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Lin F, Hu S, Chen J, Li H, Li M, Li R, Xu M, Luo M. MiR-125b suppresses bladder Cancer cell growth and triggers apoptosis by regulating IL-6/IL-6R/STAT3 axis in vitro and in vivo. Cytokine 2025; 190:156926. [PMID: 40120148 DOI: 10.1016/j.cyto.2025.156926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 03/02/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Bladder cancer (BLCA) is an aggressive malignancy characterized by limited therapeutic options and a poor prognosis. Research has indicated that abnormally expressed miRNAs play a significant role in the pathogenesis of BLCA, although the specific mechanisms remain unclear. MiR-125b plays a tumor suppressor role in a variety of cancers and affects the biological processes of cancer cells such as proliferation, invasion, migration and apoptosis by regulating different signaling pathways. Elucidation of the molecular mechanisms underlying miR-125b may provide clinical therapeutic strategies for bladder cancer. Here, miR-125b was downregulated whereas its targets IL-6R and STAT3 were upregulated in BLCA, as evidenced by bioinformatics analysis. Kaplan-Meier analysis confirmed that miR-125b serves as an independent prognostic factor linked to overall survival (OS) in patients with bladder cancer. Furthermore, overexpression of miR-125b significantly inhibited BLCA cell proliferation, migration, and invasion, while promoting apoptosis, as evidenced by an increased Bax/Bcl-2 ratio and activated cleaved caspase-3. Further investigations demonstrated that miR-125b directly targets and downregulates both IL-6R and STAT3. In a xenograft model, miR-125b overexpression effectively inhibited tumor growth in bladder cancer by blocking IL-6/IL-6R and STAT3 signaling pathways. Collectively, these findings broaden our understanding of the mechanism by which miR-125b acting as a BLCA suppressor in apoptotic regulation by targeting the IL-6/IL-6R/STAT3 signaling pathway, providing novel insights regarding the design of novel miRNA based therapeutic strategies against BLCA.
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Affiliation(s)
- Fang Lin
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Shaorun Hu
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Jinxiang Chen
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Haiyang Li
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Mengting Li
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Rong Li
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Min Xu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China.
| | - Mao Luo
- Basic Medicine Research Innovation Center for cardiometabolic diseases, Ministry of Education; Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China; Department of Pharmacy, The Second People's Hospital of Yibin, Yibin, Sichuan, China..
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Zhu M, Lu Z, Liao X, Liang Q, Xu C, Luo X, Li J. Clinical value of dysregulated miR-125b-5p in severe pneumonia children. BMC Immunol 2025; 26:31. [PMID: 40221643 PMCID: PMC11993971 DOI: 10.1186/s12865-025-00707-6] [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: 12/30/2024] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Severe pneumonia is an important contributor to the high mortality of sick young children. The microRNA-125b-5p (miR-125b-5p), which is widely involved in various cancers, is closely related to a variety of lung diseases. However, its role in severe pneumonia children remains to be studied. OBJECTIVE This study focused on the expression and clinical value of miR-125b-5p in severe pneumonia children. MATERIALS AND METHODS The study subjects included 96 pneumonia children and 127 severe pneumonia children. These children were aged between 2-10 years. The expression level of serum miR-125b-5p was assessed by qRT-PCR. The receiver operator characteristic (ROC) curve was employed to identify severe pneumonia children from pneumonia individuals. Kaplan-Meier curve was plotted based on follow-up results and multivariate Cox regression analysis was applied to evaluate the contribution of miR-125b-5p to poor prognostic in severe pneumonia children. RESULTS MiR-125b-5p was remarkedly reduced in severe pneumonia children compared to pneumonia individuals. The area under the curve (AUC) was 0.9267 and the sensitivity and specificity were 84.25% and 89.58%, respectively. The accumulative survival rate in low miR-125b-5p group showed a remarkable decrease compared to the high miR-125b-5p group (P = 0.033). Increased procalcitonin (PCT, HR: 2.631, 95% CI: 1.029-6.732, P = 0.043) and reduced miR-125b-5p (HR: 0.301, 95% CI: 0.110-0.826, P = 0.020) were found to be related to the poor prognosis in severe pneumonia children. CONCLUSION The reduced miR-125b-5p was an underlying diagnostic indicator of severe pneumonia and was an independent risk factor of poor prognosis in severe pneumonia children.
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Affiliation(s)
- Meiqin Zhu
- Department of Respiratory, The Fourth Affiliated Hospital of Jiangsu University (Zhenjiang Maternal and Child Health Hospital), Zhenjiang, 212001, China
| | - Ziyan Lu
- Department of Pediatrics, Women and Children's Hospital, Qingdao University, Qingdao, 266011, China
| | - Xingjuan Liao
- Department of Pediatrics, Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, 442000, China
| | - Qin Liang
- Department of Pediatrics, Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, 442000, China
| | - Chao Xu
- Department of Pediatrics, Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, 442000, China
| | - Xinbing Luo
- Department of Pediatrics, Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, 442000, China
| | - Jun Li
- Department of Integrated Traditional Chinese and Western Medicine, Xi'an Children's Hospital, The Affiliated Children's Hospital of Xi'an Jiaotong University, No. 69, Xijuyuan Lane, Lianhu District, Xi'an, 710003, China.
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Herbst E, Mandel-Gutfreund Y, Yakhini Z, Biran H. Inferring single-cell and spatial microRNA activity from transcriptomics data. Commun Biol 2025; 8:87. [PMID: 39827321 PMCID: PMC11743151 DOI: 10.1038/s42003-025-07454-9] [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: 03/25/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025] Open
Abstract
The activity of miRNA varies across different cell populations and systems, as part of the mechanisms that distinguish cell types and roles in living organisms and in human health and disease. Typically, miRNA regulation drives changes in the composition and levels of protein-coding RNA and of lncRNA, with targets being down-regulated when miRNAs are active. The term "miRNA activity" is used to refer to this transcriptional effect of miRNAs. This study introduces miTEA-HiRes, a method designed to facilitate the evaluation of miRNA activity at high resolution. The method applies to single-cell transcriptomics, type-specific single-cell populations, and spatial transcriptomics data. By comparing different conditions, differential miRNA activity is inferred. For instance, miTEA-HiRes analysis of peripheral blood mononuclear cells comparing Multiple Sclerosis patients to control groups revealed differential activity of miR-20a-5p and others, consistent with the literature on miRNA underexpression in Multiple Sclerosis. We also show miR-519a-3p differential activity in specific cell populations.
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Affiliation(s)
- Efrat Herbst
- Arazi School of Computer Science, Reichman University, Herzliya, Israel.
| | - Yael Mandel-Gutfreund
- Computer Science Department, Technion - Israel Institute of Technology, Haifa, Israel
- Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Zohar Yakhini
- Arazi School of Computer Science, Reichman University, Herzliya, Israel
- Computer Science Department, Technion - Israel Institute of Technology, Haifa, Israel
| | - Hadas Biran
- Computer Science Department, Technion - Israel Institute of Technology, Haifa, Israel
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Chuang YT, Yen CY, Tang JY, Chang FR, Tsai YH, Wu KC, Chien TM, Chang HW. The modulation of immune cell death in connection to microRNAs and natural products. Front Immunol 2024; 15:1425602. [PMID: 39759512 PMCID: PMC11695430 DOI: 10.3389/fimmu.2024.1425602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 11/27/2024] [Indexed: 01/07/2025] Open
Abstract
Immunogenic cell death (ICD) spatiotemporally regulates damage-associated molecular patterns (DAMPs) derived from dying cancer cells to signal the immune response. Intriguingly, these DAMPs and cytokines also induce cellular responses in non-immune cells, particularly cancer cells. Several ICD-modulating natural products and miRNAs have been reported to regulate the DAMP, cytokine, and cell death responses, but they lack systemic organization and connection. This review summarizes the impacts of natural products and miRNAs on the DAMP and cytokine responses and cancer cell death responses (apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis). We establish the rationale that ICD inducers of natural products have modulating effects on miRNAs, targeting DAMPs and cytokines for immune and cancer cell death responses. In conclusion, DAMP, cytokine, and cell death responses are intricately linked in cancer cells, and they are influenced by ICD-modulating natural products and miRNAs.
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Affiliation(s)
- Ya-Ting Chuang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Yu Yen
- School of Dentistry, Taipei Medical University, Taipei, Taiwan
- Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Jen-Yang Tang
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Fang-Rong Chang
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hong Tsai
- Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University, Pingtung, Taiwan
| | - Kuo-Chuan Wu
- Department of Computer Science and Information Engineering, National Pingtung University, Pingtung, Taiwan
| | - Tsu-Ming Chien
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Gangshan Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsueh-Wei Chang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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Darmadi D, Aminov Z, Hjazi A, R R, Kazmi SW, Mustafa YF, Hosseen B, Sharma A, Alubiady MHS, Al-Abdeen SHZ. Investigation of the regulation of EGF signaling by miRNAs, delving into the underlying mechanism and signaling pathways in cancer. Exp Cell Res 2024; 442:114267. [PMID: 39313176 DOI: 10.1016/j.yexcr.2024.114267] [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: 07/20/2024] [Revised: 09/19/2024] [Accepted: 09/21/2024] [Indexed: 09/25/2024]
Abstract
The EGF receptors (EGFRs) signaling pathway is essential for tumorigenesis and progression of cancer. Emerging evidence suggests that miRNAs are essential regulators of EGF signaling, influencing various pathway components and tumor behavior. This article discusses the underlying mechanisms and clinical implications of miRNA-mediated regulation of EGF signaling in cancer. miRNAs utilize multiple mechanisms to exert their regulatory effects on EGF signaling. They can target EGF ligands, including EGF and TGF-directly, inhibiting their expression and secretion. In addition, miRNAs can modulate EGF signaling indirectly by targeting EGF receptors, downstream signaling molecules, and transcription factors implicated in regulating the EGF pathway. These miRNAs can disrupt the delicate equilibrium of EGF signaling, resulting in aberrant activation and fostering tumor cell proliferation, survival, angiogenesis, and metastasis. The dysregulation of the expression of specific miRNAs has been linked to clinical outcomes in numerous types of cancer. Specific profiles of miRNA expression have been identified as prognostic markers, reflecting tumor characteristics, invasiveness, metastatic potential, and therapeutic response. These miRNAs can serve as potential therapeutic targets for interventions that modulate EGF signaling and improve patient outcomes. Understanding the intricate relationship between miRNAs and EGF signaling in cancer can transform cancer diagnosis, prognosis, and treatment. The identification of specific miRNAs involved in the regulation of the EGF pathway opens the door to the development of targeted therapies and personalized medicine approaches. In addition, miRNA-based interventions promise to overcome therapeutic resistance and improve the efficacy of existing treatments. miRNAs are crucial regulators of EGF signaling in cancer, affecting tumor behavior and clinical outcomes. Further research is required to decipher the complex network of miRNA-mediated EGF signaling regulation and translate these findings into clinically applicable strategies for enhanced cancer treatment.
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Affiliation(s)
- Darmadi Darmadi
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia.
| | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan.
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia.
| | - Roopashree R
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India.
| | - Syeda Wajida Kazmi
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri, Mohali, 140307, Punjab, India.
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq.
| | - Beneen Hosseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq; Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq.
| | - Abhishek Sharma
- Department of Medicine, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India.
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Md Zaki FA, Mohamad Hanif EA. Identifying miRNA as biomarker for breast cancer subtyping using association rule. Comput Biol Med 2024; 178:108696. [PMID: 38850957 DOI: 10.1016/j.compbiomed.2024.108696] [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: 02/29/2024] [Revised: 05/03/2024] [Accepted: 06/01/2024] [Indexed: 06/10/2024]
Abstract
- This paper presents a comprehensive study focused on breast cancer subtyping, utilizing a multifaceted approach that integrates feature selection, machine learning classifiers, and miRNA regulatory networks. The feature selection process begins with the CFS algorithm, followed by the Apriori algorithm for association rule generation, resulting in the identification of significant features tailored to Luminal A, Luminal B, HER-2 enriched, and Basal-like subtypes. The subsequent application of Random Forest (RF) and Support Vector Machine (SVM) classifiers yielded promising results, with the SVM model achieving an overall accuracy of 76.60 % and the RF model demonstrating robust performance at 80.85 %. Detailed accuracy metrics revealed strengths and areas for refinement, emphasizing the potential for optimizing subtype-specific recall. To explore the regulatory landscape in depth, an analysis of selected miRNAs was conducted using MIENTURNET, a tool for visualizing miRNA-target interactions. While FDR analysis raised concerns for HER-2 and Basal-like subtypes, Luminal A and Luminal B subtypes showcased significant miRNA-gene interactions. Functional enrichment analysis for Luminal A highlighted the role of Ovarian steroidogenesis, implicating specific miRNAs such as hsa-let-7c-5p and hsa-miR-125b-5p as potential diagnostic biomarkers and regulators of Luminal A breast cancer. Luminal B analysis uncovered associations with the MAPK signaling pathway, with miRNAs like hsa-miR-203a-3p and hsa-miR-19a-3p exhibiting potential diagnostic and therapeutic significance. In conclusion, this integrative approach combines machine learning techniques with miRNA analysis to provide a holistic understanding of breast cancer subtypes. The identified miRNAs and associated pathways offer insights into potential diagnostic biomarkers and therapeutic targets, contributing to the ongoing efforts to improve breast cancer diagnostics and personalized treatment strategies.
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Affiliation(s)
- Fatimah Audah Md Zaki
- Department of Internet Engineering & Computer Science, Universiti Tunku Abdul Rahman (UTAR), Selangor, Malaysia.
| | - Ezanee Azlina Mohamad Hanif
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia.
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Guo Y, Tian S, Li H, Zuo S, Yu C, Sun C. Transcription factor KLF9 inhibits the proliferation, invasion, and migration of pancreatic cancer cells by repressing KIAA1522. Asia Pac J Clin Oncol 2024; 20:423-432. [PMID: 38520660 DOI: 10.1111/ajco.14048] [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: 02/16/2023] [Revised: 01/09/2024] [Accepted: 01/15/2024] [Indexed: 03/25/2024]
Abstract
AIM Pancreatic cancer (PC) has a poor prognosis and high mortality. Kruppel-like factor 9 (KLF9), a transcription factor, is aberrantly expressed in various neoplasms. The current study sought to analyze the functional role of KLF9 in the proliferation, invasion, and migration of PC cells. METHODS The expression patterns of KLF9 and KIAA1522 in normal pancreatic cells (HPDE-C7) and PC cells (Panc 03.27, BxPc3, SW1990) were determined by real-time quantitative polymerase chain reaction and Western blot assay. After treatment of KLF9 overexpression, proliferation, invasion, and migration were evaluated by cell counting kit-8, 5-ethynyl-2'-deoxyuridine staining, and Transwell assays. The binding of KLF9 to the KIAA1522 promoter was analyzed by dual-luciferase assay and chromatin immunoprecipitation. The rescue experiment was conducted to analyze the role of KIAA1522. RESULTS KLF9 was downregulated, while KIAA1522 was upregulated in PC cells. KLF9 overexpression mitigated the proliferation, invasion, and migration of PC cells. Enrichment of KLF9 led to inhibition of the KIAA1522 promoter and repressed KIAA1522 expression. KIAA1522 overexpression neutralized the inhibitory role of KLF9 in PC cell functions. CONCLUSION KLF9 is enriched in the KIAA1522 promoter and negatively regulates KIAA1522 expression, thereby mitigating the proliferation, invasion, and migration of PC cells.
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Affiliation(s)
- Yuting Guo
- Department of General Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - She Tian
- Department of General Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Haiyang Li
- Guizhou Medical University, Guiyang, China
| | - Shi Zuo
- Guizhou Medical University, Guiyang, China
| | - Chao Yu
- Department of General Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Chengyi Sun
- Guizhou Medical University, Guiyang, China
- Soochow University, Suzhou, China
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Raj-Kumar PK, Lin X, Liu T, Sturtz LA, Gritsenko MA, Petyuk VA, Sagendorf TJ, Deyarmin B, Liu J, Praveen-Kumar A, Wang G, McDermott JE, Shukla AK, Moore RJ, Monroe ME, Webb-Robertson BJM, Hooke JA, Fantacone-Campbell L, Mostoller B, Kvecher L, Kane J, Melley J, Somiari S, Soon-Shiong P, Smith RD, Mural RJ, Rodland KD, Shriver CD, Kovatich AJ, Hu H. Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection. Breast Cancer Res 2024; 26:76. [PMID: 38745208 PMCID: PMC11094977 DOI: 10.1186/s13058-024-01835-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/05/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. METHODS We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. RESULTS We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA-protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. CONCLUSIONS This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.
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Affiliation(s)
- Praveen-Kumar Raj-Kumar
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Xiaoying Lin
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Tao Liu
- Pacific Northwest National Laboratory, Richland, WA, USA
| | - Lori A Sturtz
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | | | | | | | - Brenda Deyarmin
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | - Jianfang Liu
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | | | - Guisong Wang
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
| | | | - Anil K Shukla
- Pacific Northwest National Laboratory, Richland, WA, USA
| | - Ronald J Moore
- Pacific Northwest National Laboratory, Richland, WA, USA
| | | | | | - Jeffrey A Hooke
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
| | - Leigh Fantacone-Campbell
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
| | - Brad Mostoller
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | - Leonid Kvecher
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Jennifer Kane
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | - Jennifer Melley
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | - Stella Somiari
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | | | | | - Richard J Mural
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA
| | | | - Craig D Shriver
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
- Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD, USA.
| | - Albert J Kovatich
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA
| | - Hai Hu
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA.
- Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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Szczepanek J, Tretyn A. MicroRNA-Mediated Regulation of Histone-Modifying Enzymes in Cancer: Mechanisms and Therapeutic Implications. Biomolecules 2023; 13:1590. [PMID: 38002272 PMCID: PMC10669115 DOI: 10.3390/biom13111590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/22/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
In the past decade, significant advances in molecular research have provided a deeper understanding of the intricate regulatory mechanisms involved in carcinogenesis. MicroRNAs, short non-coding RNA sequences, exert substantial influence on gene expression by repressing translation or inducing mRNA degradation. In the context of cancer, miRNA dysregulation is prevalent and closely associated with various stages of carcinogenesis, including initiation, progression, and metastasis. One crucial aspect of the cancer phenotype is the activity of histone-modifying enzymes that govern chromatin accessibility for transcription factors, thus impacting gene expression. Recent studies have revealed that miRNAs play a significant role in modulating these histone-modifying enzymes, leading to significant implications for genes related to proliferation, differentiation, and apoptosis in cancer cells. This article provides an overview of current research on the mechanisms by which miRNAs regulate the activity of histone-modifying enzymes in the context of cancer. Both direct and indirect mechanisms through which miRNAs influence enzyme expression are discussed. Additionally, potential therapeutic implications arising from miRNA manipulation to selectively impact histone-modifying enzyme activity are presented. The insights from this analysis hold significant therapeutic promise, suggesting the utility of miRNAs as tools for the precise regulation of chromatin-related processes and gene expression. A contemporary focus on molecular regulatory mechanisms opens therapeutic pathways that can effectively influence the control of tumor cell growth and dissemination.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, ul. Wilenska 4, 87-100 Torun, Poland
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, ul. Lwowska 1, 87-100 Torun, Poland;
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10
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Muñoz JP, Pérez-Moreno P, Pérez Y, Calaf GM. The Role of MicroRNAs in Breast Cancer and the Challenges of Their Clinical Application. Diagnostics (Basel) 2023; 13:3072. [PMID: 37835815 PMCID: PMC10572677 DOI: 10.3390/diagnostics13193072] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/14/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
MicroRNAs (miRNAs) constitute a subclass of non-coding RNAs that exert substantial influence on gene-expression regulation. Their tightly controlled expression plays a pivotal role in various cellular processes, while their dysregulation has been implicated in numerous pathological conditions, including cancer. Among cancers affecting women, breast cancer (BC) is the most prevalent malignant tumor. Extensive investigations have demonstrated distinct expression patterns of miRNAs in normal and malignant breast cells. Consequently, these findings have prompted research efforts towards leveraging miRNAs as diagnostic tools and the development of therapeutic strategies. The aim of this review is to describe the role of miRNAs in BC. We discuss the identification of oncogenic, tumor suppressor and metastatic miRNAs among BC cells, and their impact on tumor progression. We describe the potential of miRNAs as diagnostic and prognostic biomarkers for BC, as well as their role as promising therapeutic targets. Finally, we evaluate the current use of artificial intelligence tools for miRNA analysis and the challenges faced by these new biomedical approaches in its clinical application. The insights presented in this review underscore the promising prospects of utilizing miRNAs as innovative diagnostic, prognostic, and therapeutic tools for the management of BC.
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Affiliation(s)
- Juan P. Muñoz
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
| | - Pablo Pérez-Moreno
- Programa de Comunicación Celular en Cáncer, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7780272, Chile
| | - Yasmín Pérez
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
| | - Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
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11
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Yang H, Feng X, Tong X. Long noncoding RNA POU6F2-AS2 contributes to the aggressiveness of nonsmall-cell lung cancer via microRNA-125b-5p-mediated E2F3 upregulation. Aging (Albany NY) 2023; 15:2689-2704. [PMID: 37053020 PMCID: PMC10120888 DOI: 10.18632/aging.204639] [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: 01/06/2023] [Accepted: 03/20/2023] [Indexed: 04/14/2023]
Abstract
The role of the majority of long noncoding RNAs (lncRNAs) in the progression of nonsmall-cell lung cancer (NSCLC) remains elusive, despite their potential value, thus warranting in-depth studies. For example, detailed functions of the lncRNA POU6F2 antisense RNA 2 (POU6F2-AS2) in NSCLC are unknown. Herein, we investigated the expression status of POU6F2-AS2 in NSCLC. Furthermore, we systematically delineated the biological roles of POU6F2-AS2 in NSCLC alongside its downstream molecular events. We measured the expression levels of POU6F2-AS2 using quantitative real-time polymerase chain reaction and performed a series of functional experiments to address its regulatory effects in NSCLC cells. Using bioinformatic platforms, RNA immunoprecipitation, luciferase reporter assays, and rescue experiments, we investigated the potential mechanisms of POU6F2-AS2 in NSCLC. Subsequently, we confirmed the remarkable overexpression of POU6F2-AS2 in NSCLC using The Cancer Genome Atlas database and our own cohort. Functionally, inhibiting POU6F2-AS2 decreased NSCLC cell proliferation, colony formation, and motility, whereas POU6F2-AS2 overexpression exhibited contrasting effects. Mechanistically, POU6F2-AS2 acts as an endogenous decoy for microRNA-125b-5p (miR-125b-5p) in NSCLC that causes the overexpression of the E2F transcription factor 3 (E2F3). Moreover, suppressing miR-125b-5p or increasing E2F3 expression levels sufficiently recovered the anticarcinostatic activities in NSCLC induced by POU6F2-AS2 silencing. Thus, POU6F2-AS2 aggravates the oncogenicity of NSCLC by targeting the miR-125b-5p/E2F3 axis. Our findings suggest that POU6F2-AS2 is a novel therapeutic target for NSCLC.
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Affiliation(s)
- Haitao Yang
- Department of Thoracic Surgery, The People’s Hospital of Liaoning Province, Liaoning 110016, P.R. China
| | - Xiao Feng
- Department of Thoracic Surgery, The People’s Hospital of Liaoning Province, Liaoning 110016, P.R. China
| | - Xiangdong Tong
- Department of Thoracic Surgery, The People’s Hospital of Liaoning Province, Liaoning 110016, P.R. China
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12
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Zhou Y, Zhu H, Han J, Xu Y, Wang D, Jin W, Zhu R, Qiao L. miR-125b-5p Suppresses Leukemia Cell Proliferation by Regulating MCL1. J Environ Pathol Toxicol Oncol 2023; 42:17-26. [PMID: 36734950 DOI: 10.1615/jenvironpatholtoxicoloncol.2022041924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Leukemia threatens children's health, and leukemia cell proliferation and apoptosis participate in the regulation of leukemia. The current study aims to probe into the miR-125b-5p biological function in regulating leukemia cell proliferation and apoptosis by myeloid cell leukemia 1 (MCL1). Quantitative real-time polymerase chain reaction was conducted to quantify miR-125b-5p expression in leukemia cells. Cell transfection, cell-counting assay 8, Western blot, and flow cytometry assays were applied to assess the miR-125b-5p function in leukemia. A dual-luciferase reporter gene assay was applied to investigate the mechanism. miR-125b-5p was lessened in leukemia cells, and the increased miR-125b-5p repressed leukemia cell proliferation and boosted apoptosis. Further, miR-125b-5p could bound with the MCL1 3'-untranslated region and regulated its expression. Furthermore, the elevated expression of miR-125b-5p repressed leukemia cell proliferation and boosted apoptosis through downregulating MCL1. miR-125b-5p inhibited leukemia cell proliferation and boosted apoptosis through decreasing MCL1.
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Affiliation(s)
- Yan Zhou
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China
| | - Huan Zhu
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China
| | - Jinan Han
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China
| | - Ying Xu
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China
| | - Dan Wang
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China
| | - Wen Jin
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China
| | - Ruyuan Zhu
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China
| | - Lixing Qiao
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China
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13
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Poor Prognostic Biomarker KIAA1522 Is Associated with Immune Infiltrates in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2023; 2023:3538928. [PMID: 36761433 PMCID: PMC9904920 DOI: 10.1155/2023/3538928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/24/2022] [Accepted: 08/30/2022] [Indexed: 02/04/2023]
Abstract
Background The prognosis is poor for hepatocellular carcinoma (HCC), a tumor and cancer associated with inflammation that is common. New data showed that significant levels of KIAA1522 were expressed in HCC tissues and cell lines, suggesting that KIAA1522 may be a highly useful prognostic marker for HCC. However, its biochemical processes and impacts on the immune system go deeper. Objective To verify the significance of KIAA1522 in HCC and investigate its related carcinogenic mechanisms. Methods Studies examining the relationship between KIAA1522 expression and clinical-pathologic characteristics in HCC have been checked in the Cancer Genome Atlas (TCGA) database. A receiver operating characteristic (ROC) curve was used to assess the diagnostic efficacy of KIAA1522 in HCC. Western blot analysis was used to find the presence of the KIAA1522 protein in the tumor and paraneoplastic tissues of eight randomly chosen HCC patients. The GSVA program in R language was used to evaluate the relationship between KIAA1522 and immune cell infiltration in HCC. We searched the Search Tool for the Retrieval of Interacting Genes (STRING) database for interacting proteins connected to the expression of KIAA1522. Pathways were involved in the enrichment analysis of KIAA1522 to anticipate potential mechanisms through which KIAA1522 may affect immunological infiltration. Results Our study found that KIAA1522 was commonly elevated in HCC tumor tissues and that it also signaled a bad outcome. We found an inverse link between KIAA1522 and cytotoxic cells and an inverse relationship between KIAA1522 and Th2 cell infiltration. In STRING analysis, the top 5 coexpressed proteins of KIAA1522 were BAIAP2, NCK2, TSNAXIP1, POGK, and KLHL31. The effect of KIAA1522 on HCC may entail cell cycle alteration, an immunological response, and suppression of the PPAR signaling pathway. Conclusion High expression of KIAA1522 was linked to HCC immune cell infiltration, disease progression, and a poor prognosis.
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14
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Integrated Microarray-Based Data Analysis of miRNA Expression Profiles: Identification of Novel Biomarkers of Cisplatin-Resistance in Testicular Germ Cell Tumours. Int J Mol Sci 2023; 24:ijms24032495. [PMID: 36768818 PMCID: PMC9916636 DOI: 10.3390/ijms24032495] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/13/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Testicular germ cell tumours (TGCTs) are the most common solid malignancy among young men, and their incidence is still increasing. Despite good curability with cisplatin (CDDP)-based chemotherapy, about 10% of TGCTs are non-responsive and show a chemoresistant phenotype. To further increase TGCT curability, better prediction of risk of relapse and early detection of refractory cases is needed. Therefore, to diagnose this malignancy more precisely, stratify patients more accurately and improve decision-making on treatment modality, new biomarkers are still required. Numerous studies showed association of differential expressions of microRNAs (miRNAs) with cancer. Using microarray analysis followed by RT-qPCR validation, we identified specific miRNA expression patterns that discriminate chemoresistant phenotypes in TGCTs. Comparing CDDP-resistant vs. -sensitive TGCT cell lines, we identified miR-218-5p, miR-31-5p, miR-125b-5p, miR-27b-3p, miR-199a-5p, miR-214-3p, let-7a and miR-517a-3p as significantly up-regulated and miR-374b-5p, miR-378a-3p, miR-20b-5p and miR-30e-3p as significantly down-regulated. In patient tumour samples, we observed the highest median values of relative expression of miR-218-5p, miR-31-5p, miR-375-5p and miR-517a-3p, but also miR-20b-5p and miR-378a-3p, in metastatic tumour samples when compared with primary tumour or control samples. In TGCT patient plasma samples, we detected increased expression of miR-218-5p, miR-31-5p, miR-517a-3p and miR-375-5p when compared to healthy individuals. We propose that miR-218-5p, miR-31-5p, miR-375-5p, miR-517-3p, miR-20b-5p and miR-378a-3p represent a new panel of biomarkers for better prediction of chemoresistance and more aggressive phenotypes potentially underlying metastatic spread in non-seminomatous TGCTs. In addition, we provide predictions of the targets and functional and regulatory networks of selected miRNAs.
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15
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Tan Q, Ma J, Zhang H, Wu X, Li Q, Zuo X, Jiang Y, Liu H, Yan L. miR-125b-5p upregulation by TRIM28 induces cisplatin resistance in non-small cell lung cancer through CREB1 inhibition. BMC Pulm Med 2022; 22:469. [PMID: 36476351 PMCID: PMC9730690 DOI: 10.1186/s12890-022-02272-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE miR-125b-5p plays an important role in the development of cancer and drug resistance. However, in cisplatin resistance of non-small cell lung cancer (NSCLC), the function and potential mechanism of miR-125b-5p is still unclear. The aim of this study was to investigate the role and molecular mechanism of miR-125b-5p in cisplatin resistance of NSCLC. METHODS A GEO dataset (GSE168707) was analyzed to find high miR-125b-5p levels were associated with DDP resistance. miR-125b-5p expression levels were detected in A549 and A549/DDP cells via real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays, western blots and mouse model xenografted were performed to identify CREB1 as a direct target gene of miR-125b-5p. Cell proliferation and apoptosis were also performed to identify whether miR-125b-5p upregulation by TRIM28 induces DDP resistance in NSCLC through CREB1 inhibition. RESULTS In A549/DDP cells, miR-125b-5p expression was upregulated compared to A549 cells. Then miR-125b-5p was found to increase DDP resistance in NSCLC in vivo and in vitro by increasing cell proliferation and suppressing cell apoptosis. Bioinformatic analyses were used to search for gene which miR-125b-5p can target. We identified miR-125b-5p can regulate CREB1 via luciferase reporter assays, qRT-PCR and western blots. Cell proliferation and apoptosis were also performed to confirm miR-125b-5p could impact on CREB1 and induce the DDP resistance in NSCLC. Additionally, we used bioinformatic analyses to find tripartite motif-containing 28 (TRIM28) as a transcriptional enhance factor of miR-125b-5p. The expression of TRIM28 was upregulated in A549/DDP cells compared with that in A549 cells by qRT-PCR. Finally, we found TRIM28 could mediate DDP resistance through miR-125b-5p/CREB1 axis via cell proliferation, western blot and apoptosis assay. CONCLUSIONS Overall, our findings demonstrated novel functions and mechanisms underlying DDP resistance in NSCLC through the TRIM28/miR-125b-5p/CREB1 axis. These may serve as novel therapeutic targets to improve the treatment efficacy using DDP for NSCLC in the future.
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Affiliation(s)
- Qiuyu Tan
- grid.452929.10000 0004 8513 0241The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241002 Anhui China ,grid.443626.10000 0004 1798 4069Provincial Key Laboratory of Biological Macro-Molecules Research, Wannan Medical College, Wuhu, 241002 Anhui China
| | - Jinzhu Ma
- grid.443626.10000 0004 1798 4069Provincial Key Laboratory of Biological Macro-Molecules Research, Wannan Medical College, Wuhu, 241002 Anhui China
| | - Hao Zhang
- grid.411525.60000 0004 0369 1599Department of Orthopedics, Changhai Hospital, Navy Medical University, Shanghai, 200433 China
| | - Xu Wu
- grid.443626.10000 0004 1798 4069Provincial Key Laboratory of Biological Macro-Molecules Research, Wannan Medical College, Wuhu, 241002 Anhui China
| | - Qiang Li
- grid.443626.10000 0004 1798 4069Provincial Key Laboratory of Biological Macro-Molecules Research, Wannan Medical College, Wuhu, 241002 Anhui China
| | - Xiaoxuan Zuo
- grid.443626.10000 0004 1798 4069Provincial Key Laboratory of Biological Macro-Molecules Research, Wannan Medical College, Wuhu, 241002 Anhui China
| | - Yuxin Jiang
- grid.411870.b0000 0001 0063 8301Department of Pathogen Biology and Immunology, Jiaxing University College of Medicine, Jiaxing, 314000 Zhejiang China
| | - Haijun Liu
- grid.452929.10000 0004 8513 0241The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241002 Anhui China
| | - Liang Yan
- grid.443626.10000 0004 1798 4069Provincial Key Laboratory of Biological Macro-Molecules Research, Wannan Medical College, Wuhu, 241002 Anhui China
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16
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Ma C, Tang X, Tang Q, Wang S, Zhang J, Lu Y, Wu J, Han L. Curcumol repressed cell proliferation and angiogenesis via SP1/mir-125b-5p/VEGFA axis in non-small cell lung cancer. Front Pharmacol 2022; 13:1044115. [PMID: 36467048 PMCID: PMC9716069 DOI: 10.3389/fphar.2022.1044115] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/07/2022] [Indexed: 12/02/2023] Open
Abstract
NSCLC (non-small cell lung cancer) is one of the most common and lethal malignant tumors, with low 5-year overall survival rate. Curcumol showed antitumor activity in several cancers, but evidence about its effect on NSCLC remains unclear. In the present study, we found that Curcumol markedly inhibited NSCLC cells proliferation, migration and invasion. Endothelial cells are an important part of tumor microenvironment. Tube formation assay and wound healing assay indicated that A549 derived conditioned medium affected HUVECs (human umbilical vein endothelial cells). Mechanistically, Curcumol downregulated the expression of SP1 (specificity protein 1) while upregulated miR-125b-5p, followed by decreasing VEGFA expression in NSCLC cells. Furthermore, overexpression of SP1 partially reversed the inhibitory effect of Curcumol on A549 and H1975 cell viability and VEGFA expression. Inhibition of miR-125b-5p presented similar effect. Interestingly, there was mutual modulation between SP1 and miR-125b-5p. Collectively, our study revealed that Curcumol inhibited cell growth and angiogenesis of NSCLC in vitro and in vivo, possibly through SP1/miR-125b-5p/VEGFA regulatory mechanism. These findings may provide effective therapy strategies for NSCLC treatment.
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Affiliation(s)
- Changju Ma
- The Postdoctoral Research Station, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- GuangDong Academy of Traditional Chinese Medicine, Research Team of Bio-molecular and System Biology of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Xiaojuan Tang
- GuangDong Academy of Traditional Chinese Medicine, Research Team of Bio-molecular and System Biology of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Central Laboratory, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, China
| | - Qing Tang
- GuangDong Academy of Traditional Chinese Medicine, Research Team of Bio-molecular and System Biology of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shiyan Wang
- Department of Emergency, The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, China
| | - Junhong Zhang
- GuangDong Academy of Traditional Chinese Medicine, Research Team of Bio-molecular and System Biology of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Yue Lu
- GuangDong Academy of Traditional Chinese Medicine, Research Team of Bio-molecular and System Biology of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingjing Wu
- The Postdoctoral Research Station, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- GuangDong Academy of Traditional Chinese Medicine, Research Team of Bio-molecular and System Biology of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
| | - Ling Han
- The Postdoctoral Research Station, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- GuangDong Academy of Traditional Chinese Medicine, Research Team of Bio-molecular and System Biology of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
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17
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MiR-125b-5p Targets MTFP1 to Inhibit Cell Proliferation, Migration, and Invasion and Facilitate Cell Apoptosis in Endometrial Carcinoma. Mol Biotechnol 2022; 65:961-969. [DOI: 10.1007/s12033-022-00601-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 10/29/2022] [Indexed: 11/16/2022]
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18
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Hu W, Wu Y, Shi Q, Wu J, Kong D, Wu X, He X, Liu T, Li S. Systematic characterization of cancer transcriptome at transcript resolution. Nat Commun 2022; 13:6803. [PMID: 36357395 PMCID: PMC9649690 DOI: 10.1038/s41467-022-34568-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 10/31/2022] [Indexed: 11/11/2022] Open
Abstract
Transcribed RNAs undergo various regulation and modification to become functional transcripts. Notably, cancer transcriptome has not been fully characterized at transcript resolution. Herein, we carry out a reference-based transcript assembly across >1000 cancer cell lines. We identify 498,255 transcripts, approximately half of which are unannotated. Unannotated transcripts are closely associated with cancer-related hallmarks and show clinical significance. We build a high-confidence RNA binding protein (RBP)-transcript regulatory network, wherein most RBPs tend to regulate transcripts involved in cell proliferation. We identify numerous transcripts that are highly associated with anti-cancer drug sensitivity. Furthermore, we establish RBP-transcript-drug axes, wherein PTBP1 is experimentally validated to affect the sensitivity to decitabine by regulating KIAA1522-a6 transcript. Finally, we establish a user-friendly data portal to serve as a valuable resource for understanding cancer transcriptome diversity and its potential clinical utility at transcript level. Our study substantially extends cancer RNA repository and will facilitate anti-cancer drug discovery.
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Affiliation(s)
- Wei Hu
- grid.16821.3c0000 0004 0368 8293Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620 China
| | - Yangjun Wu
- grid.452404.30000 0004 1808 0942Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
| | - Qili Shi
- grid.11841.3d0000 0004 0619 8943Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Jingni Wu
- grid.16821.3c0000 0004 0368 8293Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620 China
| | - Deping Kong
- grid.16821.3c0000 0004 0368 8293Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620 China
| | - Xiaohua Wu
- grid.452404.30000 0004 1808 0942Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
| | - Xianghuo He
- grid.11841.3d0000 0004 0619 8943Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Teng Liu
- grid.16821.3c0000 0004 0368 8293Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620 China ,grid.440657.40000 0004 1762 5832Institute of Big Data and Artificial Intelligence in Medicine, School of Electronics and Information Engineering, Taizhou University, Taizhou, 318000 China
| | - Shengli Li
- grid.16821.3c0000 0004 0368 8293Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620 China
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Jiang M, Yang Y, Niu L, Li P, Chen Y, Liao P, Wang Y, Zheng J, Chen F, He H, Li H, Chen X. MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2. J Immunother Cancer 2022; 10:jitc-2022-005241. [PMID: 36319063 PMCID: PMC9628696 DOI: 10.1136/jitc-2022-005241] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Tumor necrosis factor receptor type 2 (TNFR2) is primarily expressed by CD4+FoxP3+ regulatory T cells (Tregs), especially those present in tumor microenvironment. There is compelling evidence that TNFR2 plays a crucial role in the activation, expansion, and phenotypic stability of Tregs and promotes tumor immune evasion. Understanding of epigenetic regulation of TNFR2 expression in Tregs may help device a novel strategy in cancer immunotherapy. METHODS MiR-125b-5p-overexpressing or knockdown murine CD4 T cells and Tregs were constructed, and the effect of miR-125b-5p on Tregs proliferation, suppressive function and TNFR2 expression were examined. In vivo antitumor efficacy of Ago-125b-5p (miR-125b-5p agomir) was evaluated in MC38 tumor bearing mice, and tumor-infiltrating Tregs and CD8+ cytotoxic T lymphocytes (CTLs) were analyzed. RNA-seq analysis was applied to reveal the genes and signaling pathways regulated by miR-125b-5p in Tregs. RESULTS In this study, we found that TNFR2 was a direct target of miR-125b-5p. Overexpression of miR-125b-5p decreased the proportion of Tregs and their expression of TNFR2 and consequently inhibited its proliferation and suppressive function by regulating the metabolism-related signaling pathways. Moreover, in colon cancer bearing mice, the administration of Ago-125b-5p markedly inhibited the tumor growth, which was associated with reduction of Tregs and increase of IFNγ+CD8+ T cells in tumor environment. Furthermore, in human colon adenocarcinoma patients, we verified that miR-125b-5p expression was downregulated, and low levels of miR-125b-5p were associated with poor prognosis. Interestingly, the expression of miR-125b-5p and TNFR2 were negatively correlated. CONCLUSIONS Our study for the first time found that the expression of TNFR2 by Tregs was regulated by miR-125b-5p. Our results showed that miR-125b-5p had the capacity to inhibit the expression of TNFR2 and immunosuppressive activity of Tregs and consequently enhanced the antitumor efficacy. This property of miR-125b-5p may be therapeutically harnessed in the treatment of human cancers.
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Affiliation(s)
- Mengmeng Jiang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
| | - Yang Yang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
| | - Liling Niu
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China,National Clinical Research Center for Cancer, Tianjin, China
| | - Ping Li
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
| | - Yibo Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
| | - Ping Liao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
| | - Yifei Wang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
| | - Jingbin Zheng
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
| | - Fengyang Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
| | - Huanhuan He
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Hui Li
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China,National Clinical Research Center for Cancer, Tianjin, China
| | - Xin Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China,Department of Pharmaceutical Science, Faculty of Health Sciences, University of Macau, Macau, China,MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau, China,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Macau, China
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20
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Ou M, Chu Y, Zhang Q, Zhao H, Song Q. HOXA cluster antisense RNA 2 elevates KIAA1522 expression through microRNA-520d-3p and insulin like growth factor 2 mRNA binding protein 3 to promote the growth of vascular smooth muscle cells in thoracic aortic aneurysm. ESC Heart Fail 2022; 9:2955-2966. [PMID: 35730141 PMCID: PMC9715842 DOI: 10.1002/ehf2.13968] [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: 04/26/2021] [Revised: 03/15/2022] [Accepted: 04/27/2022] [Indexed: 11/12/2022] Open
Abstract
AIMS Recently, long non-coding RNAs (lncRNAs) have been revealed to mediate smooth muscle dysfunction in thoracic aortic aneurysm (TAA). LncRNA HOXA-AS2 has been proposed to engage in the regulation of diverse diseases. However, its function in TAA remains unknown. This study aimed to reveal the role and mechanism of HOXA-AS2 in VSMCs which were implicated in TAA formation. METHODS AND RESULTS RT-qPCR or western blot was performed to detect RNA or protein expression levels. The role of HOXA-AS2 in VSMCs was explored by functional assays. The relationship among HOXA-AS2/miR-520d-3p/KIAA1522/IGF2BP3 was analysed via mechanism assays. HOXA-AS2 was detected to have significantly high expression in TAA tissues and function as an oncogene to promote proliferation of VSMCs, while inhibiting cell apoptosis (Figure 1, **P < 0.01). HOXA-AS2 was unveiled to bind with miR-520d-3p (Figure 2, *P < 0.05, **P < 0.01) and further up-regulate KIAA1522 to facilitate the growth of VSMCs (Figure 3-4, *P < 0.05, **P < 0.01). HOXA-AS2 was also found to recruit IGF2BP3 to stabilize KIAA1522 mRNA (Figure 5, **P < 0.01). All data were displayed as mean ± standard deviation. CONCLUSIONS HOXA-AS2 up-regulates KIAA1522 through targeting miR-520d-3p/IGF2BP3 to drive VSMC growth in TAA.
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Affiliation(s)
- Minghui Ou
- Department of Vascular SurgeryQingdao Municipal HospitalQingdaoChina
| | - Yaonan Chu
- Department of Cardiovascular SurgeryShengli Oilfield Central HospitalDongyingChina
| | - Qian Zhang
- Department of ObstetricsQingdao Municipal HospitalQingdaoChina
| | - Huidong Zhao
- Department of ObstetricsQingdao Municipal HospitalQingdaoChina
| | - Qiang Song
- Department of Cardiovascular SurgeryShengli Oilfield Central HospitalDongyingChina
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21
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LncRNA KCNQ1OT1 accelerates ovarian cancer progression via miR-125b-5p/CD147 axis. Pathol Res Pract 2022; 239:154135. [PMID: 36191448 DOI: 10.1016/j.prp.2022.154135] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 09/02/2022] [Accepted: 09/16/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Ovarian cancer (OC) is one of the most common gynecological malignancies with a high incidence. Researches showed that lncRNA KCNQ1OT1 (KCNQ1OT1) was involved various tumors progression, including OC. However, the precise mechanism of KCNQ1OT1 in OC needs to be further clarified. OBJECTIVE For investigate the underlying mechanism of KCNQ1OT1 regulating OC progression. METHODS CCK-8 assay, colony formation assay, Transwell assay, Western blot and quantitative real-time PCR (qRT-PCR) were performed to examine viability, proliferation, migration and invasion, genes and proteins' level. To identify KCNQ1OT1 as a regulator of miR-125b-5p and miR-125b-5p as a regulator of CD147, we used miRNA target prediction algorithms, Pearson's correlation analysis and dual-luciferase reporter gene assay. RESULTS KCNQ1OT1 was high expression and miR-125b-5p was low expression in OC, and KCNQ1OT1 was negatively correlated with that of miR-125b-5p in OC specimens. KCNQ1OT1 promoted OC cell proliferation and metastasis by binding to miR-125b-5p. miR-125b-5p targeted CD147, and which was negatively correlated with that of miR-125b-5p in OC specimens. KCNQ1OT1 was positively correlated with that of CD147 in OC specimens, and KCNQ1OT1 accelerated OC progression via miR-125b-5p/CD147 axis. CONCLUSION KCNQ1OT1 accelerated OC progression via miR-125b-5p/CD147 axis indicating KCNQ1OT1 serve as a novel biomarker for OC treatment. Our research provides a new direction for OC treatment.
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22
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Ding Q, Hou Z, Zhao Z, Chen Y, Zhao L, Xiang Y. Identification of the prognostic signature based on genomic instability-related alternative splicing in colorectal cancer and its regulatory network. Front Bioeng Biotechnol 2022; 10:841034. [PMID: 35923577 PMCID: PMC9340224 DOI: 10.3389/fbioe.2022.841034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 06/27/2022] [Indexed: 11/15/2022] Open
Abstract
Background: Colorectal cancer (CRC) is a heterogeneous disease with many somatic mutations defining its genomic instability. Alternative Splicing (AS) events, are essential for maintaining genomic instability. However, the role of genomic instability-related AS events in CRC has not been investigated. Methods: From The Cancer Genome Atlas (TCGA) program, we obtained the splicing profiles, the single nucleotide polymorphism, transcriptomics, and clinical information of CRC. Combining somatic mutation and AS events data, a genomic instability-related AS signature was constructed for CRC. Mutations analyses, clinical stratification analyses, and multivariate Cox regression analyses evaluated this signature in training set. Subsequently, we validated the sensitivity and specificity of this prognostic signature using a test set and the entire TCGA dataset. We constructed a nomogram for the prognosis prediction of CRC patients. Differentially infiltrating immune cells were screened by using CIBERSORT. Inmmunophenoscore (IPS) analysis was used to evaluate the response of immunotherapy. The AS events-related splicing factors (SF) were analyzed by Pearson’s correlation. The effects of SF regulating the prognostic AS events in proliferation and migration were validated in Caco2 cells. Results: A prognostic signature consisting of seven AS events (PDHA1-88633-ES, KIAA1522-1632-AP, TATDN1-85088-ES, PRMT1-51042-ES, VEZT-23786-ES, AIG1-77972-AT, and PHF11-25891-AP) was constructed. Patients in the high-risk score group showed a higher somatic mutation. The genomic instability risk score was an independent variable associated with overall survival (OS), with a hazard ratio of a risk score of 1.537. The area under the curve of receiver operator characteristic curve of the genomic instability risk score in predicting the OS of CRC patients was 0.733. Furthermore, a nomogram was established and could be used clinically to stratify patients to predict prognosis. Patients defined as high-risk by this signature showed a lower proportion of eosinophils than the low-risk group. Patients with low risk were more sensitive to anti-CTLA4 immunotherapy. Additionally, HSPA1A and FAM50B were two SF regulating the OS-related AS. Downregulation of HSPA1A and FAM50B inhibited the proliferation and migration of Caco2 cells. Conclusion: We constructed an ideal prognostic signature reflecting the genomic instability and OS of CRC patients. HSPA1A and FAM50B were verified as two important SF regulating the OS-related AS.
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Affiliation(s)
- Qiuying Ding
- Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zhengping Hou
- Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zhibo Zhao
- The Department of Hepatobiliary Surgery of the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yao Chen
- Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- *Correspondence: Yao Chen, ; Lei Zhao, ; Yue Xiang,
| | - Lei Zhao
- Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- *Correspondence: Yao Chen, ; Lei Zhao, ; Yue Xiang,
| | - Yue Xiang
- Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- *Correspondence: Yao Chen, ; Lei Zhao, ; Yue Xiang,
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23
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Fan Y, Wang Q, Shi M, Ju G, Lu H, Zheng L, Chen J, Zhou X, Xiao T, Chen S. Circ_0020123 promotes NSCLC tumorigenesis via up-regulating KIAA1522 expression through miR-940. Cell Cycle 2022; 21:894-907. [PMID: 35196193 PMCID: PMC9037485 DOI: 10.1080/15384101.2022.2034093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Circ_0020123 was highly expressed in NSCLC tissues and cell lines, and knockdown of circ_0020123 abolished cell growth, migration and invasion in vitro and hindered tumor growth in nude mice. Mechanically, circ_0020123 directly targeted miR-940, and KIAA1522 was a target of miR-940. Thereafter, a series of rescue experiments showed that circ_0020123 served its biological functions by miR-940/KIAA1522 axis. In all, circ_0020123 acted as an oncogene to promote the tumorigenesis of NSCLC via miR-940/KIAA1522 axis, suggesting a potential therapeutic target for NSCLC treatment.
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Affiliation(s)
- Yihui Fan
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Qing Wang
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Minxin Shi
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Guanjun Ju
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Haimin Lu
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Liyun Zheng
- Department of Scientific, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Jian Chen
- Department of Clinical Laboratory, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Xiaomei Zhou
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Ting Xiao
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Saihua Chen
- Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China,CONTACT Saihua Chen Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, No. 30, Tongyang North Road, Pingchao Town, Tongzhou District, Nantong City, Jiangsu Province, China
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24
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Azari ZD, Aljubran F, Nothnick WB. Inflammatory MicroRNAs and the Pathophysiology of Endometriosis and Atherosclerosis: Common Pathways and Future Directions Towards Elucidating the Relationship. Reprod Sci 2022; 29:2089-2104. [PMID: 35476352 DOI: 10.1007/s43032-022-00955-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 04/19/2022] [Indexed: 11/25/2022]
Abstract
Emerging data indicates an association between endometriosis and subclinical atherosclerosis, with women with endometriosis at a higher risk for cardiovascular disease later in life. Inflammation is proposed to play a central role in the pathophysiology of both diseases and elevated levels of systemic pro-inflammatory cytokines including macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) are well documented. However, a thorough understanding on the mediators and mechanisms which contribute to altered cytokine expression in both diseases remain poorly understood. MicroRNAs (miRNAs) are important post-transcriptional regulators of inflammatory pathways and numerous studies have reported altered circulating levels of miRNAs in both endometriosis and atherosclerosis. Potential contribution of miRNA-mediated inflammatory cascades common to the pathophysiology of both diseases has not been evaluated but could offer insight into common pathways and early manifestation relevant to both diseases which may help understand cause and effect. In this review, we discuss and summarize differentially expressed inflammatory circulating miRNAs in endometriosis subjects, compare this profile to that of circulating levels associated with atherosclerosis when possible, and then discuss mechanistic studies focusing on these miRNAs in relevant cell, tissue, and animal models. We conclude by discussing the potential utility of targeting the relevant miRNAs in the MIF-IL-6-TNF-α pathway as therapeutic options and offer insight into future studies which will help us better understand not only the role of these miRNAs in the pathophysiology of both endometriosis and atherosclerosis but also commonality between both diseases.
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Affiliation(s)
- Zubeen D Azari
- Kansas City University of Medicine and Biosciences, Kansas City, MO, 64106, USA
| | - Fatimah Aljubran
- Department of Molecular and Integrative Physiology, Institute for Reproductive and Perinatal Sciences, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Warren B Nothnick
- Department of Molecular and Integrative Physiology, Institute for Reproductive and Perinatal Sciences, University of Kansas Medical Center, Kansas City, KS, 66160, USA. .,Department of Obstetrics and Gynecology, Institute for Reproductive and Perinatal Sciences, University of Kansas Medical Center, Kansas City, KS, 66160, USA. .,Center for Reproductive Sciences, Institute for Reproductive and Perinatal Sciences, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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25
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MicroRNAs and Progesterone Receptor Signaling in Endometriosis Pathophysiology. Cells 2022; 11:cells11071096. [PMID: 35406659 PMCID: PMC8997421 DOI: 10.3390/cells11071096] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/13/2022] [Accepted: 03/23/2022] [Indexed: 12/21/2022] Open
Abstract
Endometriosis is a significant disease characterized by infertility and pelvic pain in which endometrial stromal and glandular tissue grow in ectopic locations. Altered responsiveness to progesterone is a contributing factor to endometriosis pathophysiology, but the precise mechanisms are poorly understood. Progesterone resistance influences both the eutopic and ectopic (endometriotic lesion) endometrium. An inability of the eutopic endometrium to properly respond to progesterone is believed to contribute to the infertility associated with the disease, while an altered responsiveness of endometriotic lesion tissue may contribute to the survival of the ectopic tissue and associated symptoms. Women with endometriosis express altered levels of several endometrial progesterone target genes which may be due to the abnormal expression and/or function of progesterone receptors and/or chaperone proteins, as well as inflammation, genetics, and epigenetics. MiRNAs are a class of epigenetic modulators proposed to play a role in endometriosis pathophysiology, including the modulation of progesterone signaling. In this paper, we summarize the role of progesterone receptors and progesterone signaling in endometriosis pathophysiology, review miRNAs, which are over-expressed in endometriosis tissues and fluids, and follow this with a discussion on the potential regulation of key progesterone signaling components by these miRNAs, concluding with suggestions for future research endeavors in this area.
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26
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MiR-125b-5p/TPD52 Axis Affects Proliferation, Migration and Invasion of Breast Cancer Cells. Mol Biotechnol 2022; 64:1003-1012. [PMID: 35320453 DOI: 10.1007/s12033-022-00475-3] [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: 12/31/2021] [Accepted: 03/02/2022] [Indexed: 10/18/2022]
Abstract
Aberrant gene expression caused by miRNAs disorders plays a relevant role in multiple steps of tumorigenesis. In this attempt, we studied the functional role of miR-125b-5p and TPD52 in breast cancer. TPD52 mRNA and miR-125b-5p levels were assessed via qRT-PCR, and TPD52 protein level was analyzed via western blot. By performing CCK-8, transwell invasion and wound healing assays, the phenotype changes in breast cancer cells were assessed. miR-125b-5p was proven as an upstream miRNA of TPD52 in breast cancer via TargetScan database, luciferase activity, and western blot. MiR-125b-5p was prominently decreased while TPD52 was dramatically increased in breast cancer cells. Functional assays exhibited that forced level of TPD52 facilitated cell proliferation, invasion and migration in breast cancer. In the end, the rescue assay proved that miR-125b-5p was a cancer repressor and modulated breast cancer progression by targeting TPD52. All above offer potential biomarkers for breast cancer treatment.
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27
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Hwang T, Parker SS, Hill SM, Grant RA, Ilunga MW, Sivaraman V, Mouneimne G, Keating AE. Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH. eLife 2022; 11:70680. [PMID: 35076015 PMCID: PMC8789275 DOI: 10.7554/elife.70680] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 01/06/2022] [Indexed: 12/13/2022] Open
Abstract
The human proteome is replete with short linear motifs (SLiMs) of four to six residues that are critical for protein-protein interactions, yet the importance of the sequence surrounding such motifs is underexplored. We devised a proteomic screen to examine the influence of SLiM sequence context on protein-protein interactions. Focusing on the EVH1 domain of human ENAH, an actin regulator that is highly expressed in invasive cancers, we screened 36-residue proteome-derived peptides and discovered new interaction partners of ENAH and diverse mechanisms by which context influences binding. A pocket on the ENAH EVH1 domain that has diverged from other Ena/VASP paralogs recognizes extended SLiMs and favors motif-flanking proline residues. Many high-affinity ENAH binders that contain two proline-rich SLiMs use a noncanonical site on the EVH1 domain for binding and display a thermodynamic signature consistent with the two-motif chain engaging a single domain. We also found that photoreceptor cilium actin regulator (PCARE) uses an extended 23-residue region to obtain a higher affinity than any known ENAH EVH1-binding motif. Our screen provides a way to uncover the effects of proteomic context on motif-mediated binding, revealing diverse mechanisms of control over EVH1 interactions and establishing that SLiMs can’t be fully understood outside of their native context.
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Affiliation(s)
- Theresa Hwang
- Department of Biology, Massachusetts Institute of Technology
| | - Sara S Parker
- Department of Cellular & Molecular Medicine, University of Arizona
| | - Samantha M Hill
- Department of Cellular & Molecular Medicine, University of Arizona
| | - Robert A Grant
- Department of Biology, Massachusetts Institute of Technology
| | - Meucci W Ilunga
- Department of Biology, Massachusetts Institute of Technology
| | | | | | - Amy E Keating
- Department of Biology, Massachusetts Institute of Technology
- Department of Biological Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
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28
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Qu C, Ma T, Yan X, Li X, Li Y. Overexpressed PAQR4 predicts poor overall survival and construction of a prognostic nomogram based on PAQR family for hepatocellular carcinoma. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2022; 19:3069-3090. [PMID: 35240821 DOI: 10.3934/mbe.2022142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
OBJECTIVE We aimed to explore the expression and clinical prognostic significance of PAQR4 in hepatocellular carcinoma (HCC). METHODS We obtained the gene expression matrix and clinical data of HCC from the cancer genome atlas (TCGA) and international cancer genome consortium (ICGC) databases. The prognostic value of PAQR4 in HCC was evaluated using the Kaplan-Meier and Cox regression analyses. PAQR4-related pathways were explored by gene set enrichment analysis (GSEA). A clinical nomogram prognostic model based on the PAQR family was constructed using Cox proportional hazards models. RESULTS We found that PAQR4 is overexpressed in HCC from multiple databases; additionally, quantitative real-time polymerase chain reaction (qRT-PCR) validated the upregulation of PAQR4 in HCC. PAQR4 expression was related to age, grade, alpha fetoprotein (AFP), T classification and clinical stage of HCC patients. High PAQR4 expression was associated with poor overall survival and was an independent prognostic factor for HCC patients through Kaplan-Meier analysis and Cox regression analysis, respectively. In addition, GSEA identified that the high PAQR4 expression phenotype was involved in the cell cycle, Notch signaling pathway, mTOR signaling pathway, etc. Finally, three PAQR family genes (PAQR4, PAQR8 and PAQR9) were associated with the prognosis of patients with HCC. A clinical nomogram prediction model was verified in TCGA training and ICGC validation sets, and it exerted dramatic predictive efficiency in this study. CONCLUSIONS PAQR4 may be regarded as a promising prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Caihao Qu
- Lanzhou University Second Hospital, Lanzhou 730030, China
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, China
| | - Tengda Ma
- Lanzhou University Second Hospital, Lanzhou 730030, China
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, China
| | - Xin Yan
- Lanzhou University Second Hospital, Lanzhou 730030, China
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, China
| | - Xiaomei Li
- Lanzhou University Second Hospital, Lanzhou 730030, China
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, China
| | - Yumin Li
- Lanzhou University Second Hospital, Lanzhou 730030, China
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou 730030, China
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29
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Liu X, Shen X, Zhang J. Long non-coding RNA LINC00514 promotes the proliferation and invasion through the miR-708-5p/HOXB3 axis in cervical squamous cell carcinoma. ENVIRONMENTAL TOXICOLOGY 2022; 37:161-170. [PMID: 34652879 DOI: 10.1002/tox.23387] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/20/2021] [Accepted: 10/03/2021] [Indexed: 06/13/2023]
Abstract
Long non-coding RNA (lncRNA) LINC00514 is a cancer-related lncRNA that has been proven to be implicated in the progression of several cancers. However, the biological function of LINC00514 in cervical squamous cell carcinoma (CSCC) remains unclear. Thus, we aimed to identify the LINC00514 expression profile in CSCC and determine its exact mechanism. Our results showed that the expression of LINC00514 was up-regulated in human CSCC tissues and cell lines. Knockdown of LINC00514 significantly inhibited the proliferation and invasion of CSCC cells, as well as suppressed tumorigenesis of CSCC in vivo. In addition, LINC00514 was found to work as a miRNA sponge for miR-708-5p and suppressed the expression of miR-708-5p in CSCC cells. Homeobox B3 (HOXB3) was found to be a target gene of miR-708-5p. Rescue assays demonstrated that miR-708-5p inhibitor attenuated the effects of LINC00514 knockdown on cell proliferation and invasion in CSCC cells. In addition, overexpression of HOXB3 reversed the inhibitory effects of miR-708-5p mimics on cell proliferation and invasion. Taken together, our findings for the first time elucidated that lncRNA LINC00514 promotes the proliferation and invasion through the miR-708-5p/HOXB3 axis in CSCC. Thus, LINC00514/miR-708-5p/HOXB3 axis might be a promising therapeutic target for the treatment of CSCC.
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Affiliation(s)
- Xiaoying Liu
- Department of Gynaecology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Xin Shen
- Department of Gynaecology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Jing Zhang
- Department of Gynaecology, Shaanxi Provincial People's Hospital, Xi'an, China
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30
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Liu YP, Qiu ZZ, Li XH, Li EY. Propofol induces ferroptosis and inhibits malignant phenotypes of gastric cancer cells by regulating miR-125b-5p/STAT3 axis. World J Gastrointest Oncol 2021; 13:2114-2128. [PMID: 35070046 PMCID: PMC8713308 DOI: 10.4251/wjgo.v13.i12.2114] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/10/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer is a common malignancy with poor prognosis, in which ferroptosis plays a crucial function in its development. Propofol is a widely used anesthetic and has antitumor potential in gastric cancer. However, the effect of propofol on ferroptosis during gastric cancer progression remains unreported.
AIM To explore the function of propofol in the regulation of ferroptosis and malignant phenotypes of gastric cancer cells.
METHODS MTT assays, colony formation assays, Transwell assays, wound healing assay, analysis of apoptosis, ferroptosis measurement, luciferase reporter gene assay, and quantitative reverse transcription polymerase chain reaction were used in this study.
RESULTS Our data showed that propofol was able to inhibit proliferation and induce apoptosis of gastric cancer cells. Meanwhile, propofol markedly repressed the invasion and migration of gastric cancer cells. Importantly, propofol enhanced the erastin-induced inhibition of growth of gastric cancer cells. Consistently, propofol increased the levels of reactive oxygen species, iron, and Fe2+ in gastric cancer cells. Moreover, propofol suppressed signal transducer and activator of transcription (STAT)3 expression by upregulating miR-125b-5p and propofol induced ferroptosis by targeting STAT3 in gastric cancer cells. The miR-125b-5p inhibitor or STAT3 overexpression reversed propofol-attenuated malignant phenotypes of gastric cancer cells.
CONCLUSION Propofol induced ferroptosis and inhibited malignant phenotypes of gastric cancer cells by regulating the miR-125b-5p/STAT3 axis. Propofol may serve as a potential therapeutic candidate for gastric cancer.
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Affiliation(s)
- Yi-Ping Liu
- Department ofAnesthesiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Zhong-Zhi Qiu
- Department ofAnesthesiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xu-Hui Li
- Department of Gastroenterology, Heilongjiang Forest Industry Federation (Red Cross) Hospital, Harbin 150008, Heilongjiang Province, China
| | - En-You Li
- Department ofAnesthesiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Wu H, Xu J, Gong G, Zhang Y, Wu S. CircARL8B Contributes to the Development of Breast Cancer Via Regulating miR-653-5p/HMGA2 Axis. Biochem Genet 2021; 59:1648-1665. [PMID: 34050452 DOI: 10.1007/s10528-021-10082-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 05/15/2021] [Indexed: 02/05/2023]
Abstract
Circular RNAs (circRNAs) act as essential regulators in breast cancer (BC) progression. In this paper, we aimed to investigate the functions of circARL8B in BC. The levels of circARL8B, ADP Ribosylation Factor Like GTPase 8B (ARL8B), miR-653-5p and high-mobility group AT-hook 2 (HMGA2) mRNA were examined by qRT-PCR. The stability of circARL8B was determined by RNase R assay and Actinomycin D assay. Cell viability and metastasis were evaluated by Cell Counting Kit-8 (CCK-8) assay and transwell assay, respectively. The levels of cellular phospholipids and triglycerides were measured using relevant kits. Protein levels were measured by western blot analysis. The association between miR-653-5p and circARL8B or HMGA2 was verified by dual-luciferase reporter assay. A murine xenograft model was established to explore the function of circARL8B in vivo. CircARL8B was increased in BC tissues and cells. CircARL8B silencing inhibited cell viability, migration, invasion and fatty acid metabolism in BC cells in vitro and blocked tumor growth in vivo. MiR-653-5p was identified as the target of circARL8B and miR-653-5p was negatively modulated by circARL8B. The suppressive role of circARL8B silencing in BC cell progression was abolished by miR-653-5p downregulation. Moreover, HMGA2 was the target gene of miR-653-5p. HMGA2 overexpression abrogated the effect of miR-653-5p on BC cell development. In addition, circARL8B knockdown might block PGE2/PI3K/AKT/GSK-3β/Wnt/β-catenin pathway. Silencing of circARL8B inhibited cell viability, migration, invasion and fatty acid metabolism via miR-653-5p/HMGA2 axis in BC.
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Affiliation(s)
- Hansheng Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jingyun Xu
- Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, No. 57, Changping Road, Shantou, 515041, Guangdong, China
| | - Guoliang Gong
- Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, No. 57, Changping Road, Shantou, 515041, Guangdong, China.
- Department of Pathology, Chaonan Minsheng Hospital of Shantou, Shantou, Guangdong, China.
| | - Yuanxin Zhang
- Department of Pathology, Chaonan Minsheng Hospital of Shantou, Shantou, Guangdong, China
| | - Shenggui Wu
- Department of Pathology, Chaonan Minsheng Hospital of Shantou, Shantou, Guangdong, China
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Yu T, Li G, Wang C, Gong G, Wang L, Li C, Chen Y, Wang X. MIR210HG regulates glycolysis, cell proliferation, and metastasis of pancreatic cancer cells through miR-125b-5p/HK2/PKM2 axis. RNA Biol 2021; 18:2513-2530. [PMID: 34110962 PMCID: PMC8632125 DOI: 10.1080/15476286.2021.1930755] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 05/07/2021] [Accepted: 05/12/2021] [Indexed: 01/07/2023] Open
Abstract
Pancreatic cancer has the worst prognosis of all common cancers. Pancreatic cancer cells have a metabolic advantage due to their swiftly adaptive responses to hypoxic and low-nutrient medium. This advantage contributes to the aggressivity of pancreatic cancer. In this study, lncRNA MIR210HG was abnormally upregulated within pancreatic cancer. It acted as a key oncogenic regulator of pancreatic cancer aggressiveness and glycolysis. Knockdown of MIR210HG significantly inhibited the aggressive phenotype of pancreatic cancer cells and inhibited the growth of xenograft tumours. More importantly, MIR210HG knockdown inhibited pancreatic cancer cell glycolysis via regulating the glycolysis-related hexokinase 2 (HK2) and Pyruvate kinase muscle isozyme M2 (PKM2) expression. Compared with the MIR210HG knockdown group, miR-125b-5p inhibition promoted the aggressive phenotypes and glycolysis of pancreatic cancer cells. Furthermore, the effects of MIR210HG knockdown on HK2 and PKM2 expression, pancreatic cancer cell aggressive phenotypes, and glycolysis were significantly reversed by miR-125b-5p inhibition. In tissue samples, MIR210HG expression was negatively correlated with miR-125b-5p levels and positively correlated with HK2 and PKM2 expression. miR-125b-5p expression was negatively correlated with HK2 and PKM2 expression. In conclusion, MIR210HG affected the phenotypes of pancreatic cancer cells, including proliferation, invasion, migration, and glycolysis, via modulating the miR-125b-5p/HK2/PKM2 axis.
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Affiliation(s)
- Tianzhu Yu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institution of Medical Imaging, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guoping Li
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institution of Medical Imaging, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chenggang Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institution of Medical Imaging, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gaoquan Gong
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institution of Medical Imaging, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liangwen Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institution of Medical Imaging, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Changyu Li
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institution of Medical Imaging, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi Chen
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institution of Medical Imaging, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaolin Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institution of Medical Imaging, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
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Yi X, Hu C, Zhang C, Shao K, Sun H, Jiang Y, Sun N, Zhi X. KIAA1522 is a new biomarker of promoting the tumorigenesis and distant metastasis of colorectal carcinoma. Cell Signal 2021; 90:110202. [PMID: 34826587 DOI: 10.1016/j.cellsig.2021.110202] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/26/2021] [Accepted: 11/17/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Our research was absorbed into exploring the expression, clinicopathological value, biological significance and signaling pathway of KIAA1522 in colorectal carcinoma and its distant metastasis. MATERIALS AND METHODS The expression of KIAA1522 and survival analysis in colorectal carcinoma (CRC) were assessed using GEPIA databases. Then we evaluated the expression of KIAA1522 immunohistochemically in tissue samples of 57 patients with colorectal carcinoma liver metastasis (CRLM). The correlations between the expression of KIAA1522, clinical significance and prognosis of these 57 patients with CRLM were analyzed. The migration and invasion of KIAA1522 were explored by western blotting, CCK-8, colony formation, flow cytometry, wound healing assays and transwell invasion in vitro and tail vein injection models in vivo. Then, transcriptome sequencing and gene set enrichment analysis was performed to identify the signaling pathways involved, while western blotting analysis and immunohistochemistry (IHC) were used to identify the expression of key genes in Notch signaling. RESULTS KIAA1522 was overexpressed in CRLM tissues and colon cancer cell lines, and the expression of KIAA1522 in metastatic sites was positively correlated with that in primary sites. In addition, the overexpression of KIAA1522 is associated with poor clinicopathological features. Survival analysis showed that the overexpression of KIAA1522 predicted a low overall survival rate in patients with CRLM. Functional studies suggested that KIAA1522 promotes the proliferation, invasion and migration of colon carcinoma in vitro. KIAA1522 could promote distant metastasis of CRC in vivo. Moreover, KIAA1522 upregulated the Notch signaling pathway in colorectal cancer cell lines in vitro and lung metastatic nodes in vivo. CONCLUSION In conclusion, it is suggested that the upregulation of KIAA1522 might promote the tumorigenicity and metastasis of colorectal carcinoma through Notch signaling pathway. KIAA1522 plays a carcinogenic role in the metastasis of colorectal carcinoma and might serve as a new molecular target for the treatment.
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Affiliation(s)
- Xin Yi
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Road, Jinan, Shandong 250012, China; Department of General Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 2660035, China
| | - Conghui Hu
- Department of Endocrinology and Metabolism, Qingdao Women and Children's Hospital, Qingdao University, 6 Tongfu Road, Qingdao, Shandong 266034, China
| | - Chen Zhang
- Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 2660035, China
| | - Kai Shao
- Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 2660035, China
| | - Hui Sun
- Department of Cardiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 2660035, China
| | - Yuanhui Jiang
- Department of General Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 2660035, China
| | - Nianfeng Sun
- Department of General Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 2660035, China
| | - Xuting Zhi
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Road, Jinan, Shandong 250012, China.
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Kase-Kato I, Asai S, Minemura C, Tsuneizumi K, Oshima S, Koma A, Kasamatsu A, Hanazawa T, Uzawa K, Seki N. Molecular Pathogenesis of the Coronin Family: CORO2A Facilitates Migration and Invasion Abilities in Oral Squamous Cell Carcinoma. Int J Mol Sci 2021; 22:12684. [PMID: 34884487 PMCID: PMC8657730 DOI: 10.3390/ijms222312684] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 12/13/2022] Open
Abstract
In humans, the coronin family is composed of seven proteins containing WD-repeat domains that regulate actin-based cellular processes. Some members of the coronin family are closely associated with cancer cell migration and invasion. The Cancer Genome Atlas (TCGA) analysis revealed that CORO1C, CORO2A, and CORO7 were significantly upregulated in oral squamous cell carcinoma (OSCC) tissues (p < 0.05). Moreover, the high expression of CORO2A was significantly predictive of the 5-year survival rate of patients with OSCC (p = 0.0203). Overexpression of CORO2A was detected in OSCC clinical specimens by immunostaining. siRNA-mediated knockdown of CORO2A suppressed cancer cell migration and invasion abilities. Furthermore, we investigated the involvement of microRNAs (miRNAs) in the molecular mechanism underlying CORO2A overexpression in OSCC cells. TCGA analysis confirmed that tumor-suppressive miR-125b-5p and miR-140-5p were significantly downregulated in OSCC tissues. Notably, these miRNAs bound directly to the 3'-UTR of CORO2A and controlled CORO2A expression in OSCC cells. In summary, we found that aberrant expression of CORO2A facilitates the malignant transformation of OSCC cells, and that downregulation of tumor-suppressive miRNAs is involved in CORO2A overexpression. Elucidation of the interaction between genes and miRNAs will help reveal the molecular pathogenesis of OSCC.
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Affiliation(s)
- Ikuko Kase-Kato
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (I.K.-K.); (C.M.); (K.T.); (S.O.); (A.K.); (A.K.); (K.U.)
| | - Shunichi Asai
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
- Department of Otorhinolaryngology/Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
| | - Chikashi Minemura
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (I.K.-K.); (C.M.); (K.T.); (S.O.); (A.K.); (A.K.); (K.U.)
| | - Kenta Tsuneizumi
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (I.K.-K.); (C.M.); (K.T.); (S.O.); (A.K.); (A.K.); (K.U.)
| | - Sachi Oshima
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (I.K.-K.); (C.M.); (K.T.); (S.O.); (A.K.); (A.K.); (K.U.)
| | - Ayaka Koma
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (I.K.-K.); (C.M.); (K.T.); (S.O.); (A.K.); (A.K.); (K.U.)
| | - Atsushi Kasamatsu
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (I.K.-K.); (C.M.); (K.T.); (S.O.); (A.K.); (A.K.); (K.U.)
| | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
| | - Katsuhiro Uzawa
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (I.K.-K.); (C.M.); (K.T.); (S.O.); (A.K.); (A.K.); (K.U.)
| | - Naohiko Seki
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
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miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN. Cancers (Basel) 2021; 13:cancers13225710. [PMID: 34830864 PMCID: PMC8616371 DOI: 10.3390/cancers13225710] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/06/2021] [Accepted: 11/10/2021] [Indexed: 01/09/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is the third leading cause for cancer related death, in which metastasis exerts a pivotal role. Therefore, we aim to find out the possible mechanism underlying CRC metastasis. We found that the level of miR-125b was elevated in normal, primary CRC, and distant metastasis tissues stepwise, and high level miR-125b was positively correlated with lymph node metastasis and tumor differentiation. In vitro and in vivo assays showed miR-125b significantly promoted CRC migration and invasion. To elucidate the potential mechanism, cystic fibrosis transmembrane conductance regulator (CFTR) and cingulin (CGN) were defined as two target genes of miR-125b. On the one hand, miR-125b promoted epithelial-mesenchymal transition (EMT) and the production and secretion of urokinase plasminogen activator (uPA) by inhibiting CFTR; on the other hand, miR-125b activated Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) signaling by repressing CGN. Therefore, we provided a potential biomarker for CRC prevention and treatment in the future. Abstract Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.
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Chen F, Lao Z, Zhang H, Wang J, Wang S. Knockdown of circ_0001883 may inhibit epithelial-mesenchymal transition in laryngeal squamous cell carcinoma via the miR-125-5p/PI3K/AKT axis. Exp Ther Med 2021; 22:1007. [PMID: 34345289 PMCID: PMC8311254 DOI: 10.3892/etm.2021.10440] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 06/09/2021] [Indexed: 12/27/2022] Open
Abstract
Laryngeal squamous cell carcinoma (LSCC) is a malignant tumor with increasing incidence and poor prognosis. Circular RNAs (circRNAs) are known to modulate tumorigenesis and cancer development that may function through microRNAs (miRs). The aim of the present study was to investigate the functional roles of circ_0001883 in LSCC and the underlying molecular mechanism. The expression of circ_0001883 was upregulated and measured using reverse transcription-quantitative PCR (RT-qPCR) and RNase R. miR-125b-5p expression was downregulated in LSCC tissues and cells as determined using RT-qPCR. Subsequently, knockdown of circ_0001883 inhibited LSCC cell migration, invasion and epithelial-mesenchymal transition (EMT), which were tested by wound healing assays, Transwell assays and western blotting, respectively. Bioinformatics analysis predicted that circ_0001883 was a sponge of miR-125b-5p, which was verified using a dual-luciferase reporter assay. Knockdown of circ_0001883 played a functional role by sponging miR-125b-5p. Additionally, circ_0001883 and miR-125b-5p influenced phosphorylation of PI3K and AKT, detected via western blotting. In an in vivo study, knockdown of circ_0001883 reduced tumor volume and weight in mice, along with enhanced miR-125b-5p and E-cadherin expression levels, and decreased N-cadherin, phosphorylated (p)-PI3K/PI3K and p-AKT/AKT ratios. In conclusion, knockdown of circ_0001883 inhibited cell migration, invasion and EMT of LSCC by sponging miR-125b-5p. This is hypothesized to be via the PI3K/AKT signaling pathway, which suggested that circ_0001883 has potential for LSCC therapy.
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Affiliation(s)
- Fu Chen
- Department of Radiation Oncology, Eye and ENT Hospital of Fudan University, Shanghai 200031, P.R. China
| | - Zheng Lao
- Radiotherapy Division, Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
| | - Haiyan Zhang
- Department of Radiation Oncology, Eye and ENT Hospital of Fudan University, Shanghai 200031, P.R. China
| | - Jie Wang
- Department of Radiation Oncology, Eye and ENT Hospital of Fudan University, Shanghai 200031, P.R. China
| | - Shengzi Wang
- Department of Radiation Oncology, Eye and ENT Hospital of Fudan University, Shanghai 200031, P.R. China
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Jin FE, Xie B, Xian HZ, Wang JH. Knockdown of miR-125b-5p inhibits the proliferation and invasion of gastric carcinoma cells by targeting RYBP. Kaohsiung J Med Sci 2021; 37:863-871. [PMID: 34337862 DOI: 10.1002/kjm2.12425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 04/12/2021] [Accepted: 06/14/2021] [Indexed: 11/08/2022] Open
Abstract
Gastric carcinoma, one of the most aggressive and lethal human malignancies, is associated with poor prognosis despite progress in therapeutic strategies. This study examined the potential function and mechanism of action of microRNA-125b-5p (miR-125b-5p) in the pathogenesis of gastric carcinoma. We recognized that miR-125b-5p was elevated in gastric carcinoma, and its decreased expression was associated with a better prognosis. Loss-of-function assays showed that miR-125b-5p suppression inhibited the proliferative and invasive abilities of gastric cancer cells. Furthermore, RING1 and YY1-binding protein (RYBP) was found to be target gene for miR-125b-5p action; miR-125b-5p negatively regulates RYBP expression. According to the results of rescue experiments, RYBP downregulation partially counteracted the miR-125b-5p silence-mediated inhibitory function in gastric cancer progression. Collectively, these data elucidated the molecular mechanisms of the miR-125b-5p/RYBP axis in gastric cancer invasion and growth.
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Affiliation(s)
- Fu-E Jin
- Department of Health Management, Qingdao Huangdao District Center Hospital, Qingdao, China
| | - Bo Xie
- Gastrointestinal Surgery, Liaocheng People's Hospital, Liaocheng, China
| | - Hong-Zhen Xian
- Department of Gastroenterology, Jimo People's Hospital of Qingdao City, Qingdao, China
| | - Ji-Hai Wang
- Surgery Staff Room, Shandong Medical College, Linyi, China
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Xu J, Wen J, Li S, Shen X, You T, Huang Y, Xu C, Zhao Y. Immune-Related Nine-MicroRNA Signature for Predicting the Prognosis of Gastric Cancer. Front Genet 2021; 12:690598. [PMID: 34290743 PMCID: PMC8287335 DOI: 10.3389/fgene.2021.690598] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/21/2021] [Indexed: 12/21/2022] Open
Abstract
Recent findings have demonstrated the superiority and utility of microRNAs (miRNAs) as new biomarkers for cancer diagnosis, therapy, and prognosis. In this study, to explore the prognostic value of immune-related miRNAs in gastric cancer (GC), we analyzed the miRNA-expression profiles of 389 patients with GC, using data deposited in The Cancer Genome Atlas database. Using a forward- and backward-variable selection and multivariate Cox regression analyses model, we identified a nine-miRNA signature (the “ImmiRSig,” consisting of miR-125b-5p, miR-99a-3p, miR-145-3p, miR-328-3p, miR-133a-5p, miR-1292-5p, miR-675-3p, miR-92b-5p, and miR-942-3p) in the training cohort that enabled the division of patients into high- and low-risk groups with significantly different survival rates. The ImmiRSig was successfully validated with an independent test cohort of 193 GC patients. Univariate and multivariate Cox regression analyses indicated that the ImmiRSig would serve as an independent prognostic factor after adjusting for other clinical covariates. Pending further prospective validation, the identified ImmiRSig appears to have significant clinical importance in terms of improving outcome predictions and guiding personalized treatment for patients with GC. Finally, significant associations between the ImmiRSig and the half-maximal inhibitory concentrations of chemotherapeutic agents were observed, suggesting that ImmiRSig may predict the clinical efficacy of chemotherapy.
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Affiliation(s)
- Jingxuan Xu
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jian Wen
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Shuangquan Li
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Tao You
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yingpeng Huang
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Chongyong Xu
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yaping Zhao
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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Ding J, Wang X, Gao J, Song T. Silencing of cystatin SN abrogates cancer progression and stem cell properties in papillary thyroid carcinoma. FEBS Open Bio 2021. [PMID: 34102026 PMCID: PMC8329778 DOI: 10.1002/2211-5463.13221] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/29/2021] [Accepted: 06/07/2021] [Indexed: 01/03/2023] Open
Abstract
Papillary thyroid carcinoma (PTC) accounts for approximately 80% of total thyroid cancers worldwide. Although the prognosis for early‐stage PTC is favorable, the 5‐year survival rate of patients with late‐stage PTC is still very poor. Cystatin SN (cystatin 1, CST1) facilitates the progression of multiple cancers, but its role in regulating PTC pathogenesis is still largely unknown. In this study, we measured the expression levels of CST1 in PTC clinical tissues and cell lines by real‐time quantitative PCR and western blot analysis, and we performed gain‐ and loss‐of‐function experiments to examine the effects of CST1 on PTC cell growth, invasion, migration, epithelial–mesenchymal transition and stemness. Tumorigenicity was assessed using in vivo tumor‐bearing nude mouse models. As expected, upregulated CST1 was observed in PTC tissues (P < 0.05) and cells, compared with their normal counterparts (P < 0.05); furthermore, patients with PTC with higher levels of CST1 exhibited unfavorable prognosis (P < 0.05). In addition, CST1 ablation inhibited PTC cell growth (P < 0.05) in vivo and in vitro. Silencing of CST1 also inhibited cell motility and epithelial–mesenchymal transition in PTC cells (P < 0.05), whereas CST1 overexpression had the opposite effects on the earlier cellular functions. Notably, up‐regulation of CST1 promoted cell spheroid formation (P < 0.05) and increased the expression levels of stemness signatures (P < 0.05) in PTC cells. Collectively, these findings suggest that CST1 functions as an oncogene to facilitate cancer development and promote cancer stem cell properties in PTC cells, increasing our understanding of PTC pathogenesis mechanisms and possibly aiding in the development of potential therapeutic strategies.
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Affiliation(s)
- Jiaojiao Ding
- Department of Ultrasound, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiaorong Wang
- Department of Ultrasound, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Junxi Gao
- Department of Ultrasound, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Tao Song
- Department of Ultrasound, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Lv Y, Lv X, Yang H, Qi X, Wang X, Li C, Shang X, Guo H, Zhang J, Zhang Y. LncRNA SNHG6/miR-125b-5p/BMPR1B Axis: A New Therapeutic Target for Triple-Negative Breast Cancer. Front Oncol 2021; 11:678474. [PMID: 34026654 PMCID: PMC8137992 DOI: 10.3389/fonc.2021.678474] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/19/2021] [Indexed: 12/27/2022] Open
Abstract
Background Triple-negative breast cancer (TNBC) is a significant cause of patient morbidity. The exactly pathobiological features of this condition has yet to be completely elucidated. Methods Breast cancer data obtained from The Cancer Genome Atlas (TCGA) database were evaluated for lncRNA SNHG6 expression. Normal human breast epithelial cell line (MCF-10A) and other breast cancer cell lines (BT-549, MDA-MB-231, Hs 578t, ZR-75-30, SK-BR-3, MCF-7) were also assessed for lncRNA SNHG6 expressions. Cellular proliferative ability was evaluated with colony formation and CCK-8 assays. The ability of cells to migrate was scrutinized with the wound healing and Boyden chamber cell migration assays. qRT-PCR enabled for detection of lncRNA SNHG6, miR-125b-5p and BMPR1B mRNA expressions. Protein BMPR1B expressions were further assessed using Western Blotting. Direct binding sites between transcripts were determined using dual-luciferase reporter assays. We also constructed a xenograft mouse model to further dissect the vivo implications of lncRNA SNHG6. Ki-67 and c-Caspase-3 expressions were detected using immunohistochemistry staining. Results Breast cancer cell lines demonstrated higher lncRNA SNHG6 expressions, particularly TNBC cell lines, in contrast to normal breast epithelial cell lines. This finding coincided with those noted on analysis of TCGA breast cancer data. lncRNA SNHG6 knockdown inhibited TNBC cell proliferation, migration, while promoted cell apoptosis. Furthermore, suppressed lncRNA SNHG6 expressions resulted in lower tumor weights and volumes in a xenograft mouse model, as evidenced by Ki-67 and c-Caspase-3 expression profiles in tumor tissues. miR-125b-5p and lncRNA SNHG6/BMPR1B both possessed direct binding sites for each other which was validated utilizing a dual-luciferase reporter assay. Decreasing lncRNA SNHG6 expression in TNBC cells upregulated miR-125b-5p expression. Another side, inhibiting miR-125b-5p upregulated BMPR1B expression in these cells. Moreover, knocking down lncRNA SNHG6 downregulated BMPR1B expression in TNBC cells, and the finding was rescued in cells which were exposed to miR-125b-5p inhibitor. Downregulating miR-125b-5p mitigated the effect of suppressing lncRNA SNHG6 on TNBC cell proliferation, migration, and apoptosis. Conclusion Downregulation of lncRNA SNHG6 could inhibit TNBC cell proliferative, migratory capabilities and promote apoptosis capability, likely through modulation of the miR-125b-5p/BMPR1B axis. This axis may be targeted in formulating new therapies for TNBC.
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Affiliation(s)
- Yufei Lv
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xiaohong Lv
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Huike Yang
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xiuying Qi
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xiangchen Wang
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Chao Li
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xiaochen Shang
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Hongmin Guo
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Jianguo Zhang
- Department of Breast Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yafang Zhang
- Department of Anatomy, Harbin Medical University, Harbin, China
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Zong G, Feng X, Sun X, Du J, Wang G, Song T. LncRNA MALAT1 Promote Cell Proliferation and Invasion by Sponging miR-125b to Modulate HMGA1 Expression in Laryngocarcinoma. IRANIAN JOURNAL OF PUBLIC HEALTH 2021; 50:959-969. [PMID: 34183954 PMCID: PMC8223581 DOI: 10.18502/ijph.v50i5.6113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 07/12/2020] [Indexed: 11/24/2022]
Abstract
BACKGROUND Laryngocarcinoma is the most frequent head and neck malignant tumor. MALAT1 have a role in promoting cell proliferation and metastasis in several tumors. This research aimed to investigate the great roles of MALAT1in laryngocarcinoma. METHODS Overall, 54 cases of laryngocarcinoma tissues pathological specimens and paracancerous tissues were collected by surgical resection from the Department of Otolaryngology-Head and Neck Surgery at the Shandong Provincial Hospital affiliated to Shandong University, China from Jan 2012 to Oct 2015. The microRNA and protein levels of genes were evaluated by RT-qPCR and western blot. The proliferative and invasive ability were calculated usingCCK8 and transwell assays. Kaplan-Meier method was used to assess the survival of laryngocarcinoma patients. RESULTS In laryngocarcinoma tissues and cells, lncRNA MALAT1 expression was significantly increased compared to normal tissues and cells. LncRNA MALAT1 promotes proliferation and migration of laryngocarcinoma cells. LncRNA MALAT1 upregulates HMGA1 expression by acting as a competitive endogenous RNA (ceRNA) for miR-125b. Rescue experiments showed that microRNA-125b inhibitor reversed the change in cell viability and invasion induced by sh-MALAT1. Down regulation of lncRNA MALAT1 inhibits laryngocarcinoma proliferation and invasion by modulating miR-125b/HMGA1. CONCLUSION LncRNA MALAT1 promotes the development of laryngocarcinoma by regulating the expression level of HMGA1 by acting as a miR-125b ceRNA and may be considered as a new strategy for the development of laryngocarcinoma.
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Affiliation(s)
- Guangxin Zong
- Department of Otorhinolaryngology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Xinrong Feng
- Department of Otorhinolaryngology, Jinan Zhangqiu District Hospital of TCM, Jinan 250200, China
| | - Xiuhua Sun
- Property Management Section, the People’s Hospital of Zhangqiu Area, Jinan 250200, China
| | - Jiexin Du
- Department of Neurology, the People’s Hospital of Zhangqiu Area, Jinan 250200, China
| | - Guangsheng Wang
- Department of Neurology, the People’s Hospital of Zhangqiu Area, Jinan 250200, China
| | - Tingting Song
- No 2 Department of Oncology, Qingdao Tumor Hospital, Qingdao 266042, China
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Differential miRNA Expression Profiling Reveals Correlation of miR125b-5p with Persistent Infection of Japanese Encephalitis Virus. Int J Mol Sci 2021; 22:ijms22084218. [PMID: 33921710 PMCID: PMC8073291 DOI: 10.3390/ijms22084218] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/13/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) play versatile roles in multiple biological processes. However, little is known about miRNA’s involvement in flavivirus persistent infection. Here, we used an miRNA array analysis of Japanese encephalitis virus (JEV)-infected cells to search for persistent infection-associated miRNAs in comparison to acute infection. Among all differentially expressed miRNAs, the miR-125b-5p is the most significantly increased one. The high level of miR-125b-5p in persistently JEV-infected cells was confirmed by Northern analysis and real-time quantitative polymerase chain reaction. As soon as the cells established a persistent infection, a significantly high expression of miR-125b-5p was readily observed. Transfecting excess quantities of a miR-125b-5p mimic into acutely infected cells reduced genome replication and virus titers. Host targets of miR125b-5p were analyzed by target prediction algorithms, and six candidates were confirmed by a dual-luciferase reporter assay. These genes were upregulated in the acutely infected cells and sharply declined in the persistently infected cells. The transfection of the miR125b-5p mimic reduced the expression levels of Stat3, Map2k7, and Triap1. Our studies indicated that miR-125b-5p targets both viral and host sequences, suggesting its role in coordinating viral replication and host antiviral responses. This is the first report to characterize the potential roles of miR-125b-5p in persistent JEV infections.
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Tang Y, Zong S, Zeng H, Ruan X, Yao L, Han S, Hou F. MicroRNAs and angiogenesis: a new era for the management of colorectal cancer. Cancer Cell Int 2021; 21:221. [PMID: 33865381 PMCID: PMC8052662 DOI: 10.1186/s12935-021-01920-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/07/2021] [Indexed: 02/08/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small noncoding RNA molecules containing only 20–22 nucleotides. MiRNAs play a role in gene silencing and translation suppression by targeting and binding to mRNA. Proper control of miRNA expression is very important for maintaining a normal physiological environment because miRNAs can affect most cellular pathways, including cell cycle checkpoint, cell proliferation, and apoptosis pathways, and have a wide range of target genes. With these properties, miRNAs can modulate multiple signalling pathways involved in cancer development, such as cell proliferation, apoptosis, and migration pathways. MiRNAs that activate or inhibit the molecular pathway related to tumour angiogenesis are common topics of research. Angiogenesis promotes tumorigenesis and metastasis by providing oxygen and diffusible nutrients and releasing proangiogenic factors and is one of the hallmarks of tumour progression. CRC is one of the most common tumours, and metastasis has always been a difficult issue in its treatment. Although comprehensive treatments, such as surgery, radiotherapy, chemotherapy, and targeted therapy, have prolonged the survival of CRC patients, the overall response is not optimistic. Therefore, there is an urgent need to find new therapeutic targets to improve CRC treatment. In a series of recent reports, miRNAs have been shown to bidirectionally regulate angiogenesis in colorectal cancer. Many miRNAs can directly act on VEGF or inhibit angiogenesis through other pathways (HIF-1a, PI3K/AKT, etc.), while some miRNAs, specifically many exosomal miRNAs, are capable of promoting CRC angiogenesis. Understanding the mechanism of action of miRNAs in angiogenesis is of great significance for finding new targets for the treatment of tumour angiogenesis. Deciphering the exact role of specific miRNAs in angiogenesis is a challenge due to the high complexity of their actions. Here, we describe the latest advances in the understanding of miRNAs and their corresponding targets that play a role in CRC angiogenesis and discuss possible miRNA-based therapeutic strategies.
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Affiliation(s)
- Yufei Tang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Shaoqi Zong
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.,Graduate School of Shanghai, University of Traditional Chinese Medicine, Shanghai, China
| | - Hailun Zeng
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Xiaofeng Ruan
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Liting Yao
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Susu Han
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Fenggang Hou
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
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Lin J, Liao S, Liu Z, Li E, Wu X, Zeng W. LncRNA FGD5-AS1 accelerates cell proliferation in pancreatic cancer by regulating miR-520a-3p/KIAA1522 axis. Cancer Biol Ther 2021; 22:257-266. [PMID: 33794727 DOI: 10.1080/15384047.2021.1883184] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In recent years, FGD5 antisense RNA 1 (FGD5-AS1) was confirmed to be the long non-coding RNAs (lncRNAs) that could accelerate the development of multiple cancers. Nevertheless, specific biological functions and latent mechanism of FGD5-AS1 were not yet clear in pancreatic cancer (PC). This research was aimed to search the functions of FGD5-AS1 on the PC progression. The expression of FGD5-AS1 in PC cells was tested by using RT-qPCR assay. Colony formation assay, EdU assay, flow cytometry assay and transwell assay as well as western blot were adopted to test the cell abilities of proliferation, apoptosis and migration, separately. Furthermore, RIP experiment and pull down assay were applied for validating the correlation FGD5-AS1, miR-520a-3p and KIAA1522. As a result, the abnormal high expression of FGD5-AS1 was observed in PC cells. And cell proliferative and migratory abilities could be restrained via FGD5-AS1 depletion. Moreover, FGD5-AS1 was proven to combine with miR-520a-3p directly. It was also confirmed that KIAA1522 could be targeted by miR-520a-3p. Rescue assay results indicated that overexpressed KIAA1522 could reverse the repressive function of silencing FGD5-AS1 on PC progression. Taken together, FGD5-AS1 accelerated cell proliferation and migration via sponging miR-520a-3p and upregulating KIAA1522.
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Affiliation(s)
- Jing Lin
- Department of Oncology, The First Affiliated Hospital of Shantou Univresity Medical College, Shantou, Shantou, Guangdong, China
| | - Shasha Liao
- Department of Oncology, Shantou Longhu people's Hospital, Shantou, Guangdong, China
| | - Zewa Liu
- Department of Oncology, The First Affiliated Hospital of Shantou Univresity Medical College, Shantou, Shantou, Guangdong, China
| | - E Li
- Department of Oncology, Shantou Longhu people's Hospital, Shantou, Guangdong, China
| | - Xiaohua Wu
- Department of Oncology, Shantou Longhu people's Hospital, Shantou, Guangdong, China
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Cytotoxin-Associated Gene A-Positive Helicobacter pylori Promotes Autophagy in Colon Cancer Cells by Inhibiting miR-125b-5p. ACTA ACUST UNITED AC 2021; 2021:6622092. [PMID: 33791049 PMCID: PMC7984907 DOI: 10.1155/2021/6622092] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/31/2021] [Accepted: 02/08/2021] [Indexed: 12/25/2022]
Abstract
Objectives To investigate the effects of cytotoxin-associated gene A- (CagA-) positive Helicobacter pylori on proliferation, invasion, autophagy, and expression of miR-125b-5p in colon cancer cells. Methods Colon cancer cells were cocultured with H. pylori (CagA+) to analyze the effects of H. pylori on miR-125b-5p and autophagy. Colon cancer cells infected with H. pylori (CagA+) were mimicked by transfection of CagA plasmid. The effects of CagA on the proliferation, invasion, and autophagy of colon cancer cells were analyzed. Cell counting kit-8 (CCK-8), clone formation, and Transwell assays were used to detect cell viability, proliferation, and invasion ability, respectively. Proteins and miRNAs were detected by western blotting and qPCR, respectively. Results H. pylori (CagA+) inhibited expression of miR-125b-5p and promoted autophagy in colon cancer cells. MiR-125 b-5p was underexpressed in colon cancer cells after CagA overexpression. CagA promoted colon cancer cell proliferation, invasion, and autophagy. Overexpression of miR-125b-5p inhibited the proliferation, invasion, and autophagy of colon cancer cells and reversed the effects of CagA. Conclusion H. pylori (CagA+) infection may promote the development and invasion of colon cancer by inhibiting miR-125b-5p.
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Forouzanfar M, Lachinani L, Dormiani K, Nasr-Esfahani MH, Ghaedi K. Increased expression of MUSASHI1 in epithelial breast cancer cells is due to down regulation of miR-125b. BMC Mol Cell Biol 2021; 22:10. [PMID: 33541259 PMCID: PMC7863248 DOI: 10.1186/s12860-021-00348-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 01/26/2021] [Indexed: 01/04/2023] Open
Abstract
Background Musashi1 (MSI1) is an oncogenic protein with a crucial role in the proliferation and characteristics of the epithelial cells in breast cancer. The change in expression of MSI1 has a role in solid tumor progression. There are different factors that regulate MSI1 expression in various cancer tissues including microRNAs which are considered as one of the most important of these factors. The aim of our study is identification of the molecular cause of maximal expression of MSI1 in epithelial breast cancer cell lines. Results Among predicted microRNAs, miR-125b, miR-637 and miR-802 were able to significantly reduce the luciferase activity. In addition, the relative expression of these three miRNAs were measured in the cancerous cell lines that results showed a significant reduction in expression of all microRNAs. On the other hand, only the overexpression of miR-125b caused a change in the expression pattern of MSI1 in breast epithelial cancer cell lines. Accordingly, our results demonstrated that the exogenous expression of miR-125b decreased not only the MSI1 protein but also expression of epithelial markers in breast cancer cells. Conclusions The results of luciferase reporter assay showed that MSI1 is a direct target for miR-125b in epithelial breast cancer cells. Moreover, higher amount of MSI1 in those cell lines seems due to the reduced amount of miR-125b, which is responsible for epithelial features of those kinds of cancer cells. Therefore, the modulation of miR-125b may be a potential approach to help to combat against epithelial breast tumors. Supplementary Information The online version contains supplementary material available at 10.1186/s12860-021-00348-8.
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Affiliation(s)
- Mahboobeh Forouzanfar
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave., Azadi Square, Isfahan, P.O. Code 81746, Iran
| | - Liana Lachinani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, P.O. Code 816513-1378, Iran
| | - Kianoush Dormiani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, P.O. Code 816513-1378, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, P.O. Code 816513-1378, Iran.
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave., Azadi Square, Isfahan, P.O. Code 81746, Iran.
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Hu B, Yang XB, Yang X, Sang XT. LncRNA CYTOR affects the proliferation, cell cycle and apoptosis of hepatocellular carcinoma cells by regulating the miR-125b-5p/KIAA1522 axis. Aging (Albany NY) 2020; 13:2626-2639. [PMID: 33318318 PMCID: PMC7880333 DOI: 10.18632/aging.202306] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 10/22/2020] [Indexed: 04/27/2023]
Abstract
We aimed to investigate whether lncRNA CYTOR could sponge miR-125b-5p to affect hepatocellular carcinoma (HCC) cells through targeting KIAA1522. The expression of CYTOR, miR-125b-5p and KIAA1522 in HCC cells was detected by Real-time quantitative polymerase chain reaction (RT-qPCR) analysis. KIAA1522 expression in HCC tissues was detected by immunohistochemistry. The proliferation, cell cycle and apoptosis of HCC cells after transfection were respectively detected by Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis, and related protein expression was determined by Western blot analysis. As a result, The Cancer Genome Atlas (TCGA) database indicated that expression of CYTOR and KIAA1522 was increased in HCC tissues and high expression of CYTOR and KIAA1522 was related to worse overall survival. MiR-125b-5p expression was decreased in HCC tissues, which was negatively correlated with the expression of CYTOR and KIAA1522. The proliferation and cell cycle of HCC cells were suppressed by CYTOR interference while promoted by miR-125b-5p interference and KIAA1522 overexpression. The apoptosis of HCC cells was promoted by CYTOR interference while inhibited by miR-125b-5p interference and KIAA1522 overexpression. In conclusion, CYTOR interference suppressed the proliferation and cell cycle, and promoted the apoptosis of HCC cells by regulating the miR-125b-5p/KIAA1522 axis.
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Affiliation(s)
- Bo Hu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiao-Bo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xin-Ting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Wang C, Shi Z, Hong Z, Pan J, Chen Z, Qiu C, Zhuang H, Zheng X. MicroRNA-1276 Promotes Colon Cancer Cell Proliferation by Negatively Regulating LACTB. Cancer Manag Res 2020; 12:12185-12195. [PMID: 33273855 PMCID: PMC7705278 DOI: 10.2147/cmar.s278566] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 11/12/2020] [Indexed: 01/15/2023] Open
Abstract
Purpose LACTB, regulated by a variety of microRNAs (miRNAs), is proven to be a tumor suppressor. However, there are few reports that LACTB in colon cancer cells is regulated by miRNA. Therefore, the aim of this study was to explore the miRNAs that regulate LACTB in colon cancer. Patients and Methods Data from TCGA were analyzed in starBase and GEPIA2, and Western blot and quantitative PCR (qPCR) were used to detect the expression of LACTB in colon cancer cell lines. MiRNAs targeting LACTB were predicted by MicroT-CDS, starBase, miRDB, mirDIP, and DIANA. The relationship between LACTB and miRNA was explored by dual-luciferase assay. MTT, propidium iodide (PI), Western blot, Annexin V-FITC/PI Kit, qPCR and transwell assay were used to detect the changes in cell proliferation, cell cycle, autophagy, apoptosis, epithelial-to-mesenchymal transition (EMT), cell migration, and invasiveness in colon cancer cells that overexpressed miR-1276 and/or LACTB. Results The results showed that the LACTB mRNA level was lower and the miR-1276 level was higher in colon cancer than in normal tissue. MiR-1276 inhibited the expression of LACTB. Furthermore, overexpression of miR-1276 in colon cancer cells increased proliferation, migration, invasiveness and EMT, and decreased autophagy and apoptosis. Supplementing LACTB suppressed these effects of miR-1276. Conclusion In conclusion, miR-1276, which may be a potential therapy for colon cancer, inhibits cell growth and promotes apoptosis by targeting LACTB in colon cancer cells.
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Affiliation(s)
- Chunxiao Wang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
| | - Zesheng Shi
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
| | - Zhongshi Hong
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
| | - Jianpeng Pan
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
| | - Zhichuan Chen
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
| | - Chengzhi Qiu
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
| | - Haibin Zhuang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
| | - Xuecong Zheng
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, People's Republic of China
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Regulation of Apoptosis and Inflammatory Response in Interleukin-1β-Induced Nucleus Pulposus Cells by miR-125b-5p Via Targeting TRIAP1. Biochem Genet 2020; 59:475-490. [PMID: 33123835 DOI: 10.1007/s10528-020-10009-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022]
Abstract
The aim of the present study was to determine the function of microRNA (miR)-125b-5p in lumbar disc degeneration (LDD). Nucleus pulposus (NP) cells were stimulated with 10 ng/ml IL-1β for 24 h to establish an LDD model. Reverse transcription-quantitative PCR was used to assess miR-125b-5p levels in human lumbar degenerative NP samples and IL-1β-treated NP cells. An interaction between miR-125b-5p and TP53-regulated inhibitor of apoptosis 1 (TRIAP1) was revealed by TargetScan 7.1 and dual-luciferase reporter assay. Protein levels of pro-inflammatory factors were determined using ELISA. Cell viability and apoptosis were evaluated by MTT and flow cytometry analysis, respectively. miR-125b-5p was markedly upregulated in both human lumbar degenerative NP specimens and IL-1β-treated NP cells. TRIAP1, which directly targets miR-125b-5p, was markedly downregulated in human lumbar degenerative NP specimens and IL-1β-treated NP cells. The levels of TNF-α and IL-6 were inhibited in IL-1β-treated NP cells transfected with miR-125b-5p inhibitor. Moreover, miR-125b-5p inhibitor increased NP cell viability, prevented apoptosis and repressed the apoptotic peptidase activating factor 1/caspase 9 pathway in IL-1β-treated NP cells. Thus, the present findings suggested that miR-125b-5p could regulate LDD by adjusting NP cell apoptosis and inflammatory responses via TRIAP1.
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Guo B, Yu L, Sun Y, Yao N, Ma L. Long Non-Coding RNA USP2-AS1 Accelerates Cell Proliferation and Migration in Ovarian Cancer by Sponging miR-520d-3p and Up-Regulating KIAA1522. Cancer Manag Res 2020; 12:10541-10550. [PMID: 33122952 PMCID: PMC7591011 DOI: 10.2147/cmar.s268863] [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: 06/22/2020] [Accepted: 08/15/2020] [Indexed: 12/29/2022] Open
Abstract
Background Ovarian cancer is one of the malignant tumors attacking the female reproductive system. Currently, increasing studies have clearly determined the importance of long non-coding RNAs (lncRNAs) in various human cancers including ovarian cancer. However, the role and in-depth mechanism of ubiquitin specific peptidase 2 antisense RNA 1 (USP2-AS1) in ovarian cancer have been not reported yet. Purpose We were absorbed into exploring the character of USP2-AS1 in ovarian cancer. Methods RT-qPCR analysis reflected gene expression. The GEPIA database provided further evidences, and bioinformatics tools analyzed the potential molecules downstream USP2-AS1 in ovarian cancer. The changes on ovarian cancer cellular functions were assessed via EdU, TUNEL, JC-1 and transwell assays. RNA pull down, RIP and luciferase reporter assays estimated molecule interactions. Results USP2-AS1 was obviously up-regulated in ovarian cancer tissues and cell lines. Inhibiting USP2-AS1 had anti-proliferation, pro-apoptosis, and anti-migration effects on ovarian cancer cells. Furthermore, we confirmed that USP2-AS1 sequestered miR-520d-3p to enhance KIAA1522. In addition, miR-520d-3p silence reversed the effect of depleted USP2-AS1 on ovarian cancer cellular behaviors, while such reversion was then abolished by KIAA1522 knockdown. Conclusion USP2-AS1 facilitated ovarian cancer progression via miR-520d-3p/KIAA1522 axis, implying USP2-AS1 as a new perspective for the treatment of ovarian cancer.
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Affiliation(s)
- Bingqin Guo
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233030, Anhui, People's Republic of China
| | - Lan Yu
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233030, Anhui, People's Republic of China
| | - Yanhong Sun
- Department of Obstetrics and Gynecology, Huangshan People's Hospital of Anhui Province, Huangshan, Anhui 245000, People's Republic of China
| | - Nan Yao
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233030, Anhui, People's Republic of China
| | - Li Ma
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233030, Anhui, People's Republic of China
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