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Wu C, Gao Y, Jin Z, Huang Z, Wang H, Lu S, Guo S, Zhang F, Zhang J, Huang J, Tao X, Liu X, Zhang X, You L, Li Q, Wu J. PTPRG-AS1 regulates the KITLG/KIT pathway through the ceRNA axis to promote the malignant progression of gastric cancer and the intervention effect of Compound Kushen injection on it. Pharmacol Res 2025; 215:107743. [PMID: 40250508 DOI: 10.1016/j.phrs.2025.107743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/12/2025] [Accepted: 04/16/2025] [Indexed: 04/20/2025]
Abstract
Gastric cancer (GC) is a common malignant tumor with high mortality, recurrence, and metastasis rates. Compound Kushen injection (CKI) combination chemotherapy has been clinically used for the treatment of GC in China for many years, but its underlying mechanisms of action remain unclear. Recent reports have highlighted the important role of the competing endogenous RNA (ceRNA) mechanism of noncoding RNA (ncRNA) and messenger RNA (mRNA) formation in GC and other tumors. This study aimed to investigate the effects of CKI on GC from the ceRNA perspective. We confirmed the inhibitory effect of CKI on GC in mouse models and cell lines. By examining the GC cell lines sensitive to CKI treatment, we developed the CNScore method to analyze the ceRNA network, revealing that the CKI-GC ceRNA network promotes GC proliferation and metastasis through the PTPRG-AS1/hsa-miR-421/KITLG axis. Finally, we constructed GC cell models with PTPRG-AS1 overexpression or knockdown and GC liver metastasis models and found that PTPRG-AS1 can sponge hsa-miR-421, releasing KITLG and promoting GC proliferation and metastasis through the KITLG/KIT pathway. Taken together, CKI can suppress these malignant phenotypes by regulating the PTPRG-AS1/hsa-miR-421/KITLG axis.
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Affiliation(s)
- Chao Wu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China; Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Yifei Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhengsen Jin
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhihong Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Haojia Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shan Lu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Siyu Guo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Fanqin Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jingyuan Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jiaqi Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiaoyu Tao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xinkui Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China; Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - Xiaomeng Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Leiming You
- School of Life Science, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang Province 310022, China.
| | - Jiarui Wu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
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Li S, Cui Z, Gao M, Shan Y, Ren Y, Zhao Y, Wang D, Meng T, Liu H, Yin Z. Hsa_circ_0072088 promotes non-small cell lung cancer progression through modulating miR-1270/TOP2A axis. Cancer Cell Int 2025; 25:156. [PMID: 40259294 PMCID: PMC12010575 DOI: 10.1186/s12935-025-03749-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 03/12/2025] [Indexed: 04/23/2025] Open
Abstract
According to the data released by the International Agency for Research on Cancer (IARC) in 2020, lung cancer ranks second among newly diagnosed malignant tumors globally. As a special class of non-coding RNA, circRNA has become a new hotspot in the field of biomarker research. With the continuous deepening of molecular-level investigations, the underlying mechanisms of circRNA are being gradually unveiled. The more widely studied mechanism is the competitive endogenous RNA mechanism of circRNA. Studies related to circRNA expression were searched in GEO database and statistically analyzed using the "limma" package and weighted gene co-expression network analysis. The expression of circRNA, microRNA and mRNA in cells and tissues were examined via qRT-PCR. MTS assay was used to measure cell proliferation, Transwell assay was used to measure cell migration, and apoptosis assay was carried out to detect cell apoptosis. Additionally, a dual-luciferase reporter assay was further executed to explore the targeted binding relationships between circRNA-microRNA and microRNA-mRNA. It was discovered that hsa_circRNA_103809 was differentially highly expressed in non-small cell lung cancer cells, whereas miR-1270 was differentially lowly expressed. The knockdown of circ_0072088 inhibited the cell proliferation and migration, while promoting cell apoptosis. The same biological function was found with the overexpression of miR-1270. The rescue experiment further validated that circ_0072088 could regulate the biological function of cells by influencing miR-1270. Finally, the targeted binding relationship was verified by dual luciferase reporting experiment. In conclusion, circ_0072088 is differentially highly expressed in non-small cell lung cancer and can affect the progression of non-small cell lung cancer through the circ_0072088/miR-1270/TOP2A axis.
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Affiliation(s)
- Sixuan Li
- Postdoctoral Research Station, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China
| | - Zhigang Cui
- School of Nursing, China Medical University, Shenyang, 110122, Liaoning, China
| | - Min Gao
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China
| | - Yanan Shan
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China
| | - Yihong Ren
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China
| | - Yuxin Zhao
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China
| | - Di Wang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China
| | - Tingyu Meng
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China
| | - Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
| | - Zhihua Yin
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China.
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Wang W, Huang L, Lv J, Miao Z, Jin S, Li S, Cheng Q. Silencing circRNA-ZFAND6 induces trophoblast apoptosis by activating the mitochondrial pathway through the miR-575/SOD2 axis in unexplained recurrent spontaneous abortion. BMC Womens Health 2025; 25:164. [PMID: 40200350 PMCID: PMC11977909 DOI: 10.1186/s12905-025-03682-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 03/20/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Unexplained recurrent spontaneous abortion (URSA) is a major problem in the field of human reproductive health. At present, several circRNAs have been reported to be differentially expressed and play an important biological function in pregnancy-related diseases. However, the role of circRNAs in URSA remains unclear. METHODS Levels of circRNA and miRNA were examined by RT-qPCR. The si-RNA and overexpression plasmid were respectively used to silence and overexpress circRNA-ZFAND6. We investigated the biological function of circRNA-ZFAND6 on trophoblasts through CCK8, EdU, Flow cytometric assay, Wound-healing assays and Transwell. Dual luciferase activity assay was conducted to identify the interaction between miR-575 and circRNA-ZFAND6. RESULTS We confirmed that circRNA-ZFAND6 was a stable circular RNA and was mostly localized in the cytoplasm. CircRNA-ZFAND6 was downregulated in placental villous tissues of URSA. CCK-8 and EdU assays showed that circRNA-ZFAND6 promoted the proliferation of HTR-8/SVneo cells. Flow cytometry and western blot assays prompted that circRNA-ZFAND6 obviously reduced cells apoptosis. Scratch wound healing and transwell assays revealed that circRNA-ZFAND6 had no effect on cell migration and invasion. CircRNA-ZFAND6 worked by adsorbing miR-575 through the ceRNA mechanism. MiR-575 can inhibit the proliferation and promote the apoptosis of HTR8/SVneo cells. SOD2 was identified as a direct target of miR-575 and was associated with mitochondrial apoptosis. Transmission electron microscopy, TMRM and ROS staining assays both suggested that circRNA-ZFAND6 affected mitochondrial apoptosis. Excessive trophoblast apoptosis was a key event to promote the development of URSA. CONCLUSION CircRNA-ZFAND6, which is low expressed in URSA and regulates the apoptosis of trophoblast cells, may affect the expression of SOD2 and thus affect mitochondrial apoptosis by regulating miR-575. This is closely related to the occurrence of URSA.
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Affiliation(s)
- Wenting Wang
- Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210004, China
| | - Linxiang Huang
- Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210004, China
| | - Juan Lv
- Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210004, China
| | - Zhijing Miao
- Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210004, China
| | - Shuping Jin
- Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210004, China
| | - Shan Li
- Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210004, China.
| | - Qing Cheng
- Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210004, China.
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Sur S, Pal JK, Shekhar S, Bafna P, Bhattacharyya R. Emerging role and clinical applications of circular RNAs in human diseases. Funct Integr Genomics 2025; 25:77. [PMID: 40148685 DOI: 10.1007/s10142-025-01575-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/01/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025]
Abstract
Circular RNAs (circRNAs) are a large family of non-coding RNAs characterized by a single-stranded, covalently closed structure, predominantly synthesized through a back-splicing mechanism. While thousands of circRNAs have been identified, only a few have been functionally characterized. Although circRNAs are less abundant than other RNA types, they exhibit exceptional stability due to their covalently closed structure and demonstrate high cell and tissue specificity. CircRNAs play a critical role in maintaining cellular homeostasis by influencing gene transcription, translation, and post-translation processes, modulating the immune system, and interacting with mRNA, miRNA, and proteins. Abnormal circRNA expression has been associated with a wide range of human diseases and various infections. Due to their remarkable stability in body fluids and tissues, emerging research suggests that circRNAs could serve as diagnostic and therapeutic biomarkers for these diseases. This review focuses on the emerging role of circRNAs in various human diseases, exploring their biogenesis, molecular functions, and potential clinical applications as diagnostic and therapeutic biomarkers with current evidence, challenges, and future perspectives. The key theme highlights the significance of circRNAs in regulating gene expression, their involvement in diseases like cancer, neurodegenerative disorders, cardiovascular diseases, and diabetes, and their potential use in translational medicine for developing novel therapeutic strategies. We also discuss recent clinical trials involving circRNAs. Thus, this review is important for both basic researchers and clinical scientists, as it provides updated insights into the role of circRNAs in human diseases, aiding further exploration and advancements in the field.
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Affiliation(s)
- Subhayan Sur
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, 411033, India.
| | - Jayanta K Pal
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, 411033, India.
| | - Soumya Shekhar
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, 411033, India
| | - Palak Bafna
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, 411033, India
| | - Riddhiman Bhattacharyya
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, 411033, India
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Yu H, Tang J, Dong L, Tang M, Arif A, Zhang T, Zhang G, Xie K, Zhao Z, Chen X, Dai G. CircNIPBLL modulates the inflammatory response against Eimeria tenella infection via sponging gga-miR-2954. Int J Biol Macromol 2025; 297:139901. [PMID: 39818375 DOI: 10.1016/j.ijbiomac.2025.139901] [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: 09/13/2024] [Revised: 12/31/2024] [Accepted: 01/13/2025] [Indexed: 01/18/2025]
Abstract
Coccidiosis, a parasitic disease caused by Eimeria protozoa that parasitizes intestinal tissues of chicken, poses a challenge to the development of the poultry industry. circRNAs are a class of circular RNA macromolecules crucial in the immune response to pathogens. Previous studies have shown that gga-miR-2954 inhibits the inflammatory response to Eimeria tenella (E. tenella) infection. In this study, we screened the key circRNA (circNIPBLL) regulating gga-miR-2954 using a co-expression network. The RNase R and Actinomycin D assays showed that the circular structure of the circNIPBLL was stable. Besides, the circNIPBLL expression was mainly distributed in the cytoplasm but did not have coding capacity. Overexpression of circNIPBLL significantly promoted the production of the IL-6, IL-1β, TNF-α, and IL-8 in sporozoite-stimulated DF-1 cells, whereas circNIPBLL knockdown significantly inhibited these effects. Moreover, circNIPBLL induced apoptosis of DF-1 cells stimulated by sporozoites. Mechanistically, circNIPBLL functioned as a sponge for gga-miR-2954, and overexpression of circNIPBLL rescued the effect of gga-miR-2954 mimic on the inflammatory response of DF-1 cells stimulated with sporozoites. Taken together, this study suggested that circNIPBLL modulated the inflammatory response against E. tenella infection by sponging gga-miR-2954, which may provide novel insights into the immune mechanisms of chicken resistance to E. tenella.
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Affiliation(s)
- Hailiang Yu
- College of Animal Science and Technology, Anhui Agricultural University, Heifei, China; Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-Breeding, Anhui Agricultural University, Hefei, China
| | - Jianqiang Tang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Liyue Dong
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Meihui Tang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - AreeJ Arif
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Tao Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Genxi Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Kaizhou Xie
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Zhenhua Zhao
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, China
| | - Xingyong Chen
- College of Animal Science and Technology, Anhui Agricultural University, Heifei, China; Anhui Province Key Laboratory of Local Livestock and Poultry Genetic Resource Conservation and Bio-Breeding, Anhui Agricultural University, Hefei, China.
| | - Guojun Dai
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.
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Zhou H, Zheng Z, Fan C, Zhou Z. Mechanisms and strategies of immunosenescence effects on non-small cell lung cancer (NSCLC) treatment: A comprehensive analysis and future directions. Semin Cancer Biol 2025; 109:44-66. [PMID: 39793777 DOI: 10.1016/j.semcancer.2025.01.001] [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: 09/20/2024] [Revised: 12/29/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025]
Abstract
Non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer, remains a leading cause of cancer-related mortality worldwide, particularly among elderly individuals. The phenomenon of immunosenescence, characterized by the progressive decline in immune cell functionality with aging, plays a pivotal role in NSCLC progression and contributes to the diminished efficacy of therapeutic interventions in older patients. Immunosenescence manifests through impaired immune surveillance, reduced cytotoxic responses, and increased chronic inflammation, collectively fostering a pro-tumorigenic microenvironment. This review provides a comprehensive analysis of the molecular, cellular, and genetic mechanisms of immunosenescence and its impact on immune surveillance and the tumor microenvironment (TME) in NSCLC. We explore how aging affects various immune cells, including T cells, B cells, NK cells, and macrophages, and how these changes compromise the immune system's ability to detect and eliminate tumor cells. Furthermore, we address the challenges posed by immunosenescence to current therapeutic strategies, particularly immunotherapy, which faces significant hurdles in elderly patients due to immune dysfunction. The review highlights emerging technologies, such as single-cell sequencing and CRISPR-Cas9, which offer new insights into immunosenescence and its potential as a therapeutic target. Finally, we outline future research directions, including strategies for rejuvenating the aging immune system and optimizing immunotherapy for older NSCLC patients, with the goal of improving treatment efficacy and survival outcomes. These efforts hold promise for the development of more effective, personalized therapies for elderly patients with NSCLC.
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Affiliation(s)
- Huatao Zhou
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha 410011, China
| | - Zilong Zheng
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha 410011, China
| | - Chengming Fan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha 410011, China.
| | - Zijing Zhou
- Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha 410011, China.
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Pu J, Yan X, Zhang H. The potential of circular RNAs as biomarkers and therapeutic targets for gastric cancer: A comprehensive review. J Adv Res 2024:S2090-1232(24)00551-4. [PMID: 39617262 DOI: 10.1016/j.jare.2024.11.032] [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: 07/11/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a global health concern, contributing significantly to cancer-related mortality rates. Early detection is vital for improving patient outcomes. Recently, circular RNAs (circRNAs) have emerged as crucial players in the development and progression of various cancers, including GC. AIM This comprehensive review underscores the promising potential of circRNAs as innovative biomarkers for the early diagnosis of GC, as well as their possible utility as therapeutic targets for this life-threatening disease. Specifically, the review focuses on recent findings, mechanistic insights, and clinical applications of circRNAs in GC. KEY SCIENTIFIC CONCEPTS OF REVIEW Dysregulation of circRNAs has been consistently observed in GC tissues, offering potential diagnostic value due to their stability in bodily fluids such as blood and urine. For instance, circPTPN22 and hsa_circ_000200. Furthermore, the expression levels of circRNAs such as circCUL2, hsa_circ_0000705 and circSHKBP1 have shown strong associations with critical clinical features of GC, including diagnosis, prognosis, tumor size, lymph node metastasis, tumor-node-metastasis (TNM) stage, and treatment response. Additionally, circRNAs such as circBGN, circLMO7, and circMAP7D1 have shown interactions with specific microRNAs (miRNAs), proteins, and other molecules that play key roles in development and progression of GC. This further highlighting their potential as therapeutic targets. Despite their potential, several challenges need to be addressed to effectively apply circRNAs as GC biomarkers. These include standardizing detection methods, establishing cutoff values for diagnostic accuracy, and validating findings in larger patient cohorts. Moreover, the functional mechanisms by which circRNAs contribute to GC pathogenesis and therapeutic resistance warrant further investigation. Advances in circRNAs research could provide valuable insights into the early detection and targeted treatment of GC, ultimately improving patient outcomes.
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Affiliation(s)
- Junlin Pu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiuli Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Majidpour M, Sargazi S, Ghasemi M, Sabeti Akbar-Abad M, Sarhadi M, Saravani R. LncRNA MEG3, GAS5, and HOTTIP Polymorphisms Association with Risk of Polycystic Ovary Syndrome: A Case-Control Study and Computational Analyses. Biochem Genet 2024:10.1007/s10528-024-10977-1. [PMID: 39613922 DOI: 10.1007/s10528-024-10977-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 11/12/2024] [Indexed: 12/01/2024]
Abstract
As a multifactorial and endocrine disease, polycystic ovary syndrome (PCOS) affects approximately 5-20% of women worldwide. Recently, long noncoding RNAs (lncRNAs) have emerged as potent predictors of a particular phenotype in PCOS. Our preliminary study examines the link between polymorphisms in lncRNAs MEG3, HOTTIP, and GAS5 and the risk of PCOS. The present study included 200 women with PCOS and 200 healthy women. The studied variations were genotyped by applying the PCR-RFLP and the tetra-ARMS-PCR reaction) techniques. The effect of variation in lncRNA on miRNA:lncRNA interactions, lncRNA-RNA interaction network, and the impact of the variations on the splicing site were predicted using different computational databases. The codominant heterozygous (TC vs. TT) model, the dominant (TC + CC vs. TT) model, the overdominant (TT + CC vs. TC) model, the C allele of rs2023843, and the C allele of rs55829688 had a protective role against PCOS. The A allele of rs4081134 and G allele of rs7158663 of the MEG3 conferred an increased risk of PCOS by 1.37 and 1.44 folds, respectively. The interaction analysis revealed that TC/GG/AA/TC and TC/GG/GA/TC strongly decreased the risk of PCOS by 94 and 92%, respectively. Interestingly, MEG3 and HOTTIP variants can create or disrupt binding sites for several splicing factors. In our population, MEG3 rs4081134 and rs7158663, GAS5 rs55829688, and HOTTIP rs2023843 polymorphisms were associated with PCOS risk. Replication studies on larger sample sizes must be conducted to confirm these findings and investigate other potential causative factors involved in the pathophysiology of PCOS.
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Affiliation(s)
- Mahdi Majidpour
- Clinical Immunology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Saman Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Marzieh Ghasemi
- Pregnancy Health Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
- Moloud Infertility Center, Ali Ibn Abitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mahboobeh Sabeti Akbar-Abad
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohammad Sarhadi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Ramin Saravani
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
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9
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Jia Y, Yuan X, Feng L, Xu Q, Fang X, Xiao D, Li Q, Wang Y, Ye L, Wang P, Ao X, Wang J. m 6A-modified circCacna1c regulates necroptosis and ischemic myocardial injury by inhibiting Hnrnpf entry into the nucleus. Cell Mol Biol Lett 2024; 29:140. [PMID: 39533214 PMCID: PMC11558890 DOI: 10.1186/s11658-024-00649-8] [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: 07/08/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) are differentially expressed in various cardiovascular diseases, including myocardial infarction (MI) injury. However, their functional role in necroptosis-induced loss of cardiomyocytes remains unclear. We identified a cardiac necroptosis-associated circRNA transcribed from the Cacna1c gene (circCacna1c) to investigate the involvement of circRNAs in cardiomyocyte necroptosis. METHODS To investigate the role of circCacna1c during oxidative stress, H9c2 cells and neonatal rat cardiomyocytes were treated with hydrogen peroxide (H2O2) to induce reactive oxygen species (ROS)-induced cardiomyocyte death. The N6-methyladenosine (m6A) modification level of circCacna1c was determined by methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP-qPCR) analysis. Additionally, an RNA pull-down assay was performed to identify interacting proteins of circCacna1c in cardiomyocytes, and the regulatory role of circCacna1c in target protein expression was tested using a western blotting assay. Furthermore, the MI mouse model was constructed to analyze the effect of circCacna1c on heart function and cardiomyocyte necroptosis. RESULTS The expression of circCacna1c was found to be reduced in cardiomyocytes exposed to oxidative stress and in mouse hearts injured by MI. Overexpression of circCacna1c inhibited necroptosis of cardiomyocytes induced by hydrogen peroxide and MI injury, resulting in a significant reduction in myocardial infarction size and improved cardiac function. Mechanistically, circCacna1c directly interacts with heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in the cytoplasm, preventing its nuclear translocation and leading to reduced Hnrnpf levels within the nucleus. This subsequently suppresses Hnrnpf-dependent receptor-interacting protein kinase 1 (RIPK1) expression. Furthermore, fat mass and obesity-associated protein (FTO) mediates demethylation of m6A modification on circCacna1c during necrosis and facilitates degradation of circCacna1c. CONCLUSION Our study demonstrates that circCacna1c can improve cardiac function following MI-induced heart injury by inhibiting the Hnrnpf/RIPK1-mediated cardiomyocyte necroptosis. Therefore, the FTO/circCacna1c/Hnrnpf/RIPK1 axis holds great potential as an effective target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.
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Affiliation(s)
- Yi Jia
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiaosu Yuan
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Luxin Feng
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266003, China
| | - Qingling Xu
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xinyu Fang
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Dandan Xiao
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Qi Li
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
- School of Nursing, Qingdao University, Qingdao, 266071, China
| | - Yu Wang
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Lin Ye
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Peiyan Wang
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiang Ao
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
| | - Jianxun Wang
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
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Wang B, Liu W, Zhang M, Li Y, Tang H, Wang Y, Song C, Song B, Tan B. Circ_0001947 encapsulated by small extracellular vesicles promotes gastric cancer progression and anti-PD-1 resistance by modulating CD8 + T cell exhaustion. J Nanobiotechnology 2024; 22:563. [PMID: 39272146 PMCID: PMC11401313 DOI: 10.1186/s12951-024-02826-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 08/31/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND While small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) have been emerged as significant players in cancer, the function and underlying mechanism of sEVs-derived circRNAs in anti-cancer immunity remain unclear. METHODS Gastric cancer (GC)-derived circRNAs were identified using RNA-seq data from GEO datasets and quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA immunoprecipitation, dual-luciferase assay, and bioinformatics analysis were performed to investigate the regulatory axis. Transwell assay, wound healing assay, cell counting kit-8 (CCK-8) assay, and xenograft models were used to evaluate its role in GC progression in vivo and in vitro. The delivery of specific circRNAs into sEVs were verified through electron microscopy, nanoparticle tracking analysis (NTA) and fuorescence in situ hybridization (FISH). Flow cytometric analysis and immunohistochemical staining were conducted to find out how specific circRNAs mediated CD8+ T cell exhaustion and resistant to anti-programmed cell death 1 (PD-1) therapy. RESULTS We identified that circ_0001947, packaged by GC-derived sEVs, was obviously elevated in GC and was associated with poor clinical outcome. High circ0001947 level augmented the proliferation, migration, and invasion of GC cells. Mechanistically, circ0001947 sponged miR-661 and miR-671-5p to promote the expression of CD39, which further facilitated CD8+ T cell exhaustion and immune resistance. Conversely, blocking circ_0001947 attenuated CD8+ T cell exhaustion and increased the response to anti-PD-1 therapy. CONCLUSIONS Our study manifested the therapeutic potential of targeting sEVs-transmitted circ_0001947 to prohibit CD8+ T cell exhaustion and immune resistance in GC.
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Affiliation(s)
- Bingyu Wang
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
| | - Wenbo Liu
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
| | - Mingming Zhang
- Hebei Key Laboratory of Metabolic Disease, Shijiazhuang, 050011, China
| | - Yong Li
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
| | - Hongyue Tang
- Hebei Key Laboratory of Metabolic Disease, Shijiazhuang, 050011, China
| | - Yingying Wang
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
| | - Chao Song
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
| | - Buyun Song
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
| | - Bibo Tan
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China.
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11
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Hama Faraj GS, Hussen BM, Abdullah SR, Fatih Rasul M, Hajiesmaeili Y, Baniahmad A, Taheri M. Advanced approaches of the use of circRNAs as a replacement for cancer therapy. Noncoding RNA Res 2024; 9:811-830. [PMID: 38590433 PMCID: PMC10999493 DOI: 10.1016/j.ncrna.2024.03.012] [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: 12/14/2023] [Revised: 03/18/2024] [Accepted: 03/29/2024] [Indexed: 04/10/2024] Open
Abstract
Cancer is a broad name for a group of diseases in which abnormal cells grow out of control and are characterized by their complexity and recurrence. Although there has been progress in cancer therapy with the entry of precision medicine and immunotherapy, cancer incidence rates have increased globally. Non-coding RNAs in the form of circular RNAs (circRNAs) play crucial roles in the pathogenesis, clinical diagnosis, and therapy of different diseases, including cancer. According to recent studies, circRNAs appear to serve as accurate indicators and therapeutic targets for cancer treatment. However, circRNAs are promising candidates for cutting-edge cancer therapy because of their distinctive circular structure, stability, and wide range of capabilities; many challenges persist that decrease the applications of circRNA-based cancer therapeutics. Here, we explore the roles of circRNAs as a replacement for cancer therapy, highlight the main challenges facing circRNA-based cancer therapies, and discuss the key strategies to overcome these challenges to improve advanced innovative therapies based on circRNAs with long-term health effects.
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Affiliation(s)
- Goran Sedeeq Hama Faraj
- Department of Medical Laboratory Science, Komar University of Science and Technology, Sulaymaniyah, 46001, Iraq
| | - Bashdar Mahmud Hussen
- Department of Biomedical Sciences, College of Science, Cihan University-Erbil, Erbil, Kurdistan Region, 44001, Iraq
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, 44001, Iraq
| | - Snur Rasool Abdullah
- Medical Laboratory Science, Lebanese French University, Erbil, Kurdistan Region, 44001, Iraq
| | - Mohammed Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | | | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Wang JB, Lin TX, Fan DH, Gao YX, Chen YJ, Wu YK, Xu KX, Qiu QZ, Li P, Xie JW, Lin JX, Chen QY, Cao LL, Huang CM, Zheng CH. CircUBA2 promotes the cancer stem cell-like properties of gastric cancer through upregulating STC1 via sponging miR-144-5p. Cancer Cell Int 2024; 24:276. [PMID: 39103836 PMCID: PMC11302268 DOI: 10.1186/s12935-024-03423-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 06/27/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are critical factors that limit the effectiveness of gastric cancer (GC) therapy. Circular RNAs (circRNAs) are confirmed as important regulators of many cancers. However, their role in regulating CSC-like properties of GC remains largely unknown. Our study aimed to investigate the role of circUBA2 in CSC maintenance and the underlying mechanisms. METHODS We identified circUBA2 as an upregulated gene using circRNA microarray analysis. qRT-PCR was used to examine the circUBA2 levels in normal and GC tissues. In vitro and in vivo functional assays were performed to validate the role of circUBA2 in proliferation, migration, metastasis and CSC-like properties of GC cell. The relationship between circUBA2, miR-144-5p and STC1 was characterised using bioinformatics analysis, a dual fluorescence reporter system, FISH, and RIP assays. RESULTS CircUBA2 expression was significantly increased in GC tissues, and patients with GC with high circUBA2 expression had a poor prognosis. CircUBA2 enhances CSC-like properties of GC, thereby promoting cell proliferation, migration, and metastasis. Mechanistically, circUBA2 promoted GC malignancy and CSC-like properties by acting as a sponge for miR-144-5p to upregulate STC1 expression and further activate the IL-6/JAK2/STAT3 signaling pathway. More importantly, the ability of circUBA2 to enhance CSC-like properties was inhibited by tocilizumab, a humanised Interleukin-6 receptor (IL-6R) antibody. Thus, circUBA2 knockdown and tocilizumab synergistically inhibited CSC-like properties. CONCLUSIONS Our study demonstrated the critical role of circUBA2 in regulating CSC-like properties in GC. CircUBA2 may be a promising prognostic biomarker for GC.
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Affiliation(s)
- Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Tong-Xing Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Deng-Hui Fan
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - You-Xin Gao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Yu-Jing Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Yu-Kai Wu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Kai-Xiang Xu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Qing-Zhu Qiu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China.
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China.
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China.
- Fujian Province Minimally Invasive Medical Center, Fuzhou, China.
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
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Yang TN, Xiao RW, Su F, Dai HY, Zhao D, Guo CH, Zhu KL, Jiang N, Guan QL, Hou XM. CircVDAC3 sequesters microRNA-592 and elevates EIF4E3 expression to inhibit the progression of gastric cancer. Transl Oncol 2024; 45:101972. [PMID: 38705053 PMCID: PMC11087954 DOI: 10.1016/j.tranon.2024.101972] [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: 01/26/2024] [Revised: 03/30/2024] [Accepted: 04/18/2024] [Indexed: 05/07/2024] Open
Abstract
BACKGROUND Accumulating evidence has shown that circular RNAs (circRNAs) are involved in gastric cancer (GC) tumorigenesis. However, specific functional circRNAs in GC remain to be discovered, and their underlying mechanisms remain to be elucidated. METHODS CircRNAs that were differentially expressed between GC tissues and controls were analyzed using a circRNA microarray dataset. The expression of circVDAC3 in GC was determined using quantitative real-time PCR (qRT-PCR), and the structural features of circVDAC3 were validated. Cell function assays and animal experiments were conducted to explore the effects of circVDAC3 on GC. Finally, bioinformatics analysis, fluorescent in situ hybridization, and dual luciferase assays were used to analyze the downstream mechanisms of circVDAC3. RESULTS Our results showed that circVDAC3 was downregulated in GC and inhibited the proliferation and metastasis of GC cells. Mechanistically, circVDAC3 acts as a competing endogenous RNA (ceRNA) of miR-592 and deregulates the repression of EIF4E3 by miR-592. EIF4E3 is downregulated in GC and overexpression of miR-592 or knockdown of EIF4E3 in circVDAC3-overexpressing cells weakens the anticancer effect of circVDAC3. CONCLUSION Our study provides evidence that circVDAC3 affects the growth and metastasis of GC cells via the circVDAC3/miR-592/EIF4E3 axis. Our findings offer valuable insights into the mechanisms underlying GC tumorigenesis and suggest novel therapeutic strategies.
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Affiliation(s)
- Tian-Ning Yang
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, PR China; Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China
| | - Ruo-Wen Xiao
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China
| | - Fei Su
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, PR China; Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China
| | - Huan-Yu Dai
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China
| | - Da Zhao
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China
| | - Chen-Hao Guo
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, PR China
| | - Kai-Li Zhu
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, PR China
| | - Nan Jiang
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, PR China
| | - Quan-Lin Guan
- Department of Oncology Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China.
| | - Xiao-Ming Hou
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu, PR China.
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14
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Tang X, Liu Z, Liu H, Zhang H, Tian Y, Xia S, Sun Z, Luo G. Construction of lncRNA- and circRNA-associated ceRNA networks in the prostatic urethra of rats after simulating transurethral laser prostatectomy (TULP). Mol Cell Biochem 2024; 479:1363-1377. [PMID: 37410211 PMCID: PMC11224087 DOI: 10.1007/s11010-023-04804-1] [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: 04/05/2023] [Accepted: 06/27/2023] [Indexed: 07/07/2023]
Abstract
Non-coding RNA appears to be involved in wound repair. Competing endogenous RNA (ceRNA) appears to be an important post-transcriptional mechanism, it means that long noncoding RNA (lncRNA) or circular RNA (circRNA) acts as a microRNA (miRNA) sponge to further regulate mRNA. However, ceRNA network related to wound repair after prostatectomy has yet been constructed. TULP is the main surgical method of prostatectomy, but there have been no reports of TULP rat models in the past. We simulated TULP on rats, and observed the whole process of wound injury and repair after operation through pathological examination of wound tissue. Next, we discovered 732 differentially expressed lncRNAs (DElncRNAs), 47 differentially expressed circRNAs (DEcircRNAs), 17 differentially expressed miRNAs (DEmiRNAs), and 1892 differentially expressed mRNAs (DEmRNAs) related to wound repair after TULP through full transcriptome microarray and bioinformatics methods, and confirmed the reliability of transcriptome data by quantitative Reverse Transcription PCR (qRT-PCR), and immunohistochemistry. Then, we constructed the lncRNA- and circRNA-associated ceRNA regulatory networks related to wound repair after TULP in rats. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that molecules in these networks were mainly involved in inflammatory infiltration, cell differentiation, and intercellular interactions and involved signal pathways such as the PI3K-Akt signaling pathway. Thus, this study successfully established the TULP model in rats, revealed potentially important biomarkers and ceRNA networks after prostatectomy in rats, and provided theoretical support for the repair of post-prostatectomy wound.
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Affiliation(s)
- XiaoHu Tang
- Medical College, Guizhou University, Guiyang, 550025, Guizhou Province, China
- Department of Urology Surgery, Guizhou Province People's Hospital, Guiyang, 550002, Guizhou Province, China
| | - ZhiYan Liu
- School of Clinical Medicine, Guizhou Medical University, Guiyang, 550025, Guizhou Province, China
| | - Hao Liu
- Department of Urology Surgery, Guizhou Province People's Hospital, Guiyang, 550002, Guizhou Province, China
| | - Heng Zhang
- Department of Urology Surgery, Guizhou Province People's Hospital, Guiyang, 550002, Guizhou Province, China
| | - Ye Tian
- Department of Urology Surgery, Guizhou Province People's Hospital, Guiyang, 550002, Guizhou Province, China
| | - ShuJie Xia
- Department of Urology Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, 201620, China
| | - ZhaoLin Sun
- Medical College, Guizhou University, Guiyang, 550025, Guizhou Province, China
| | - GuangHeng Luo
- Department of Urology Surgery, Guizhou Province People's Hospital, Guiyang, 550002, Guizhou Province, China.
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15
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Li X, Lei Y. Construction of a prognostic risk model for Stomach adenocarcinoma based on endoplasmic reticulum stress genes. Wien Klin Wochenschr 2024; 136:319-330. [PMID: 37993598 DOI: 10.1007/s00508-023-02306-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 10/21/2023] [Indexed: 11/24/2023]
Abstract
OBJECTIVE Stomach adenocarcinoma (STAD) is caused by malignant transformation of gastric glandular cells and is characterized by a high incidence rate and a poor prognosis. This study was designed to establish a prognostic risk model for STAD according to endoplasmic reticulum (ER) stress feature genes as cancer cells are susceptible to ER stress. METHODS The TCGA-STAD dataset was downloaded to screen differentially expressed genes (DEGs). By intersecting DEGs with ER stress genes retrieved from GeneCards, ER stress-related DEGs in STAD were obtained. Kmeans cluster analysis of STAD subtypes and Single sample gene set enrichment analysis (ssGSEA) analysis of immune infiltration were performed. Cox regression analysis was utilized to construct a risk prognostic model. Samples were split into high-risk and low-risk groups according to the median risk score. Survival analysis and Receiver Operating Characteristic (ROC) curves were conducted to assess the validity of the model. Gene set enrichment analysis (GSEA) was performed to investigate differential pathways in the two risk groups. Cox analysis was performed to verify the independence of the risk model, and a nomogram was generated. RESULTS A total of 162 ER stress-related DEGs in STAD were identified by bioinformatics analysis. Kmeans cluster analysis showed that STAD was divided into 3 subgroups. The ssGSEA showed that the levels of immune infiltration in subgroups 2 and 3 were significantly higher than subgroup 1. With 12 prognostic genes (MATN3, ATP2A1, NOX4, AQP11, HP, CAV1, STARD3, FKBP10, EGF, F2, SERPINE1, CNGA3) selected from ER stress-related DEGs using Cox regression analysis, we then constructed a prognostic model. Kaplan-Meier (K‑M) survival curves and ROC curves showed good prediction performance of the model. Significant enrichment of genes in the high-risk group was found in extracellular matrix (ECM) receptor interaction. Cox regression analysis combined with clinical factors showed that the risk model could be used as an independent prognostic factor. The prediction correction curve showed that the good prediction ability of the nomogram. CONCLUSION The STAD could be divided into three subgroups, and the 12-gene model constructed by ER stress signatures had a good prognostic performance for STAD patients.
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Affiliation(s)
- Xi Li
- Department of General Surgery, Zigong Fourth People's Hospital, No. 19 Tanmulin Street, Ziliujing District, 643000, Zigong City, Sichuan Province, China
| | - Yuehua Lei
- Department of General Surgery, Zigong Fourth People's Hospital, No. 19 Tanmulin Street, Ziliujing District, 643000, Zigong City, Sichuan Province, China.
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16
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Mao Y, Su X, Guo Q, Yao X, Zhao Q, Guo Y, Wang Y, Li X, Lu Y. Long non-coding RNA LINC00930 targeting miR-6792-3p/ZBTB16 regulates the proliferation and EMT of pancreatic cancer. BMC Cancer 2024; 24:638. [PMID: 38789960 PMCID: PMC11127394 DOI: 10.1186/s12885-024-12365-9] [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: 07/06/2023] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Emerging evidence suggests the dysregulation of long non-coding RNAs (lncRNAs) involved in pancreatic cancer (PC). However, the function of LINC00930 in PC has not been elaborated. In this study, we found that LINC00930 was significantly down-regulated in PC cell lines and tissues, and associated with tumor size, lymphatic metastasis, TNM stage and poor prognosis. According to the bioinformatics database, the downregulation of LINC00930 was a common event in PC associated with prognosis and EMT. Overexpression of LINC00930 inhibited the aggressive cancer phenotypes including proliferation, metastasis and epithelial-mesenchymal transition (EMT) of PC in vitro and in vivo. Bioinformatics and dual-luciferase reporter assay indicated that miR-6792-3p could directly bind to LINC00930. Additionally, the Zinc finger and BTB domain containing 16 (ZBTB16) was significantly declined in PC, which was predicted to be the downstream gene of miR-6792-3p. MiR-6792-3p mimic rescued the decreased proliferation, metastasis and EMT caused by ZBTB16 in PC cells. The LINC00930/miR-6792-3p/ZBTB16 axis was associated with the malignant progression and process of PC. The relative expression of LINC00930 was negatively correlated with the expression of miR-6792-3p and was closely linked with ZBTB16 levels in PC. LINC00930 might serve as a potential prognostic biomarker and therapeutic target for PC.
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Affiliation(s)
- Yingqing Mao
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China
- The Sixth People's Hospital of Nantong, Nantong, 226001, P. R. China
| | - Xian Su
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China
- Department of Hepatobiliary Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200000, P. R. China
| | - Qingsong Guo
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China
| | - Xihao Yao
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China
| | - Qun Zhao
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China
| | - Yibing Guo
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China
| | - Yao Wang
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China
| | - Xiaohong Li
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China.
| | - Yuhua Lu
- Research Center of Clinical Medical, Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, P. R. China.
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17
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Jia S, Yu L, Wang L, Peng L. The functional significance of circRNA/miRNA/mRNA interactions as a regulatory network in lung cancer biology. Int J Biochem Cell Biol 2024; 169:106548. [PMID: 38360264 DOI: 10.1016/j.biocel.2024.106548] [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: 09/15/2023] [Revised: 01/22/2024] [Accepted: 02/02/2024] [Indexed: 02/17/2024]
Abstract
Lung cancer, the leading cause of cancer-related deaths, presents significant challenges to patients due to its poor prognosis. Recent research has increasingly implicated circular RNAs in the development and progression of lung cancer. These circular RNAs have been found to impact various aspects of tumor behavior, including proliferation, metastasis, cell cycle regulation, apoptosis, cancer stem cells, therapy response, and the tumor microenvironment. One of the key mechanisms by which circular RNAs exert their influence is through their ability to act as miRNA sponges, sequestering microRNAs and preventing them from targeting other RNA molecules. Accumulating evidence suggests that circular RNAs can function as competing endogenous RNAs, affecting the expression of target mRNAs by sequestering microRNAs. Dysregulation of competing endogenous RNAs networks involving circular RNAs, microRNAs, and mRNAs leads to the aberrant expression of oncogenes and tumor suppressors involved in lung cancer pathogenesis. Understanding the dynamic interplay and molecular mechanisms among circular RNAs, microRNAs, and mRNAs holds great promise for advancing early diagnosis, personalized therapeutic interventions, and improved patient outcomes in lung cancer. Therefore, this study aims to provide an in-depth exploration of the executive roles of circular RNAs/microRNAs/ mRNAs interactions in lung cancer pathogenesis and their potential utility for diagnosing lung cancer, predicting patient prognosis, and guiding targeted therapies. By offering a comprehensive overview of the dysregulation of the axes as driving factors in lung cancer, we aim to pave the way for their translation into clinical practice in the future.
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Affiliation(s)
- Shengnan Jia
- Department of Respiratory Medicine, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, China; Department of Hepatopancreatobiliary Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Ling Yu
- Department of Pharmacy, The Second Hospital of Jilin University, Changchun 130041, China
| | - Lihui Wang
- Department of Respiratory Medicine, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, China.
| | - Liping Peng
- Department of Respiratory Medicine, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, China.
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Cao SQ, Xue ST, Li WJ, Hu GS, Wu ZG, Zheng JC, Zhang SL, Lin X, Chen C, Liu W, Zheng B. CircHIPK3 regulates fatty acid metabolism through miR-637/FASN axis to promote esophageal squamous cell carcinoma. Cell Death Discov 2024; 10:110. [PMID: 38431720 PMCID: PMC10908791 DOI: 10.1038/s41420-024-01881-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 03/05/2024] Open
Abstract
The oncogenic role of circRNA in cancers including esophageal cancer (EC) has been well studied. However, whether and how circRNAs are involved in cancer cell metabolic processes remains largely unknown. Here, we reported that circRNA, circHIPK3, is highly expressed in ESCC cell lines and tissues. Knockdown of circHIPK3 significantly restrained cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, circHIPK3 was found to act as a ceRNA by sponging miR-637 to regulate FASN expression and fatty acid metabolism in ESCC cells. Anti-sense oligonucleotide (ASO) targeting circHIPK3 substantially inhibited ESCC both in vitro and in vivo. Therefore, these results uncover a modulatory axis constituting of circHIPK3/miR-637/FASN may be a potential biomarker and therapeutic target for ESCC in the clinic.
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Affiliation(s)
- Shi-Qiang Cao
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Song-Tao Xue
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Wen-Juan Li
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Guo-Sheng Hu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China
- Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China
| | - Zhi-Gang Wu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Jian-Cong Zheng
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Shu-Liang Zhang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Xiao Lin
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Chun Chen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China.
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China.
| | - Wen Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
- Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
| | - Bin Zheng
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China.
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, No. 29 Xinquan Road, Fuzhou, Fujian, 350001, China.
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Wu K, Yu X, Wang Y, Li X, An Y, Zhao Z, Ma L. MALAT1 DEREPRESSES MIR-433-3P-MEDIATED RPTOR SUPPRESSION TO IMPAIR AUTOPHAGY AND DRIVE PYROPTOSIS IN ENDOTOXEMIA. Shock 2024; 61:477-489. [PMID: 38010109 DOI: 10.1097/shk.0000000000002249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
ABSTRACT Objective: Autophagy elevation in endotoxemia plays a protective role by negatively regulating the pyroptosis of vascular endothelial cells, but the molecular mechanisms are still poorly understood. The present study aimed to identify the mechanism underlying autophagy and pyroptosis in endotoxemia. Methods: Bioinformatics analysis and whole-gene transcriptome sequencing prediction were used to identify the endotoxemia-related lncRNA-miRNA-mRNA axis of interest. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) to mimic the inflammatory environment encountered in endotoxemia. Autophagy and pyroptosis of LPS-treated HUVECs were assessed in response to the knockdown of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1)/miR-433-3p (miRNA-433-3p)/RPTOR (regulatory-associated protein of mTOR). The binding affinity of MALAT1, miR-433-3p, and RPTOR was detected by RNA pull-down and luciferase activity assays. The endothelial cell-specific RPTOR knockout mice were developed and rendered septic using LPS induction to verify the role of RPTOR in autophagy, pyroptosis, and inflammatory response in vivo . Results: The in vitro experiments indicated that LPS could stimulate HUVECs to highly express RPTOR, and its knockdown enhanced cellular autophagy and restricted pyroptosis to curb inflammatory responses. Mechanically, MALAT1 is competitively bound to miR-433-3p to release RPTOR expression, thereby promoting pyroptosis and aggravating endotoxemia. In vivo experiments further confirmed that the knockdown of RPTOR activated autophagy and curtailed pyroptosis in septic mice. Conclusion: MALAT1 is highly expressed in endotoxemia. MALAT1 promotes RPTOR expression by competitively absorbing miR-433-3p, inhibits LPS-activated HUVEC cell autophagy, promotes cell death, enhances LPS-induced inflammatory activation of vascular endothelial cells, and ultimately promotes the progression of endotoxemia.
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Affiliation(s)
- Kun Wu
- Department of Gastrointestinal Surgery, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huaian, People's Republic China
| | - Xiangyou Yu
- Department of Critical Care Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic China
| | - Yi Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic China
| | - Xiang Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic China
| | - Yuanyuan An
- Department of VIP Internal Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, People's Republic China
| | - Zuyi Zhao
- Department of VIP Internal Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, People's Republic China
| | - Long Ma
- Department of Critical Care Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic China
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Whittle BJ, Izuogu OG, Lowes H, Deen D, Pyle A, Coxhead J, Lawson RA, Yarnall AJ, Jackson MS, Santibanez-Koref M, Hudson G. Early-stage idiopathic Parkinson's disease is associated with reduced circular RNA expression. NPJ Parkinsons Dis 2024; 10:25. [PMID: 38245550 PMCID: PMC10799891 DOI: 10.1038/s41531-024-00636-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 01/08/2024] [Indexed: 01/22/2024] Open
Abstract
Neurodegeneration in Parkinson's disease (PD) precedes diagnosis by years. Early neurodegeneration may be reflected in RNA levels and measurable as a biomarker. Here, we present the largest quantification of whole blood linear and circular RNAs (circRNA) in early-stage idiopathic PD, using RNA sequencing data from two cohorts (PPMI = 259 PD, 161 Controls; ICICLE-PD = 48 PD, 48 Controls). We identified a replicable increase in TMEM252 and LMNB1 gene expression in PD. We identified novel differences in the expression of circRNAs from ESYT2, BMS1P1 and CCDC9, and replicated trends of previously reported circRNAs. Overall, using circRNA as a diagnostic biomarker in PD did not show any clear improvement over linear RNA, minimising its potential clinical utility. More interestingly, we observed a general reduction in circRNA expression in both PD cohorts, accompanied by an increase in RNASEL expression. This imbalance implicates the activation of an innate antiviral immune response and suggests a previously unknown aspect of circRNA regulation in PD.
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Affiliation(s)
- Benjamin J Whittle
- Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Osagie G Izuogu
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK
| | - Hannah Lowes
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Dasha Deen
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Angela Pyle
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Jon Coxhead
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Rachael A Lawson
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Alison J Yarnall
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Michael S Jackson
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | | | - Gavin Hudson
- Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
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ZENG F, ZHAO J, TONG M, HE W, LI N, FAN Y, ZHU Y, ZHANG L, ZHANG H. CircRNA LDLR promotes proliferation and aerobic glycolysis of gastric cancer cells by targeting CHD1 with miR-449b-5p. Turk J Biol 2023; 48:46-58. [PMID: 38665782 PMCID: PMC11042865 DOI: 10.55730/1300-0152.2681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 02/27/2024] [Accepted: 12/07/2023] [Indexed: 04/28/2024] Open
Abstract
Background/aim Circular RNAs can serve as detection biomarkers and therapeutic targets for tumors. Our study aimed to elucidate the mechanisms associated with circRNA LDLR (circLDLR) in gastric cancer (GC) proliferation and aerobic glycolysis. Materials and methods Expression signatures of circLDLR, miR-449b-5p, and CHD1 were examined in GC samples using quantitative PCR. Proliferation ability of MKN-45 cells was assessed via CCK-8 and EdU assays, and cell apoptosis was measured by flow cytometry. Glucose uptake, lactate production, ATP/ADP ratios, and NAD+/NADH ratios in cell supernatants were quantified to evaluate aerobic glycolysis. Subcellular isolation assay, quantitative PCR, immunoblot analysis, RNA immunoprecipitation (RIP), and dual luciferase reporter assay were employed to investigate the relationship between genes. Results Expression of circLDLR and CHD1 was elevated, while miR-449b-5p expression decreased in GC. Functionally, overexpression of circLDLR enhanced proliferation and aerobic glycolysis and hampered apoptosis of MKN-45 cells. However, upregulation of miR-449b-5p or downregulation of CHD1 reversed these effects. CircLDLR acted as an miRNA spongeand regulated the expression of miR-449b-5p, thereby affecting CHD1 and accelerating GC malignant progression. Conclusion CircLDLR drives the proliferation and aerobic glycolysis of GC cells by targeting CHD1 with miR-449b-5p, which is an ideal potential target for early diagnosis and clinical treatment of GC.
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Affiliation(s)
- FanYe ZENG
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
| | - JunTao ZHAO
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
| | - MengTing TONG
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
| | - WenTing HE
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
| | - Nan LI
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
| | - YuXiang FAN
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
| | - YanHua ZHU
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
| | - LiPing ZHANG
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
| | - HongLiang ZHANG
- Department of Oncology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region,
China
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Cao S, Yin Y, Hu H, Hong S, He W, Lv W, Liu R, Li Y, Yu S, Xiao H. CircGLIS3 inhibits thyroid cancer invasion and metastasis through miR-146b-3p/AIF1L axis. Cell Oncol (Dordr) 2023; 46:1777-1789. [PMID: 37610691 DOI: 10.1007/s13402-023-00845-2] [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] [Accepted: 07/12/2023] [Indexed: 08/24/2023] Open
Abstract
PURPOSE Studies have shown that circRNA is involved in the occurrence and development of human cancers. However, it remains unclear that the contribution of circRNA in thyroid carcinoma and its role in the process of tumorigenesis. METHODS The expression profile of circRNA-miRNA-mRNA in thyroid carcinoma was detected by RNA sequencing and verified by qRT-PCR. The characteristics of circGLIS3 were verified by RNase R and actinomycin assays, subcellular fractionation, and fluorescence in situ hybridization. The functions of circGLIS3 and AIF1L were detected by wound healing, transwell, 3D culture and Western blot. RNA Immunoprecipitation (RIP), RNA pulldown and dual-luciferase reporter assays were used to verify the target genes of circGLIS3 and downstream miRNAs. Functional rescue experiments were performed by transfecting miRNA mimics or siRNA of target genes. Finally, metastatic mouse models were used to investigate circGLIS3 function in vivo. RESULTS In this study, we discovered a novel circRNA (has_circ_0007368, named as circGLIS3) by RNA sequencing. CircGLIS3 was down-regulated in thyroid carcinoma tissues and cells line, and was negatively associated with malignant clinical features of thyroid carcinoma. Functional studies found that circGLIS3 could inhibit the migration and invasion of thyroid carcinoma cells, and was related to the EMT process. Mechanistically, circGLIS3 can upregulate the expression of the AIF1L gene by acting as a miR-146b-3p sponge to inhibit the progression of thyroid carcinoma. CONCLUSION Our study identified circGLIS3 as a novel tumor suppressor in thyroid cancer, indicating the potential of circGLIS3 as a promising diagnostic and prognostic marker for thyroid cancer.
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Affiliation(s)
- Siting Cao
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Yali Yin
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Huijuan Hu
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Shubin Hong
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Weiman He
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Weiming Lv
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Rengyun Liu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanbing Li
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Shuang Yu
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - Haipeng Xiao
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
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Jian S, Kong D, Tian J. Expression of miR-425-5p in Pancreatic Carcinoma and Its Correlation with Tumor Immune Microenvironment. J INVEST SURG 2023; 36:2216756. [PMID: 37455016 DOI: 10.1080/08941939.2023.2216756] [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: 01/09/2023] [Accepted: 05/17/2023] [Indexed: 07/18/2023]
Abstract
Background: Pancreatic carcinoma (PC) is a global health threat with a high death rate. miRNAs are implicated in tumor initiation and progression. This study explored the expression of miR-425-5p in PC patients and its correlation with tumor immune microenvironment (TIME).Method: miR-425-5p expression in cancer tissues and adjacent non-tumor tissues of PC patients was examined by RT-qPCR. The levels of immune cells and cytokines were measured by flow cytometry and ELISA. The correlation of miR-425-5p with TNM stage and TIME was assessed by Spearman method. The death of PC patients was recorded through 36-month follow-ups. The prognosis of patients was assessed by Kaplan-Meier curves.Results: miR-425-5p expression was upregulated in PC tissues and elevated with increasing TNM stage. miR-425-5p expression was positively correlated with TNM stage. The PC tissues had decreased levels of CD3+, CD4+, CD8+, and natural killer (NK) cells, CD4+/CD8+ ratio, IL-2, and INF-γ, but increased levels of Tregs, IL-4, IL-10, and TGF-β. miR-425-5p level in cancer tissues was positively correlated with Tregs/IL-10/TGF-β, but negatively related to CD3+/CD4+/CD8+/NK cells and IL-2/INF-γ. Moreover, high miR-425-5p expression predicted a poor prognosis in PC patients.Conclusion: miR-425-5p is upregulated in PC patients and is prominently associated with the TIME, and high miR-425-5p predicts a poor prognosis in PC patients.
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Affiliation(s)
- Shuo Jian
- Department of Oncology, Suining Central Hospital, Suining, Sichuan Province, China
| | - Dehua Kong
- Department of Oncology, Suining Central Hospital, Suining, Sichuan Province, China
| | - Jieli Tian
- Department of Oncology, Suining Central Hospital, Suining, Sichuan Province, China
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24
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Yu N, Tian W, Liu C, Zhang P, Zhao Y, Nan C, Jin Q, Li X, Liu Y. miR-122-5p Promotes Peripheral and Central Nervous System Inflammation in a Mouse Model of Intracerebral Hemorrhage via Disruption of the MLLT1/PI3K/AKT Signaling. Neurochem Res 2023; 48:3665-3682. [PMID: 37594575 DOI: 10.1007/s11064-023-04014-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 08/19/2023]
Abstract
Intracerebral hemorrhage (ICH) is a recognized central nervous system inflammation complication. Several microRNAs (miRNAs or miRs) have been documented to be vital modulators in peripheral and central nervous system inflammation. Based on whole transcriptome sequencing and bioinformatics analysis, this study aims to reveal the possible molecular mechanisms by which miR-122-5p affects the inflammatory response in the peripheral and central nervous system in a mouse model of ICH. Differentially expressed ICH-related miRNAs were screened. Adeno-associated viral vectors were used to knock down miR-122-5p in mice to evaluate the effect of miR-122-5p on peripheral and central nervous system inflammation. The downstream target gene of miR-122-5p was analyzed. Neurons were isolated from mice and treated with hemin to construct an in vitro model of ICH, followed by transduction with miR-122-5p mimic or combined with oe-MLLT1. The neurons were then co-cultured with microglia BV2 to assess their activation. It was found that miR-122-5p was highly expressed in ICH, and MLLT1 was lowly expressed. In vivo experiments showed that miR-122-5p knockdown decreased neurological deficits, BBB permeability, and inflammation in the peripheral and central nervous system in ICH mice. It involved its binding to MLLT1 and downregulation of the activity of the PI3K/AKT pathway. In vitro data exhibited that miR-122-5p stimulated the generation of inflammatory factors and microglia activation by targeting MLLT1 and inhibiting the PI3K/AKT pathway. Collectively, our work reveals a novel miR-122-5p/MLLT1-mediated regulatory network in ICH that may be a viable target for neuroinflammation alleviation.
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Affiliation(s)
- Ning Yu
- Department of Anesthesiology and Intensive Care Unit, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, P.R. China
| | - Wenbin Tian
- Department of Anesthesiology and Intensive Care Unit, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, P.R. China
| | - Chao Liu
- Department of Anesthesiology and Intensive Care Unit, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, P.R. China
| | - Pei Zhang
- Department of Anesthesiology and Intensive Care Unit, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, P.R. China
| | - Yinlong Zhao
- Department of Anesthesiology and Intensive Care Unit, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, P.R. China
| | - Chengrui Nan
- Department of Anesthesiology and Intensive Care Unit, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, P.R. China
| | - Qianxu Jin
- Department of Neurosurgery, Hebei Medical University, Shijiazhuang, 050000, P.R. China
| | - Xiaopeng Li
- Department of Neurosurgery, The First Hospital of Handan City, Handan, 056000, P.R. China
| | - Ya Liu
- Department of Anesthesiology and Intensive Care Unit, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, P.R. China.
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25
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Deng M, Xu Y, Yao Y, Wang Y, Yan Q, Cheng M, Liu Y. Circular RNA hsa_circ_0051246 acts as a microRNA-375 sponge to promote the progression of gastric cancer stem cells via YAP1. PeerJ 2023; 11:e16523. [PMID: 38505381 PMCID: PMC10950207 DOI: 10.7717/peerj.16523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/05/2023] [Indexed: 03/21/2024] Open
Abstract
Background Gastric cancer (GC) stem cells play an important role in GC progression. Circular RNAs (circRNAs) act as microRNA (miRNA) sponges and inhibit the biological function of miRNAs in GC cytoplasm. MiRNAs also participate in GC progress. circ_0051246 was shown to be associated with miR-375 after analyzing GC microarray data GSE78091 and GSE83521. The oncoprotein Yes-associated protein 1 (YAP1) is targeted by miR-375 and can be inactivated via the Hippo tumor suppressor pathway. Due to insufficient research on circ_0051246, this study aimed to investigate its relationship with miR-375 and YAP1 in cancer stem cells (CSCs). Methods SGC-7901 CSCs were used to establish knockdown/overexpression models of circ_0051246, miR-375, and YAP1. Malignant phenotypes of CSCs were assessed using Cell Counting Kit 8, colony/sphere formation, 5-Ethynyl-2'-deoxyuridine assay, flow cytometry, Transwell, and wound healing assays. To detect the interactions between circ_0051246, miR-375, and YAP1 in CSCs, a dual-luciferase reporter assay and fluorescence in situ hybridization were performed. In addition, 24 BALB/c nude mice were used to establish orthotopic xenograft tumor models. Four groups of mice were injected with CSCs (1 × 106 cells/100 µL) with circ_0051246 knockdown, miR-375 overexpression, or their respective control cells, and tumor progression and gene expression were observed by hematoxylin-eosin staining, immunohistochemistry. Western blot and quantitative real-time PCR were utilized to examine protein and gene expression, respectively. Results Circ_0051246 silencing reduced viability, promoted apoptosis, and inhibited proliferation, migration and invasion of CSCs. The functional effects of miR-375 mimics were comparable to those of circ_0051246 knockdown; however, the opposite was observed after miR-375 inhibitors treatment of CSCs. Furthermore, circ_0051246-overexpression antagonized the miR-375 mimics' effects on CSCs. Additionally, YAP1 overexpression promoted CSC features, such as self-renewal, migration, and invasion, inhibited apoptosis and E-cadherin levels, and upregulated the expression of N-cadherin, vimentin, YAP1, neurogenic locus notch homolog protein 1, and jagged canonical notch ligand 1. Conversely, YAP1-silenced produced the opposite effect. Moreover, miR-375 treatment antagonized the malignant effects of YAP1 overexpression in CSCs. Importantly, circ_0051246 knockdown and miR-375 activation suppressed CSC tumorigenicity in vivo. Conclusion This study highlights the promotion of circ_0051246-miR-375-YAP1 axis activation in GC progression and provides a scientific basis for research on the molecular mechanism of CSCs.
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Affiliation(s)
- Minghui Deng
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Oncology, Hangzhou Third People’s Hospital, Hangzhou, Zhejiang, China
| | - Yefeng Xu
- Department of Oncology, Hangzhou Third People’s Hospital, Hangzhou, Zhejiang, China
| | - Yongwei Yao
- Department of Oncology, Hangzhou Third People’s Hospital, Hangzhou, Zhejiang, China
| | - Yiqing Wang
- Department of Oncology, Hangzhou Third People’s Hospital, Hangzhou, Zhejiang, China
| | - Qingying Yan
- Department of Oncology, Hangzhou Third People’s Hospital, Hangzhou, Zhejiang, China
| | - Miao Cheng
- Department of Oncology, Hangzhou Third People’s Hospital, Hangzhou, Zhejiang, China
| | - YunXia Liu
- Department of Oncology, Hangzhou Third People’s Hospital, Hangzhou, Zhejiang, China
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Gao Y, Wang X, Luo H, Chen C, Li J, Sun R, Li D, Sun Z. Exosomal Long Non-Coding Ribonucleic Acid Ribonuclease Component of Mitochondrial Ribonucleic Acid Processing Endoribonuclease Is Defined as a Potential Non-Invasive Diagnostic Biomarker for Bladder Cancer and Facilitates Tumorigenesis via the miR-206/G6PD Axis. Cancers (Basel) 2023; 15:5305. [PMID: 37958478 PMCID: PMC10649581 DOI: 10.3390/cancers15215305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/27/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023] Open
Abstract
Bladder cancer (BLCA) is one of the cancers that is highly sensitive to specific non-invasive tumor biomarkers that facilitate early diagnosis. Exosome-derived long non-coding RNAs (lncRNAs) hold promise as diagnostic biomarkers for BLCA. In this study, we employed RNA-sequencing to compare the expression patterns of lncRNAs in urine exosomes from three BLCA patients and three healthy individuals. RMRP displayed the most significant differential expression. Elevated RMRP expression levels were observed in urinary and plasma exosomes from BLCA patients compared with those from healthy individuals. RMRP exhibited significant associations with certain BLCA patient clinicopathological features, including tumor stage, poor prognosis, and tumor grade. Combined diagnosis using RMRP in urine and plasma exosomes demonstrated a superior diagnostic performance with receiver operating characteristic curve analysis. RMRP was found to be related to BLCA tumor progression and the cell migration and invasion processes via the miR-206/G6PD axis both in vitro and in vivo. Mechanistically, RMRP serves as an miR-206 sponge, as suggested by dual-luciferase reporter assays and RNA immunoprecipitation. Our study suggests that the combined diagnosis of RMRP in urinary and plasma exosomes can serve as an excellent non-invasive diagnostic biomarker for BLCA patients. Additionally, targeting the RMRP/miR-206/G6PD axis holds promise as a therapeutic strategy for BLCA.
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Affiliation(s)
- Yuting Gao
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; (Y.G.); (C.C.); (R.S.)
| | - Xuan Wang
- Department of Pharmacy, Putuo People’s Hospital, School of Medicine, Tongji University, Shanghai 200060, China;
| | - Huarong Luo
- Department of Urology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
| | - Chen Chen
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; (Y.G.); (C.C.); (R.S.)
| | - Jing Li
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; (Y.G.); (C.C.); (R.S.)
| | - Ruixin Sun
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; (Y.G.); (C.C.); (R.S.)
| | - Dong Li
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; (Y.G.); (C.C.); (R.S.)
| | - Zujun Sun
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; (Y.G.); (C.C.); (R.S.)
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Wang Y, Hong Z, Wei S, Ye Z, Chen L, Qiu C. Investigating the role of LncRNA PSMG3-AS1 in gastric cancer: implications for prognosis and therapeutic intervention. Cell Cycle 2023; 22:2161-2171. [PMID: 37946320 PMCID: PMC10732658 DOI: 10.1080/15384101.2023.2278942] [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: 02/27/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023] Open
Abstract
LncRNAs are widely linked to the complex development of gastric cancer, which is acknowledged worldwide as the third highest contributor to cancer-related deaths and the fifth most common form of cancer. The primary focus of this study is to examine the role of LncRNA PSMG3-AS1 in a group of individuals with gastric cancer. The results of our study indicate that PSMG3-AS1 is highly expressed in over 20 different types of cancer. Significantly, there was a clear association found between the expression of PSMG3-AS1 and a multitude of TMB and MSI tumors. PSMG3-AS1 exhibited significant upregulation in gastric cancer patients compared to healthy individuals within the gastric cancer cohort. The prognosis of gastric cancer patients is intrinsically associated with PSMG3-AS1, as confirmed by survival analysis and ROC curves. Furthermore, we created a disruption vector based on LncRNA PSMG3-AS1 and introduced it into AGS and MKN-45 cells, which are human gastric cancer cells. Significant decreases in the expression of the PSMG3-AS1 gene were noticed in both intervention groups compared to the NC group, reflecting the protein level expressions. Significantly, the proliferative and invasive capabilities of MKN-45 and AGS cells were notably reduced following transfection with PSMG3-AS1 siRNA. The results of our study indicate that disruption of the LncRNA PSMG3-AS1 gene may impact the CAV1/miR-451a signaling pathway, thereby leading to a reduction in the ability of gastric cancer cells to multiply and invade.
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Affiliation(s)
- Yi Wang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, China
| | - Zhongshi Hong
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shenghong Wei
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, China
| | - Zaisheng Ye
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, China
| | - Luchuan Chen
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, China
| | - Chengzhi Qiu
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Zhao J, Zhao Z, Ying P, Zhou Y, Xu Z, Wang H, Tang L. METTL3-mediated m 6 A modification of circPRKAR1B promotes Crohn's colitis by inducing pyroptosis via autophagy inhibition. Clin Transl Med 2023; 13:e1405. [PMID: 37679886 PMCID: PMC10485333 DOI: 10.1002/ctm2.1405] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/23/2023] [Accepted: 08/28/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND The roles of circRNA and N6-methyladenosine (m6 A) methylation in Crohn's disease (CD) have drawn much attention. Therefore, this investigation aimed to discover how the m6 A modification of circRNAs contributes to CD progression. METHODS The study performed circRNA sequencing on colon samples from four CD patients and four normal controls (NCs) to screen for dysregulated circRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the candidate circRNA expression and determine its correlation to CD-associated inflammatory indicators. In vivo and in vitro investigations were conducted to examine the functions and pathways of circPRKAR1B in CD, besides investigating the m6 A modification role in circRNA expression modulation. RESULTS The RNA-seq revealed that hsa_circ_0008039 (circPRKAR1B) was the most significant upregulated circRNA and was identified as the candidate circRNA for further examinations. Relative circPRKAR1B expression was significantly upregulated in CD colon tissues and closely related to CD-associated inflammatory indices. The circPRKAR1B expression and function were regulated by methyltransferase-like 3 (METTL3)-mediated m6 A methylation. In vitro studies indicated that circPRKAR1B promoted pyroptosis mediated by NLRP3 inflammasome (NLRP3; nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3) and impaired autophagy by interacting with the RNA-binding protein (RBP) SPTBN1, (SPTBN1; spectrin beta, non-erythrocytic 1). The in vivo investigations revealed the treatment effects of si-circPRKAR1B and si-METTL3 in colitis models of IL-10-deficient mice. CONCLUSION Our study reveals that METTL3-mediated m6 A modification of circPRKAR1B promotes Crohn's colitis by aggravating NLRP3 inflammasome-mediated pyroptosis via autophagy impairment in colonic epithelial cells.
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Affiliation(s)
- Jie Zhao
- Department of Gastrointestinal SurgeryAffiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical UniversityChangzhouP. R. China
| | - Zhibin Zhao
- Department of GastroenterologyAffiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical UniversityTaizhouP. R. China
| | - Pu Ying
- Department of OrthopedicsChangshu Hospital Affiliated to Nanjing University of Chinese MedicineChangshuP. R. China
| | - Yan Zhou
- Department of Gastrointestinal SurgeryAffiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical UniversityChangzhouP. R. China
| | - Ziwei Xu
- Department of General SurgeryFirst Affiliated Hospital of Nanjing Medical UniversityNanjingP. R. China
| | - Honggang Wang
- Department of General SurgeryAffiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical UniversityTaizhouP. R. China
| | - Liming Tang
- Department of Gastrointestinal SurgeryAffiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical UniversityChangzhouP. R. China
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Liu J, Xie J, Xu E, Xu B, Zhou J, Zhou J, Yang Q. CircRNA hsa_circ_0000043 acts as a miR-4492 sponge to promote lung cancer progression via BDNF and STAT3 expression regulation in anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide-transformed 16HBE cells. Toxicol Sci 2023; 195:87-102. [PMID: 37326964 DOI: 10.1093/toxsci/kfad060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023] Open
Abstract
Increasing evidence shows that circular RNA (circRNA) plays an important role in the progression of lung cancer. In this study, we found that has_circ_0000043 was highly expressed in 16HBE-T human bronchial epithelial cells that were malignantly transformed by benzo[a]pyrene-trans-7,8-diol-9,10-epoxide via circRNA microarray. We verified that hsa_circ_0000043 was also significantly overexpressed in lung cancer cell lines and tissues. Moreover, hsa_circ_0000043 overexpression was positively correlated with poor clinicopathological parameters, such as tumor-node metastasis stage, distant metastasis, lymph-node metastasis, and overall survival. In vitro assays revealed that hsa_circ_0000043 inhibition suppressed 16HBE-T cell proliferation, migration, and invasion. Furthermore, hsa_circ_0000043 inhibition suppressed tumor growth in a mouse xenograft model. We discovered that hsa_circ_0000043 binds with miR-4492, acting as a miR-4492 sponge. Decreased miR-4492 expression was also associated with poor clinicopathological parameters. Thus, hsa_circ_0000043 was shown to contribute to the proliferation, malignant transformation ability, migration, and invasion of 16HBE-T cells via miR-4492 sponging and BDNF and STAT3 involvement.
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Affiliation(s)
- Jiayu Liu
- The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Xinzao, Guangzhou 511436, China
| | - Jiaying Xie
- The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Xinzao, Guangzhou 511436, China
| | - Enwu Xu
- Department of Thoracic Surgery, General Hospital of Southern Theater Command, PLA, Guangzhou 510010, China
| | - Binhe Xu
- Basic Medicine College, Zunyi Medical University, Zunyi 563000, China
| | - Jiaxin Zhou
- The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Xinzao, Guangzhou 511436, China
| | - Jiazhen Zhou
- The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Xinzao, Guangzhou 511436, China
| | - Qiaoyuan Yang
- The Institute for Chemical Carcinogenesis, School of Public Health, Guangzhou Medical University, Xinzao, Guangzhou 511436, China
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Tu G, Peng W, Peng X, Zhao Z, Shi S, Cai Q, He B, Yin W, Peng S, Wang L, Yu F, Wang X. hsa_circ_0000519 promotes the progression of lung adenocarcinoma through the hsa-miR-1296-5p/DARS axis. Am J Cancer Res 2023; 13:3342-3367. [PMID: 37693148 PMCID: PMC10492121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/18/2023] [Indexed: 09/12/2023] Open
Abstract
Emerging research indicates that circRNAs serve a crucial role in occurrence and development of cancers. This study aimed to uncover the biological role of hsa_circ_0000519 in the progression of LUAD (lung adenocarcinoma). hsa_circ_0000519 was identified by bioinformatic analysis, and its differential expression was validated in LUAD tissues and cell lines. CCK8, colony formation, wound healing, transwell assays, and xenograft tumor models were used to observe the biological functions of hsa_circ_0000519. FISH, RIP, dual luciferase reporter assays, and recovery experiments were implemented to explore the underlying mechanisms of hsa_circ_0000519. hsa_circ_0000519 was significantly upregulated in LUAD tissues and cell lines. The expression of hsa_circ_0000519 was positively correlated with T grade and TNM stage in patients with LUAD. Downregulation of hsa_circ_0000519 remarkably reduced cell proliferation, migration, invasion in vitro, and tumor growth in vivo. Mechanistic investigation demonstrated that hsa_circ_0000519 directly sponged hsa-miR-1296-5p to reduce its repressive impact on DARS as well as activate the PI3K/AKT/mTOR signaling pathway. The malignant phenotypes of LUAD cells induced by upregulation of hsa_circ_0000519 could be rescued by hsa-miR-1296-5p overexpression or knockdown of DARS. In conclusion, hsa_circ_0000519 promotes LUAD progression through the hsa-miR-1296-5p/DARS axis and may be expected as a novel biomarker and therapeutic for LUAD.
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Affiliation(s)
- Guangxu Tu
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Weilin Peng
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Xiong Peng
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Zhenyu Zhao
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Shuai Shi
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Qidong Cai
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Boxue He
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Wei Yin
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Shaoliang Peng
- College of Computer Science and Electronic Engineering, Hunan UniversityChangsha 410082, Hunan, China
- School of Computer Science, National University of Defense TechnologyChangsha 410073, Hunan, China
| | - Li Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Fenglei Yu
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
| | - Xiang Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South UniversityChangsha 410011, Hunan, China
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Zhu H, Zhang P, Shi J, Kou D, Bai X. Exosome-delivered circRPS5 inhibits the progression of melanoma via regulating the miR-151a/NPTX1 axis. PLoS One 2023; 18:e0287347. [PMID: 37384727 PMCID: PMC10310028 DOI: 10.1371/journal.pone.0287347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 06/04/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have been reported to exert critical functions in tumorigenesis and development. However, the underlying mechanism by which circRNAs regulate melanoma progression remain to be elucidated. METHODS The differentially expressed circRNAs were first identified by circRNA-seq, and circRNAs were validated via qRT-PCR and Sanger sequencing. Then, the impact of circRPS5, miR-151a and NPTX1 expression on the progression of melanoma cell were determined by gain- and loss-of-function assays. The relationship between circRPS5, miR-151a, and NPTX1 was predicted by StarBase website and authenticated by luciferase reporter assay. The melanoma cells-derived exosomes were characterized using nanoparticle tracking analysis (NTA) and western blot. RESULTS CircRPS5 was significantly downregulated in melanoma tissues and cell lines. Functionally, circRPS5 suppressed the proliferation, migration, and invasion of melanoma cells, and induced cell cycle arrest and apoptosis in vitro. Mechanistically, circRPS5 harbor miR-151a, acting as miRNA sponge, and then miR-151a targeted the 3'-UTR of NPTX1. Finally, circRPS5 was mainly incorporated into exosomes to inhibit the progression of melanoma cells. CONCLUSIONS This finding reveal circRPS5 suppressed the progression of melanoma through miR-151a/NPTX1 pathway, and may provide a promising therapeutic strategies for melanoma.
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Affiliation(s)
- Haijun Zhu
- Department of Plastic Surgery, The Central Hospital of Wuhan, Tong ji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pan Zhang
- Department of Plastic Surgery, The Central Hospital of Wuhan, Tong ji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Shi
- Department of Plastic Surgery, The Central Hospital of Wuhan, Tong ji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Deqiang Kou
- Department of Plastic Surgery, The Central Hospital of Wuhan, Tong ji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinping Bai
- Department of Plastic Surgery, The Central Hospital of Wuhan, Tong ji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Li WD, Wang HT, Huang YM, Cheng BH, Xiang LJ, Zhou XH, Deng QY, Guo ZG, Yang ZF, Guan ZF, Wang Y. Circ_0003356 suppresses gastric cancer growth through targeting the miR-668-3p/SOCS3 axis. World J Gastrointest Oncol 2023; 15:787-809. [PMID: 37275445 PMCID: PMC10237019 DOI: 10.4251/wjgo.v15.i5.787] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/06/2023] [Accepted: 04/07/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have attracted extensive attention as therapeutic targets in gastric cancer (GC). Circ_0003356 is known to be downregulated in GC tissues, but its cellular function and mechanisms remain undefined.
AIM To investigate the role of circ_0003356 in GC at the molecular and cellular level.
METHODS Circ_0003356, miR-668-3p, and SOCS3 expression were assessed via quantitative real time-polymerase chain reaction (qRT-PCR). Wound healing, EdU, CCK-8, flow cytometry and transwell assays were used to analyze the migration, proliferation, viability, apoptosis and invasion of GC cells. The subcellular localization of circ_0003356 was monitored using fluorescence in situ hybridization. The interaction of circ_0003356 with miR-668-3p was confirmed using RIP-qRT-PCR, RNA pull-down, and dual luciferase reporter assays. We observed protein levels of genes via western blot. We injected AGS cells into the upper back of mice and performed immunohistochemistry staining for examining E-cadherin, N-cadherin, Ki67, and SOCS3 expressions. TUNEL staining was performed for the assessment of apoptosis in mouse tumor tissues.
RESULTS Circ_0003356 and SOCS3 expression was downregulated in GC cells, whilst miR-668-3p was upregulated. Exogenous circ_0003356 expression and miR-668-3p silencing suppressed the migration, viability, proliferation, epithelial to mesenchy-mal transition (EMT) and invasion of GC cells and enhanced apoptosis. Circ_0003356 overexpression impaired tumor growth in xenograft mice. Targeting of miR-668-3p by circ_0003356 was confirmed through binding assays and SOCS3 was identified as a downstream target of miR-668-3p. The impacts of circ_0003356 on cell proliferation, apoptosis, migration, invasion and EMT were reversed by miR-668-3p up-regulation or SOCS3 down-regulation in GC cells.
CONCLUSION Circ_0003356 impaired GC development through its interaction with the miR-668-3p/SOCS3 axis.
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Affiliation(s)
- Wei-Dong Li
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Hai-Tao Wang
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Yue-Ming Huang
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Bo-Hao Cheng
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Li-Jun Xiang
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Xin-Hao Zhou
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Qing-Yan Deng
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Zhi-Gang Guo
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Zhi-Feng Yang
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Zhi-Fen Guan
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
| | - Yao Wang
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan 528403, Guangdong Province, China
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Mirzaei S, Gholami MH, Aghdaei HA, Hashemi M, Parivar K, Karamian A, Zarrabi A, Ashrafizadeh M, Lu J. Exosome-mediated miR-200a delivery into TGF-β-treated AGS cells abolished epithelial-mesenchymal transition with normalization of ZEB1, vimentin and Snail1 expression. ENVIRONMENTAL RESEARCH 2023; 231:116115. [PMID: 37178752 DOI: 10.1016/j.envres.2023.116115] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/05/2023] [Accepted: 05/11/2023] [Indexed: 05/15/2023]
Abstract
Exosomes are small extracellular vesicles that can be derived from human cells such as mesenchymal stem cells (MSCs). The size of exosomes is at nano-scale range and owing to their biocompatibility and other characteristics, they have been promising candidates for delivery of bioactive compounds and genetic materials in disease therapy, especially cancer therapy. Gastric cancer (GC) is a leading cause of death among patients and this malignant disease affects gastrointestinal tract that its invasiveness and abnormal migration mediate poor prognosis of patients. Metastasis is an increasing challenge in GC and microRNAs (miRNAs) are potential regulators of metastasis and related molecular pathways, especially epithelial-to-mesenchymal transition (EMT). In the present study, our aim was to explore role of exosomes in miRNA-200a delivery for suppressing EMT-mediated GC metastasis. Exosomes were isolated from MSCs via size exclusion chromatography. The synthetic miRNA-200a mimics were transfected into exosomes via electroporation. AGS cell line exposed to TGF-β for EMT induction and then, these cells cultured with miRNA-200a-loaded exosomes. The transwell assays performed to evaluate GC migration and expression levels of ZEB1, Snail1 and vimentin measured. Exosomes demonstrated loading efficiency of 5.92 ± 4.6%. The TGF-β treatment transformed AGS cells into fibroblast-like cells expressing two stemness markers, CD44 (45.28%) and CD133 (50.79%) and stimulated EMT. Exosomes induced a 14.89-fold increase in miRNA-200a expression in AGS cells. Mechanistically, miRNA-200a enhances E-cadherin levels (P < 0.01), while it decreases expression levels of β-catenin (P < 0.05), vimentin (P < 0.01), ZEB1 (P < 0.0001) and Snail1 (P < 0.01). Leading to EMT inhibition in GC cells. This pre-clinical experiment introduces a new strategy for miRNA-200a delivery that is of importance for preventing migration and invasion of GC cells.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Molecular and Cellular Sciences, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Science Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kazem Parivar
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Amin Karamian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34485, Istanbul, Turkey
| | - Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Jianlin Lu
- Department of Geriatrics, The Fifth People's Hospital of Wujiang District, Suzhou, China.
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Lin XH, Li DP, Liu ZY, Zhang S, Tang WQ, Chen RX, Weng SQ, Tseng YJ, Xue RY, Dong L. Six immune-related promising biomarkers may promote hepatocellular carcinoma prognosis: a bioinformatics analysis and experimental validation. Cancer Cell Int 2023; 23:52. [PMID: 36959615 PMCID: PMC10035283 DOI: 10.1186/s12935-023-02888-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/23/2023] [Indexed: 03/25/2023] Open
Abstract
BACKGROUND Abnormal miRNA and mRNA expression and dysregulated immune microenvironment have been found to frequently induce the progression of hepatocellular carcinoma (HCC) in recent reports. In particular, the immune-related competing endogenous RNAs (ceRNA) mechanism plays a crucial role in HCC progression. However, the underlying mechanisms remain unclear. METHODS Differentially expressed immune-related genes were obtained from the Immport, GEO, and TCGA databases. The mRNA and protein expression levels in HCC tissues and adjacent normal tissues were confirmed, and we further investigated the methylation levels of these biomarkers to explore their function. Then, the TIMER and TISCH databases were used to assess the relationship between immune infiltration and hub genes. Survival analysis and univariate and multivariate Cox models were used to evaluate the association between hub genes and HCC diagnosis. Hub gene expression was experimentally validated in six HCC cell lines and 15 HCC samples using qRT-PCR and immunohistochemistry. The hub genes were uploaded to DSigDB for drug prediction enrichment analysis. RESULTS We identified that patients with abnormal miRNAs (hsa-miR-125b-5p and hsa-miR-21-5p) and their targeted genes (NTF3, PSMD14, CD320, and SORT1) had a worse prognosis. Methylation analysis of miRNA-targeted genes suggested that alteration of methylation levels is also a factor in the induction of tumorigenesis. We also found that the development of HCC progression caused by miRNA-mRNA interactions may be closely correlated with the infiltration of immunocytes. Moreover, the GSEA, GO, and KEGG analysis suggested that several common immune-related biological processes and pathways were related to miRNA-targeted genes. The results of qRT-PCR, immunohistochemistry, and western blotting were consistent with our bioinformatics results, suggesting that abnormal miRNAs and their targeted genes may affect HCC progression. CONCLUSIONS Briefly, our study systematically describes the mechanisms of miRNA-mRNA interactions in HCC and predicts promising biomarkers that are associated with immune filtration for HCC progression.
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Affiliation(s)
- Xia-Hui Lin
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Liver Disease, Shanghai, 200032, China
| | - Dong-Ping Li
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Liver Disease, Shanghai, 200032, China
| | - Zhi-Yong Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Liver Disease, Shanghai, 200032, China
| | - Si Zhang
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Wen-Qing Tang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Liver Disease, Shanghai, 200032, China
| | - Rong-Xin Chen
- Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Shu-Qiang Weng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Disease, Shanghai, 200032, China.
| | - Yu-Jen Tseng
- Department of Digestive Diseases, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, China.
| | - Ru-Yi Xue
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Disease, Shanghai, 200032, China.
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Disease, Shanghai, 200032, China.
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Hou MY, Liu YK. Progress in research of exosomal circRNAs in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2023; 31:172-177. [DOI: 10.11569/wcjd.v31.i5.172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/08/2023] Open
Abstract
Exosomes are lipid bilayer vesicles secreted by almost various cell types, including circRNAs, microRNAs (miRNAs), proteins, and nucleic acids. CircRNAs act as molecular sponges of miRNAs and participate in regulating gene transcription. This paper reviews the biogenesis, function, isolation, and identification of exosomal circRNAs and their role in the early diagnosis, prognosis, therapy, and drug resistance of colorectal cancer.
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Affiliation(s)
- Meng-Yuan Hou
- Graduate College of North China University of Technology, Tangshan 063200, Hebei Province, China
| | - Yan-Kun Liu
- Department of Medical Molecular Diagnosis, Tangshan People's Hospital, Tangshan Key Laboratory of Precision Medicine Testing, Tangshan 063000, Hebei Province, China
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The Tumorigenic Role of Circular RNA-MicroRNA Axis in Cancer. Int J Mol Sci 2023; 24:ijms24033050. [PMID: 36769372 PMCID: PMC9917898 DOI: 10.3390/ijms24033050] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023] Open
Abstract
Circular RNAs (circRNAs) are a class of endogenous RNAs that control gene expression at the transcriptional and post-transcriptional levels. Recent studies have increasingly demonstrated that circRNAs act as novel diagnostic biomarkers and promising therapeutic targets for numerous cancer types by interacting with other non-coding RNAs such as microRNAs (miRNAs). The miRNAs are presented as crucial risk factors and regulatory elements in cancer by regulating the expression of their target genes. Some miRNAs are derived from transposable elements (MDTEs) that can transfer their location to another region of the genome. Genetic interactions between miRNAs and circular RNAs can form complex regulatory networks with various carcinogenic processes that play critical roles in tumorigenesis and cancer progression. This review focuses on the biological regulation of the correlative axis among circular RNAs, miRNAs, and their target genes in various cancer types and suggests the biological importance of MDTEs interacting with oncogenic or tumor-suppressive circRNAs in tumor progression.
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Yang H, Gou X, Feng C, Zhang Y, Chai F, Hong N, Ye Y, Wang Y, Gao B, Cheng J. Computed tomography-detected extramural venous invasion-related gene signature: a potential negative biomarker of immune checkpoint inhibitor treatment in patients with gastric cancer. J Transl Med 2023; 21:4. [PMID: 36604653 PMCID: PMC9814439 DOI: 10.1186/s12967-022-03845-2] [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: 08/02/2022] [Accepted: 12/23/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND To investigate the association between computed tomography (CT)-detected extramural venous invasion (EMVI)-related genes and immunotherapy resistance and immune escape in patients with gastric cancer (GC). METHODS Thirteen patients with pathologically proven locally advanced GC who had undergone preoperative abdominal contrast-enhanced CT and radical resection surgery were included in this study. Transcriptome sequencing was multidetector performed on the cancerous tissue obtained during surgery, and EMVI-related genes (P value for association < 0.001) were selected. A single-sample gene set enrichment analysis algorithm was also used to divide all GC samples (n = 377) in The Cancer Genome Atlas (TCGA) database into high and low EMVI-immune related groups based on immune-related differential genes. Cluster analysis was used to classify EMVI-immune-related genotypes, and survival among patients was validated in TCGA and Gene Expression Omnibus (GEO) cohorts. The EMVI scores were calculated using principal component analysis (PCA), and GC samples were divided into high and low EMVI score groups. Microsatellite instability (MSI) status, tumor mutation burden (TMB), response rate to immune checkpoint inhibitors (ICIs), immune escape were compared between the high and low EMVI score groups. Hub gene of the model in pan-cancer analysis was also performed. RESULTS There were 17 EMVI-immune-related genes used for cluster analysis. PCA identified 8 genes (PCH17, SEMA6B, GJA4, CD34, ACVRL1, SOX17, CXCL12, DYSF) that were used to calculate EMVI scores. High EMVI score groups had lower MSI, TMB and response rate of ICIs, status but higher immune escape status. Among the 8 genes used for EMVI scores, CXCL12 and SOX17 were at the core of the protein-protein interaction (PPI) network and had a higher priority in pan-cancer analysis. Immunohistochemical analysis showed that the expression of CXCL12 and SOX17 was significantly higher in CT-detected EMVI-positive samples than in EMVI-negative samples (P < 0.0001). CONCLUSION A CT-detected EMVI gene signature could be a potential negative biomarker for ICIs treatment, as the signature is negatively correlated with TMB, and MSI, resulting in poorer prognosis.
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Affiliation(s)
- Hao Yang
- grid.412463.60000 0004 1762 6325Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinyi Gou
- grid.411634.50000 0004 0632 4559Department of Radiology, Peking University People’s Hospital, 11 Xizhimen South St., Beijing, 100044 China
| | - Caizhen Feng
- grid.411634.50000 0004 0632 4559Department of Radiology, Peking University People’s Hospital, 11 Xizhimen South St., Beijing, 100044 China
| | - Yinli Zhang
- grid.411634.50000 0004 0632 4559Department of Pathology, Peking University People’s Hospital, Beijing, China
| | - Fan Chai
- grid.411634.50000 0004 0632 4559Department of Radiology, Peking University People’s Hospital, 11 Xizhimen South St., Beijing, 100044 China
| | - Nan Hong
- grid.411634.50000 0004 0632 4559Department of Radiology, Peking University People’s Hospital, 11 Xizhimen South St., Beijing, 100044 China
| | - Yingjiang Ye
- grid.411634.50000 0004 0632 4559Department of Gastrointestinal Surgery, Peking University People’s Hospital, Beijing, China
| | - Yi Wang
- grid.411634.50000 0004 0632 4559Department of Radiology, Peking University People’s Hospital, 11 Xizhimen South St., Beijing, 100044 China
| | - Bo Gao
- grid.411634.50000 0004 0632 4559Department of General Surgery, Peking University People’s Hospital, Beijing, 100044 China
| | - Jin Cheng
- grid.411634.50000 0004 0632 4559Department of Radiology, Peking University People’s Hospital, 11 Xizhimen South St., Beijing, 100044 China
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Novel hypoxia-induced HIF1α-circTDRD3-positive feedback loop promotes the growth and metastasis of colorectal cancer. Oncogene 2023; 42:238-252. [PMID: 36418471 DOI: 10.1038/s41388-022-02548-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 11/09/2022] [Accepted: 11/11/2022] [Indexed: 11/24/2022]
Abstract
Tumor hypoxia and circular RNAs (circRNAs) are considered to play key roles in tumor progression and malignancy, respectively. Nevertheless, the biological functions and underlying mechanisms of specific circRNAs exposed to hypoxic microenvironments in colorectal cancer (CRC) remain largely elusive. Herein, a novel circRNA, circTDRD3, which is upregulated under hypoxic conditions, was identified. The expression of circTDRD3 was highly expressed in CRC tissues and positively correlated with overall survival, tumor size, lymph node invasion and clinical stage. CircTDRD3 facilitated CRC cell proliferation, migration and metastasis in vitro and in vivo. Mechanistically, circTDRD3 promoted HIF1α expression by sponging miR-1231, which facilitated CRC progression. Meanwhile, HIF1α directly combined with TDRD3 promoter to increase the expression of TDRD3 pre-mRNA. Then HIF1a-induced PTBP1 accelerated the formation of circTDRD3. Our findings reveal that circTDRD3 facilitates the proliferation and metastasis of CRC through a positive feedback loop mediated by the HIF1α/PTBP1/circTDRD3/miR-1231/HIF1α axis. Therefore, circTDRD3 may serve as a prognostic biomarker and therapeutic target for patients with CRC.
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Yang H, Zou X, Yang S, Zhang A, Li N, Ma Z. Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer. Front Immunol 2023; 14:1149989. [PMID: 36936929 PMCID: PMC10020516 DOI: 10.3389/fimmu.2023.1149989] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
Background The epigenetic regulatory chemical lactate is a product of glycolysis. It can regulate gene expression through histone lactylation, thereby promoting tumor proliferation, metastasis, and immunosuppression. Methods In this study, a lactylation-related model for gastric cancer (GC) was constructed, and its relationships to prognosis, immune cell infiltration, and immunotherapy were investigated. By contrasting normal tissues and tumor tissues, four lactylation-related pathways that were substantially expressed in GC tissues were found in the GSEA database. Six lactylation-related genes were screened for bioinformatic analysis. The GC data sets from the TCGA and GEO databases were downloaded and integrated to perform cluster analysis, and the lactylation related model was constructed by secondary clustering. Results The fingding demonstrated that the lactylation score has a strong correlation with the overall survival rate from GC and the progression of GC. Mechanistic experiments showed that abundant immune cell infiltration (macrophages showed the highest degree of infiltration) and increased genetic instability are traits of high lactylation scores. Immune checkpoint inhibitors (ICIs) demonstrated a reduced response rate in GC with high lactylation scores. At the same time, tumors with high lactylation scores had high Tumor Immune Dysfunction and Exclusion scores, which means that they had a higher risk of immune evasion and dysfunction. Discussion These findings indicate that the lactylation score can be used to predict the malignant progression and immune evasion of GC. This model also can guide the treatment response to ICIs of GC. The constructed model of the lactate gene is also expected to become a potential therapeutic target for GC and diagnostic marker.
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Ahangar Davoodi N, Najafi S, Naderi Ghale-Noie Z, Piranviseh A, Mollazadeh S, Ahmadi Asouri S, Asemi Z, Morshedi M, Tamehri Zadeh SS, Hamblin MR, Sheida A, Mirzaei H. Role of non-coding RNAs and exosomal non-coding RNAs in retinoblastoma progression. Front Cell Dev Biol 2022; 10:1065837. [PMID: 36619866 PMCID: PMC9816416 DOI: 10.3389/fcell.2022.1065837] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Retinoblastoma (RB) is a rare aggressive intraocular malignancy of childhood that has the potential to affect vision, and can even be fatal in some children. While the tumor can be controlled efficiently at early stages, metastatic tumors lead to high mortality. Non-coding RNAs (ncRNAs) are implicated in a number of physiological cellular process, including differentiation, proliferation, migration, and invasion, The deregulation of ncRNAs is correlated with several diseases, particularly cancer. ncRNAs are categorized into two main groups based on their length, i.e. short and long ncRNAs. Moreover, ncRNA deregulation has been demonstrated to play a role in the pathogenesis and development of RB. Several ncRNAs, such as miR-491-3p, miR-613,and SUSD2 have been found to act as tumor suppressor genes in RB, but other ncRNAs, such as circ-E2F3, NEAT1, and TUG1 act as tumor promoter genes. Understanding the regulatory mechanisms of ncRNAs can provide new opportunities for RB therapy. In the present review, we discuss the functional roles of the most important ncRNAs in RB, their interaction with the genes responsible for RB initiation and progression, and possible future clinical applications as diagnostic and prognostic tools or as therapeutic targets.
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Affiliation(s)
- Nasrin Ahangar Davoodi
- Eye Research Center, Rassoul Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zari Naderi Ghale-Noie
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ashkan Piranviseh
- Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Sahar Ahmadi Asouri
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammadamin Morshedi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran,School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Amirhossein Sheida
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran,School of Medicine, Kashan University of Medical Sciences, Kashan, Iran,*Correspondence: Amirhossein Sheida, ; Hamed Mirzaei, ,
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran,*Correspondence: Amirhossein Sheida, ; Hamed Mirzaei, ,
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Chen Y, Yu Y, Lv M, Shi Q, Li X. E2F1-mediated up-regulation of TOP2A promotes viability, migration, and invasion, and inhibits apoptosis of gastric cancer cells. J Biosci 2022. [DOI: 10.1007/s12038-022-00322-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Xu Q, Yao Y, Ni H, Gu J, Wang X, Jiang L, Wang B, Zhu X. Hsa‐circ‐0052001 promotes gastric cancer cell proliferation and invasion via the
MAPK
pathway. Cancer Med 2022; 12:7246-7257. [PMID: 36453441 PMCID: PMC10067131 DOI: 10.1002/cam4.5446] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 08/29/2022] [Accepted: 11/04/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) ranks fourth among the causes of death from malignant tumors in the world. Studies have implicated the dysregulation of circRNAs with GC. However, the relationship between hsa-circ-0052001 and GC is unclear. METHODS In our current study, we assessed the expression levels of hsa-circ-0052001 in GC cells and tissues using quantitative real-time PCR (qPCR). The role of hsa-circ-0052001 expression on the proliferation and invasion of GC cells was assessed using in vitro experiments. The role of hsa-circ-0052001 on the proliferation of GC cells was also analyzed using in vivo models. The pathways downstream of hsa-circ-0052001 were identified using bioinformatics analyses, western blot (WB) assays, and qRT-PCR. RESULTS We found that compared with normal gastric mucosa epithelial cells and adjacent paracancer tissues, hsa-circ-0052001 was overexpressed in GC cells and tissues. Also, the hsa-circ-0052001 level was linked to patient clinicopathological characteristics of GC. Cell proliferation and metastatic ability were inhibited in gastric cancer cells when hsa-circ-0052001 was knocked down in vitro and cancer growth in vivo. Mechanistically, hsa-circ-0052001 promoted the carcinogenesis of GC cells via the MAPK signal pathway. CONCLUSION Hsa-circ-0052001 functions as a tumor gene in promoting the progression of GC through MAPK pathway, which has provided a promising target for patients with GC.
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Affiliation(s)
- Qixuan Xu
- Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou People's Republic of China
| | - Yizhou Yao
- Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou People's Republic of China
| | - Haishun Ni
- Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou People's Republic of China
| | - Jinrong Gu
- Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou People's Republic of China
| | - Xuchao Wang
- Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou People's Republic of China
| | - Linhua Jiang
- Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou People's Republic of China
| | - Bin Wang
- Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou People's Republic of China
| | - Xinguo Zhu
- Department of General Surgery The First Affiliated Hospital of Soochow University Suzhou People's Republic of China
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Tan Z, Jiang Y, Liang L, Wu J, Cao L, Zhou X, Song Z, Ye Z, Zhao Z, Feng H, Dong Z, Lin S, Zhou Z, Wang Y, Li X, Guan F. Dysregulation and prometastatic function of glycosyltransferase C1GALT1 modulated by cHP1BP3/ miR-1-3p axis in bladder cancer. J Exp Clin Cancer Res 2022; 41:228. [PMID: 35864552 PMCID: PMC9306173 DOI: 10.1186/s13046-022-02438-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 07/12/2022] [Indexed: 11/10/2022] Open
Abstract
Background Abnormal glycosylation in a variety of cancer types is involved in tumor progression and chemoresistance. Glycosyltransferase C1GALT1, the key enzyme in conversion of Tn antigen to T antigen, is involved in both physiological and pathological conditions. However, the mechanisms of C1GALT1 in enhancing oncogenic phenotypes and its regulatory effects via non-coding RNA are unclear. Methods Abnormal expression of C1GALT1 and its products T antigen in human bladder cancer (BLCA) were evaluated with BLCA tissue, plasma samples and cell lines. Effects of C1GALT1 on migratory ability and proliferation were assessed in YTS-1 cells by transwell, CCK8 and colony formation assay in vitro and by mouse subcutaneous xenograft and trans-splenic metastasis models in vivo. Dysregulated circular RNAs (circRNAs) and microRNAs (miRNAs) were profiled in 3 pairs of bladder cancer tissues by RNA-seq. Effects of miR-1-3p and cHP1BP3 (circRNA derived from HP1BP3) on modulating C1GALT1 expression were investigated by target prediction program, correlation analysis and luciferase reporter assay. Functional roles of miR-1-3p and cHP1BP3 on migratory ability and proliferation in BLCA were also investigated by in vitro and in vivo experiments. Additionally, glycoproteomic analysis was employed to identify the target glycoproteins of C1GALT1. Results In this study, we demonstrated upregulation of C1GALT1 and its product T antigen in BLCA. C1GALT1 silencing suppressed migratory ability and proliferation of BLCA YTS-1 cells in vitro and in vivo. Subsets of circRNAs and miRNAs were dysregulated in BLCA tissues. miR-1-3p, which is reduced in BLCA tissues, inhibited transcription of C1GALT1 by binding directly to its 3′-untranslated region (3′-UTR). miR-1-3p overexpression resulted in decreased migratory ability and proliferation of YTS-1 cells. cHP1BP3 was upregulated in BLCA tissues, and served as an miR-1-3p “sponge”. cHP1BP3 was shown to modulate migratory ability, proliferation, and colony formation of YTS-1 cells, and displayed tumor-suppressing activity in BLCA. Target glycoproteins of C1GALT1, including integrins and MUC16, were identified. Conclusions This study reveals the pro-metastatic and proliferative function of upregulated glycosyltransferase C1GLAT1, and provides preliminary data on mechanisms underlying dysregulation of C1GALT1 via miR-1-3p / cHP1BP3 axis in BLCA. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02438-7.
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Saranya I, Akshaya R, Selvamurugan N. Regulation of Wnt signaling by non-coding RNAs during osteoblast differentiation. Differentiation 2022; 128:57-66. [DOI: 10.1016/j.diff.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/10/2022] [Accepted: 10/11/2022] [Indexed: 11/03/2022]
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Xu CY, Zeng XX, Xu LF, Liu M, Zhang F. Circular RNAs as diagnostic biomarkers for gastric cancer: A comprehensive update from emerging functions to clinical significances. Front Genet 2022; 13:1037120. [PMID: 36386850 PMCID: PMC9650219 DOI: 10.3389/fgene.2022.1037120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/10/2022] [Indexed: 08/30/2023] Open
Abstract
The incidence and mortality of gastric cancer ranks as a fouth leading cause of cancer death worldwide, especially in East Asia. Due to the lack of specific early-stage symptoms, the majority of patients in most developing nations are diagnosed at an advanced stage. Therefore, it is urgent to find more sensitive and reliable biomarkers for gastric cancer screening and diagnosis. Circular RNAs (circRNAs), a novel type of RNAs with covalently closed loops, are becoming a latest hot spot in the field of. In recent years, a great deal of research has demonstrated that abnormal expression of circRNAs was associated with the development of gastric cancer, and suggested that circRNA might serve as a potential biomarker for gastric cancer diagnosis. In this review, we summarize the structural characteristics, formation mechanism and biological function of circRNAs, and elucidate research progress and existing problems in early screening of gastric cancer.
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Affiliation(s)
- Chun-Yi Xu
- Zhejiang Chinese Medical University, Hangzhou, China
- Core Facility, Quzhou People’s Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, China
| | - Xi-Xi Zeng
- Core Facility, Quzhou People’s Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, China
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou, China
| | - Li-Feng Xu
- Core Facility, Quzhou People’s Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, China
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou, China
| | - Ming Liu
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou, China
- The Joint Innovation Center for Engineering in Medicine, Quzhou, China
- University of Electronic Science and Technology of China, Chengdu, China
| | - Feng Zhang
- Core Facility, Quzhou People’s Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, China
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou, China
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Shin VY, Liu MX, Siu JMT, Kwong A, Chu KM. Inhibition of EP2 receptor suppresses tumor growth and chemoresistance of gastric cancer. Am J Cancer Res 2022; 12:4680-4692. [PMID: 36381319 PMCID: PMC9641405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 07/20/2022] [Indexed: 06/16/2023] Open
Abstract
Gastric cancer is one of the leading causes of cancer death in the world. Early diagnosis and effective chemotherapy are vital to reduce the overall mortality. Prostaglandin E2 (PGE2) has been implicated as an important factor in gastric cancer carcinogenesis. ECF based regimen (epirubicin, cisplatin, 5-fluorouracil) is the first-line chemotherapy for advanced gastric cancer. However, patients develop resistance after chemotherapy. The aim of this study is sought to investigate the role of EP2 receptor, a PGE2 receptor, and the antagonism of EP2 receptor in response to ECF treatment. Expression of EP2 receptor was evaluated in gastric cancer tissue samples and cell lines. Cell proliferation and cell apoptosis assays were performed in vitro and in vivo, upon knockdown of EP2 receptor, antagonist of EP2 receptor and/or ECF treatment. Western Blot was applied for evaluation of proteins relating to cell cycle, apoptosis and drug transporter. Next generation sequencing and ingenuity pathway analysis were applied for screening for downstream targets of EP2 receptor. Expressions of the targets of EP2 receptor were further evaluated in gastric cancer cells and tissues. In this study, we found that expression of EP2 receptor was significantly upregulated in gastric cancer. Inhibition of EP2 receptor reduced gastric cancer cell proliferation, induced cell cycle arrest proteins, and enhanced cell apoptosis. Moreover, knockdown of EP2 receptor by siRNA or antagonist sensitized gastric cancer cells to ECF. Silence of EP2 receptor also significantly abrogated gastric cancer growth in a mice model. Analysis revealed that CAV1 was a downstream target of EP2 receptor in gastric cancer. Our findings illustrated that blocking EP2 receptor reduced tumor growth and induced apoptosis in gastric cancer. This novel study unraveled CAV1 was a downstream target of EP2 receptor. Antagonizing EP2 receptor could be a potential therapeutic target in gastric cancer, in particular those with high EP2 receptor expression.
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Zhao J, Lin Z, Ying P, Zhao Z, Yang H, Qian J, Gong Y, Zhou Y, Dai Y, Jiao Y, Zhu W, Wang H, Tang L. circSMAD4 promotes experimental colitis and impairs intestinal barrier functions by targeting JAK2 through sponging miR-135a-5p. J Crohns Colitis 2022; 17:593-613. [PMID: 36239525 DOI: 10.1093/ecco-jcc/jjac154] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Numerous studies have explored the association between circular RNAs (circRNAs) and Crohn's disease (CD). However, the pathological role, biological functions, and molecular mechanisms of circRNAs in CD have not been fully elucidated. METHODS The circRNA microarray analysis was performed to identify deregulated circRNAs in colon tissues. The identified circRNA were verified through quantitative real time-polymerase chain reaction (qRT-PCR). In vivo and in vitro functional studies were performed to verify the role of circSMAD4 in CD and investigate the mechanisms involved. RESULTS We found that circSMAD4 was the most significantly upregulated circRNA. The expression level of circSMAD4 was positively correlated with levels of inflammatory factors. Overexpression of circSMAD4 impaired tight junction (TJ) proteins and enhanced apoptosis of epithelial cells. These effects were reversed by treatment with miR-135a-5p mimic. Mechanistic studies showed that circSMAD4 exerts its effects on CD by "sponging" miR-135a-5p to regulate Janus kinase 2 (JAK2). Si-circSMAD4 delivery through microspheres ameliorated experimental colitis and protected the intestinal barrier function in IL-10 knock-out mice. CONCLUSION This study shows that circSMAD4 regulates the progression of experimental colitis via the miR-135a-5p/JAK2 signaling axis and it may be a potential therapeutic target.
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Affiliation(s)
- Jie Zhao
- Department of Gastrointestinal Surgery and and Central Laboratory, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Zhiliang Lin
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tenth People's Hospital of Tongji University
| | - Pu Ying
- Department of Orthopedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine
| | - Zhibin Zhao
- Department of Gastroenterology, Taizhou People's Hospital Affiliated to Nanjing Medical University
| | - Haojun Yang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Jun Qian
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yu Gong
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yan Zhou
- Department of Gastrointestinal Surgery and and Central Laboratory, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yi Dai
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yuwen Jiao
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Honggang Wang
- Department of General Surgery, Taizhou People's Hospital Affiliated to Nanjing Medical University
| | - Liming Tang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
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Xie J, Ning Y, Zhang L, Lin Y, Guo R, Wang S. Overexpression of hsa_circ_0006470 inhibits the malignant behavior of gastric cancer cells <em>via</em> regulation of miR-1234/TP53I11 axis. Eur J Histochem 2022; 66. [PMID: 36190397 PMCID: PMC9577378 DOI: 10.4081/ejh.2022.3477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/09/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) is a subtype of a common malignant tumor found in the digestive system. Hsa_circ_0006470 is known to be closely associated with the development of GC. Nevertheless, the mechanism by which hsa_circ_0006470 regulates the tumorigenesis of GC has not been fully elucidated. To investigate the role of hsa_circ_0006470 in GC, its expression levels were assessed in GES-1, AGS, MKN45, and SNU5 cells by reverse transcription-quantitative PCR. Fluorescence in situ hybridization was used to evaluate the localization of hsa_circ_0006470 in AGS and MKN45 cells. In addition, cell counting kit-8 and 5-ethynyl- 2’-deoxyuridine assays were performed to evaluate the viability and proliferation of GC cells, respectively. The dual-luciferase reporter assay was used to explore the interaction among hsa_circ_0006470, microRNA (miR)- 1234, and TP53I11. The expression levels of TP53I11, Akt, p-Akt, forkhead box O1, and cyclin dependent kinase 2 in AGS cells were analyzed by Western blotting. The data indicated that hsa_circ_0006470 expression was downregulated in AGS cells. In addition, overexpression (OE) of hsa_circ_0006470 could inhibit the viability and proliferation of GC cells. Moreover, OE of hsa_circ_0006470 inhibited the migration of GC cells and induced G1 cell cycle phase arrest. Moreover, miR-1234 was bound to hsa_circ_0006470 and TP53I11 was targeted by miR-1234. Furthermore, OE of hsa_circ_0006470 inhibited the tumorigenesis of GC via the regulation of the miR-1234/TP53I11 axis. In summary, the present study demonstrated that OE of hsa_circ_0006470 notably inhibited the tumorigenesis of GC by regulating the miR-1234/TP53I11 axis. Therefore, the present study may provide a theoretical basis for exploring novel therapeutic strategies for the treatment of GC.
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Affiliation(s)
- Jinbi Xie
- Department of Gastroenterology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai.
| | - Yong Ning
- Department of Gastroenterology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai.
| | - Lihang Zhang
- Department of Gastroenterology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai.
| | - Yuan Lin
- Department of Gastroenterology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai.
| | - Runsheng Guo
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai.
| | - Shanjuan Wang
- Department of Gastroenterology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai.
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Guo Q, Guo J, Liu W, Hu S, Hu X, Wang Q, Jiang X. Circ-EGFR Functions as an Inhibitory Factor in the Malignant Progression of Glioma by Regulating the miR-183-5p/TUSC2 Axis. Cell Mol Neurobiol 2022; 42:2245-2256. [PMID: 33993369 PMCID: PMC11421611 DOI: 10.1007/s10571-021-01099-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 05/07/2021] [Indexed: 10/21/2022]
Abstract
Circular RNAs (circRNAs) have pivotal functions in regulating diverse biological processes of human tumors, including glioma. Herein, a novel circRNA epidermal growth factor receptor (circ-EGFR, hsa_circ_0080223) was researched in glioma. The molecular expression levels were analyzed via quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) and colony formation assays were conducted to assess cell proliferation. Apoptosis was analyzed using flow cytometry. Cell migration and invasion were examined via transwell assay. Interaction relations between targets were verified using dual-luciferase reporter assay. Tumor Suppressor Candidate 2 (TUSC2) protein expression was examined by Western blot. In vivo experiment was performed by establishing xenograft model in mice. The qRT-PCR showed the downregulation of circ-EGFR and TUSC2 but the upregulation of microRNA-183-5p (miR-183-5p) in glioma samples. In vitro assays revealed that circ-EGFR overexpression induced the repression of cell proliferation, migration, and invasion but the promotion of apoptosis. Circ-EGFR was identified as a sponge of miR-183-5p and circ-EGFR-mediated glioma progression inhibition was abolished by miR-183-5p downregulation. Additionally, miR-183-5p targeted TUSC2 and miR-183-5p inhibitor impeded the development of glioma by upregulating the expression of TUSC2. Furthermore, circ-EGFR could regulate the TUSC2 level by sponging miR-183-5p. Glioma growth in vivo was also reduced by circ-EGFR via targeting the miR-183-5p/TUSC2 axis. Altogether, our results suggested that circ-EGFR inhibited the malignant progression of glioma by regulating the levels of miR-183-5p and TUSC2. Circ-EGFR may be a useful therapeutic target to antagonize the glioma progression.
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Affiliation(s)
- Qingdong Guo
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.127, Changle West Road, Xincheng District, Xi'an, 710032, China
| | - Jun Guo
- Department of Radiology, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China
| | - Wei Liu
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.127, Changle West Road, Xincheng District, Xi'an, 710032, China
| | - Shijie Hu
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.127, Changle West Road, Xincheng District, Xi'an, 710032, China
| | - Xuean Hu
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.127, Changle West Road, Xincheng District, Xi'an, 710032, China
| | - Qianliang Wang
- Department of Neurosurgery, Xi'an Hospital of Traditional Chinese Medicine Encephalopathy, Xi'an, 710043, China
| | - Xiaofan Jiang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.127, Changle West Road, Xincheng District, Xi'an, 710032, China.
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Yu CQ, Wang XF, Li LP, You ZH, Huang WZ, Li YC, Ren ZH, Guan YJ. SGCNCMI: A New Model Combining Multi-Modal Information to Predict circRNA-Related miRNAs, Diseases and Genes. BIOLOGY 2022; 11:biology11091350. [PMID: 36138829 PMCID: PMC9495879 DOI: 10.3390/biology11091350] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/21/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022]
Abstract
Computational prediction of miRNAs, diseases, and genes associated with circRNAs has important implications for circRNA research, as well as provides a reference for wet experiments to save costs and time. In this study, SGCNCMI, a computational model combining multimodal information and graph convolutional neural networks, combines node similarity to form node information and then predicts associated nodes using GCN with a distributive contribution mechanism. The model can be used not only to predict the molecular level of circRNA–miRNA interactions but also to predict circRNA–cancer and circRNA–gene associations. The AUCs of circRNA—miRNA, circRNA–disease, and circRNA–gene associations in the five-fold cross-validation experiment of SGCNCMI is 89.42%, 84.18%, and 82.44%, respectively. SGCNCMI is one of the few models in this field and achieved the best results. In addition, in our case study, six of the top ten relationship pairs with the highest prediction scores were verified in PubMed.
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Affiliation(s)
- Chang-Qing Yu
- School of Information Engineering, Xijing University, Xi’an 710123, China
- Correspondence:
| | - Xin-Fei Wang
- School of Information Engineering, Xijing University, Xi’an 710123, China
| | - Li-Ping Li
- College of Grassland and Environment Sciences, Xinjiang Agricultural University, Urumqi 830052, China
| | - Zhu-Hong You
- School of Computer Science, Northwestern Polytechnical University, Xi’an 710129, China
| | - Wen-Zhun Huang
- School of Information Engineering, Xijing University, Xi’an 710123, China
| | - Yue-Chao Li
- School of Information Engineering, Xijing University, Xi’an 710123, China
| | - Zhong-Hao Ren
- School of Information Engineering, Xijing University, Xi’an 710123, China
| | - Yong-Jian Guan
- School of Information Engineering, Xijing University, Xi’an 710123, China
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