017.7243] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 06/06/2017] [Indexed: 01/23/2023] Open
Abstract
Krüppel-like factors (KLFs) regulate a wide variety of cellular functions and modulate pathological processes. In the present study, a post-translational mechanism of microRNAs (miRs) was investigated in H2O2-induced human cardiomyocyte (HCM) injury. In H2O2-cultured HCM cells, reactive oxygen species and apoptotic cells were measured via flow cytometry. miR-506/-124 mimics and inhibitors were transfected to induce gain or loss of miR-506/-124 function. Cell proliferation was analyzed by an MTT assay. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The mRNA and protein expression levels were measured by reverse transcription-polymerse chain reaction analysis and western blotting, respectively. The results indicated that H2O2 induced significant apoptosis and increased the concentration of reactive oxygen species (ROS) in HCMs. H2O2 markedly upregulated the expression levels of KLF4 and KLF5, and downregulated the expression levels of miR-506 and miR-124 in the HCMs. In addition, bioinformatics analysis showed the potential miR-506 and miR-124 binding sites within the 3′-untranslated region of KLF4 and KLF5 in the HCMs. The overexpression of miR-506 and miR-124 inhibited the H2O2-induced upregulation of KLF4 and KLF5 in the HCMs. The overexpression of miR-506 and miR-214 reversed the H2O2-induced apoptosis and increase of ROS in the HCMs. In conclusion, the overexpression of miR-506 and miR-214 were confirmed to have a protective effect against H2O2-induced HCM injury by suppressing the expression of KLF4 and KLF5.
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Affiliation(s)
- Xiuzhou Zhang
- Department of Cardiology, Binzhou People's Hospital, Binzhou, Shandong 256610, P.R. China
| | - Fuyan Liu
- Department of Anesthesiology, Binzhou People's Hospital, Binzhou, Shandong 256610, P.R. China
| | - Qingqing Wang
- Department of Pharmacy, Binzhou People's Hospital, Binzhou, Shandong 256610, P.R. China
| | - Yuxue Geng
- Department of Cardiology, Binzhou People's Hospital, Binzhou, Shandong 256610, P.R. China
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Zhang J, Liu Y, Yu CJ, Dai F, Xiong J, Li HJ, Wu ZS, Ding R, Wang H. Role of ARPC2 in Human Gastric Cancer. Mediators Inflamm 2017; 2017:5432818. [PMID: 28694563 PMCID: PMC5485321 DOI: 10.1155/2017/5432818] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 03/06/2017] [Indexed: 01/01/2023] Open
Abstract
Gastric cancer continues to be the second most frequent cause of cancer deaths worldwide. However, the exact molecular mechanisms are still unclear. Further research to find potential targets for therapy is critical and urgent. In this study, we found that ARPC2 promoted cell proliferation and invasion in the human cancer cell line MKN-28 using a cell total number assay, MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, cell colony formation assay, migration assay, invasion assay, and wound healing assay. For downstream pathways, CTNND1, EZH2, BCL2L2, CDH2, VIM, and EGFR were upregulated by ARPC2, whereas PTEN, BAK, and CDH1 were downregulated by ARPC2. In a clinical study, we examined the expression of ARPC2 in 110 cases of normal human gastric tissues and 110 cases of human gastric cancer tissues. ARPC2 showed higher expression in gastric cancer tissues than in normal gastric tissues. In the association analysis of 110 gastric cancer tissues, ARPC2 showed significant associations with large tumor size, lymph node invasion, and high tumor stage. In addition, ARPC2-positive patients exhibited lower RFS and OS rates compared with ARPC2-negative patients. We thus identify that ARPC2 plays an aneretic role in human gastric cancer and provided a new target for gastric cancer therapy.
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Affiliation(s)
- Jun Zhang
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Yi Liu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chang-Jun Yu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fu Dai
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Jie Xiong
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Hong-Jun Li
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Zheng-Sheng Wu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Rui Ding
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Hong Wang
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
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26
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Kim CK, He P, Bialkowska AB, Yang VW. SP and KLF Transcription Factors in Digestive Physiology and Diseases. Gastroenterology 2017; 152:1845-1875. [PMID: 28366734 PMCID: PMC5815166 DOI: 10.1053/j.gastro.2017.03.035] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 03/21/2017] [Accepted: 03/24/2017] [Indexed: 12/14/2022]
Abstract
Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies have shown that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins.
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Affiliation(s)
- Chang-Kyung Kim
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY
| | - Ping He
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY
| | - Agnieszka B. Bialkowska
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY,Corresponding Authors: Vincent W. Yang & Agnieszka B. Bialkowska, Department of Medicine, Stony Brook University School of Medicine, HSC T-16, Rm. 020; Stony Brook, NY, USA. Tel: (631) 444-2066; Fax: (631) 444-3144; ;
| | - Vincent W. Yang
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY,Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, NY,Corresponding Authors: Vincent W. Yang & Agnieszka B. Bialkowska, Department of Medicine, Stony Brook University School of Medicine, HSC T-16, Rm. 020; Stony Brook, NY, USA. Tel: (631) 444-2066; Fax: (631) 444-3144; ;
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27
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Malcomson FC, Willis ND, McCallum I, Xie L, Lagerwaard B, Kelly S, Bradburn DM, Belshaw NJ, Johnson IT, Mathers JC. Non-digestible carbohydrates supplementation increases miR-32 expression in the healthy human colorectal epithelium: A randomized controlled trial. Mol Carcinog 2017; 56:2104-2111. [PMID: 28418082 PMCID: PMC5573932 DOI: 10.1002/mc.22666] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 03/31/2017] [Accepted: 04/13/2017] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) risk is modulated by diet and there is convincing evidence of reduced risk with higher non‐digestible carbohydrates (NDCs) consumption. Resistant starch (RS), a NDC, positively modulates the expression of oncogenic microRNAs, suggesting that this could be a mechanism through which NDCs protect against CRC. The present study aimed to investigate the effects of supplementation with two NDCs, RS, and polydextrose (PD), on microRNA expression in the macroscopically‐normal human rectal epithelium using samples from the DISC Study, a randomized, double‐blind, placebo‐controlled dietary intervention. We screened 1008 miRNAs in pooled post‐intervention rectal mucosal samples from participants allocated to the double placebo group and those supplemented with both RS and PD. A total of 111 miRNAs were up‐ or down‐regulated by at least twofold in the RS + PD group compared with the control group. From these, eight were selected for quantification in individual participant samples by qPCR, and fold‐change direction was consistent with the array for seven miRNAs. The inconsistency for miR‐133b and the lower fold‐change values observed for the seven miRNAs is probably because qPCR of individual participant samples is a more robust and sensitive method of quantification than the array. miR‐32 expression was increased by approximately threefold (P = 0.033) in the rectal mucosa of participants supplemented with RS + PD compared with placebo. miR‐32 is involved in the regulation of processes such as cell proliferation that are dysregulated in CRC. Furthermore, miR‐32 may affect non‐canonical NF‐κB signaling via regulation of TRAF3 expression and consequently NIK stabilization.
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Affiliation(s)
- Fiona C Malcomson
- Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Naomi D Willis
- Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Iain McCallum
- Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Long Xie
- Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Bart Lagerwaard
- Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Seamus Kelly
- Northumbria Healthcare NHS Foundation Trust, North Shields, UK
| | | | - Nigel J Belshaw
- Institute of Food Research, Norwich Research Park, Norwich, Norfolk, UK
| | - Ian T Johnson
- Institute of Food Research, Norwich Research Park, Norwich, Norfolk, UK
| | - John C Mathers
- Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
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Zhang ZM, Zhang AR, Xu M, Lou J, Qiu WQ. TLR-4/miRNA-32-5p/FSTL1 signaling regulates mycobacterial survival and inflammatory responses in Mycobacterium tuberculosis-infected macrophages. Exp Cell Res 2017; 352:313-321. [PMID: 28215633 DOI: 10.1016/j.yexcr.2017.02.025] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 02/13/2017] [Accepted: 02/15/2017] [Indexed: 02/06/2023]
Abstract
Macrophages play a pivotal role in host immune response against mycobacterial infection, which is tightly modulated by multiple factors, including microRNAs. The purpose of the present study was to investigate the biological function and potential mechanism of miR-32-5p in human macrophages during Mycobacterium tuberculosis (M.tb) infection. The results demonstrated that miR-32-5p was robustly enhanced in THP-1 and U937 cells in response to M.tb infection. TLR-4 signaling was required for upregulation of miR-32-5p induced by M.tb infection. Additionally, the introduction of miR-32-5p strongly increased the survival rate of intracellular mycobacteria, whereas inhibition of miR-32-5p suppressed intracellular growth of mycobacteria during M.tb challenged. Furthermore, forced expression of miR-32-5p dramatically attenuated the accumulation of inflammatory cytokines IL-1β, IL-6 and TNF-α induced by M.tb infection. Conversely, downregulated expression of miR-32-5p led to enhancement in these inflammatory cytokines. More importantly, our study explored that Follistatin-like protein 1 (FSTL1) was a direct and functional target of miR-32-5p. qRT-PCR and western blot analysis further validated that miR-32-5p negatively regulated the expression of FSTL1. Mechanistically, re-expression of FSTL1 attenuated the ability of miR-32-5p to promote mycobacterial survival. Meanwhile, miR-32-5p-mediated inhibition of the inflammatory cytokine production were completely reversed by overexpression of FSTL1. Collectively, our findings demonstrated a novel role of TLR-4/miRNA-32-5p/FSTL1 in the modulation of host defense against mycobacterial infection, which may provide a better understanding of the pathogenesis of tuberculosis and useful information for developing potential therapeutic interventions against the disease.
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Affiliation(s)
- Zhi-Min Zhang
- Department of Clinical Laboratory, the Central Hospital of Zhumadian, Zhumadian, Henan 463000, PR China.
| | - Ai-Rong Zhang
- Department of Clinical Laboratory, the Central Hospital of Zhumadian, Zhumadian, Henan 463000, PR China
| | - Min Xu
- Department of Clinical Laboratory, the Central Hospital of Zhumadian, Zhumadian, Henan 463000, PR China
| | - Jun Lou
- Department of Clinical Laboratory, the Central Hospital of Zhumadian, Zhumadian, Henan 463000, PR China
| | - Wei-Qiang Qiu
- Department of Clinical Laboratory, the Central Hospital of Zhumadian, Zhumadian, Henan 463000, PR China
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Zhao L, Han T, Li Y, Sun J, Zhang S, Liu Y, Shan B, Zheng D, Shi J. The lncRNA SNHG5/miR-32 axis regulates gastric cancer cell proliferation and migration by targeting KLF4. FASEB J 2016; 31:893-903. [PMID: 27871067 DOI: 10.1096/fj.201600994r] [Citation(s) in RCA: 140] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 11/07/2016] [Indexed: 12/31/2022]
Abstract
Long noncoding RNAs (lncRNAs) are emerging as important regulators in cellular processes, including the development, proliferation, and migration of cancer cells. We have demonstrated in a prior study that small nucleolar RNA host gene 5 (SNHG5) is dysregulated in gastric cancer (GC). To further explore the underlying mechanisms of SNGH5 function in the development of GC, in this study, we screened the microRNAs interacting with SNHG5 and elucidated their roles in GC. We showed that SNHG5 contains a putative miR-32-binding site and that deletion of this site abolishes the responsiveness to miR-32. Suppression of SNHG5 expression by miR-32 was found to be Argonaute (Ago)2-dependent. Immunoprecipitation showed that SNHG5 could be pulled down from the Ago-2 complex with miR-32. Furthermore, it was reported that Kruppel-like factor 4 (KLF4) is a target gene of miR-32. In agreement with SNHG5 being a decoy for miR-32, we showed that KLF4 suppression by miR-32 could be partially rescued by SNHG5 overexpression, whereas miR-32 mimic rescued SNHG5 overexpression-mediated suppression of GC cell migration. In addition, we identified a negative correlation between the expression of SNHG5 and miR-32 in GC tissues. Furthermore, KLF4 expression was significantly downregulated in GC specimens, and a negative correlation between miR-32 and KLF4 expression and a positive correlation between KLF4 and SNHG5 expression levels were detected. Overall, this study demonstrated, for the first time, that the SNHG5/miR-32/KLF4 axis functions as an important player in GC cell migration and potentially contributes to the improvement of GC diagnosis and therapy.-Zhao, L., Han, T., Li, Y., Sun, J., Zhang, S., Liu, Y., Shan, B., Zheng D., Shi, J. The lncRNA SNHG5/miR-32 axis regulates gastric cancer cell proliferation and migration by targeting KLF4.
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Affiliation(s)
- Lianmei Zhao
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and.,Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Taotao Han
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Yanshuang Li
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Jiazeng Sun
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Shang Zhang
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Yanxin Liu
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Baoen Shan
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dexian Zheng
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Juan Shi
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
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