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LIANG HAISU, YAN WEI, LIU ZHI, HE YUNBO, HU JIAO, SHU ZHIWEI, LI HUIHUANG, OTHMANE BELAYDI, REN WENBIAO, QUAN CHAO, QIU DONGXU, CHEN MINFENG, XIONG WEI, ZHANG BINGNAN, LIU PEIHUA. Immunomodulatory behavior of CircRNAs in tumor microenvironment. Oncol Res 2025; 33:1105-1119. [PMID: 40296917 PMCID: PMC12034001 DOI: 10.32604/or.2024.054623] [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: 06/03/2024] [Accepted: 11/13/2024] [Indexed: 04/30/2025] Open
Abstract
Circular RNAs (circRNAs) are a type of non coding RNA that possess unique single stranded circular structures formed through reverse splicing mechanisms. Due to the lack of a free end that is typically susceptible to degradation by nucleases, circular RNAs exhibit resistance to ribonuclease R, making them highly stable in eukaryotic cells. The complex relationship between circRNA dysregulation and various pathophysiological conditions, especially cancer. Tumor microenvironment (TME) is a collective term for various components surrounding tumors and is an important factor affecting tumor development. Simultaneous infiltration of TME by different types of immune cells; These immune cells interact with the TME, collectively forming the so-called "tumor immune microenvironment". The complex interactions between tumor cells and TME profoundly affect the behavior of malignant tumors, and circRNAs derived from tumor cells and TME cell components have become important mediators of immune response and evasion within the TME. CircRNAs can directly or indirectly regulate immune cells, thereby modulating anti-tumor immunity. This review highlights how circRNAs, especially those encapsulated in extracellular vesicles like exosomes, influence the differentiation, chemotaxis, and anti-tumor immune functions of immune cells within the TME. Metabolic reprogramming plays an important role in this process. The process of circRNAs regulating tumor immunity is affected by multiple factors, such as hypoxia and viral infection. This review emphasizes the roles of the interaction between circRNAs and the TME in tumor immune regulation and prospects the guiding significance of circRNAs in tumor immune checkpoint therapy.
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Affiliation(s)
- HAISU LIANG
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - WEI YAN
- Department of Urology, Shimen Hospital of TCM, Changde, 415300, China
| | - ZHI LIU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- Department of Urology, The Second Affiliated Hospital, Guizhou Medical University, Kaili, 556000, China
| | - YUNBO HE
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, China
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - JIAO HU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - ZHIWEI SHU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - HUIHUANG LI
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - BELAYDI OTHMANE
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - WENBIAO REN
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- George Whipple Lab for Cancer Research, University of Rochester Medical Institute, Rochester, NY 14627, USA
| | - CHAO QUAN
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - DONGXU QIU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - MINFENG CHEN
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - WEI XIONG
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - BINGNAN ZHANG
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - PEIHUA LIU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, China
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Lou Y, Yan J, Liu Q, Miao M, Shao Y. Biological functions and molecular mechanisms of exosome-derived circular RNAs and their clinical implications in digestive malignancies: the vintage in the bottle. Ann Med 2024; 56:2420861. [PMID: 39484707 PMCID: PMC11536637 DOI: 10.1080/07853890.2024.2420861] [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: 07/21/2024] [Revised: 10/05/2024] [Accepted: 10/11/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) are identified as a novel family of endogenous RNA molecules through 'back-splicing' and covalently linked at the 5' and 3' ends. Emerging researches have demonstrated circRNAs are stable and abundant in exosomes called exosomal circRNAs (exo-circRNA). MATERIALS AND METHODS We searched recent studies and references to summary the research progress of exosomal circRNA. RESULTS Recent studies have revealed that exosome-derived circRNAs including exo-CDR1as, exo-circRanGAP1, exo-circIAR play vital roles in cell proliferation and apoptosis, epithelial mesenchymal transition, invasion and metastasis, angiogenesis, immune evasion, cellular crosstalk, cancer cachexia through a variety of biological mechanisms, such as serving as microRNA sponges, interacting with RNA binding proteins, regulating gene transcription, N6-Methyladenosine modification and so on. Due to their characteristics of origin, structure, properties and biological functions, exo-circRNAs are expected to apply in precious diagnosis and prognostic indicators, improving drug and radiation resistance and sensitivity, becoming biological therapeutic targets. CONCLUSION We summarize the update of digestive malignancies associated exo-circRNAs in biogenesis, biological functions, molecular mechanisms, clinical implications, potential applications and experimental technique in order to effectively promote transformation and application in the future.
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Affiliation(s)
- Yuanyan Lou
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, China
- Health Science Center, Ningbo University, Ningbo, China
| | - Jianing Yan
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Qingqing Liu
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Min Miao
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yongfu Shao
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, China
- Health Science Center, Ningbo University, Ningbo, China
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Zhang Y, Xie J. Targeting non-coding RNAs as a promising biomarker in peritoneal metastasis: Background, mechanism, and therapeutic approach. Biomed Pharmacother 2024; 179:117294. [PMID: 39226726 DOI: 10.1016/j.biopha.2024.117294] [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: 06/09/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 09/05/2024] Open
Abstract
Peritoneal metastasis (PM) pathophysiology is complex and not fully understood. PM, originating from gastrointestinal (GI) cancer, is a condition that significantly worsens patient prognosis due to its complex nature and limited treatment options. The non-coding RNAs (ncRNAs) have been shown to play pivotal roles in cancer biology, influencing tumorigenesis, progression, metastasis, and therapeutic resistance. Increasing evidence has demonstrated the regulatory functions of different classes of ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in PM. Identifying biomarkers for early detection of PM is a crucial step towards improving patient outcomes, and how ncRNA profiles correlate with survival rates, response to therapy, and recurrence risks have raised much attention in recent years. Additionally, exploring innovative therapeutic approaches utilizing ncRNAs, such as targeted therapy and gene silencing, may offer new horizons in treating this dire condition. Recent advances in systemic treatments and the development of novel loco-regional therapies have opened doors to multimodal treatment approaches. Radical surgeries combined with hyperthermic intraperitoneal chemotherapy (HIPEC) have shown promising results, leading to extended patient survival. Current research is focused on the molecular characterization of PM, which is crucial for early detection and developing future therapeutic strategies. By summarizing the latest findings, this study underscores the transformative potential of ncRNAs in enhancing the diagnosis, prognosis, and treatment of PM in GI cancer, paving the way for more personalized and effective clinical strategies.
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Affiliation(s)
- Yiping Zhang
- School of Life Sciences, Fudan University, Shanghai 200438, China; Wanchuanhui (Shanghai) Medical Technology Co., Ltd, Shanghai 201501, China.
| | - Jun Xie
- School of Life Sciences, Fudan University, Shanghai 200438, China; Wanchuanhui (Shanghai) Medical Technology Co., Ltd, Shanghai 201501, China.
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Lin L, Wusiman J, Zhang Z. Circular RNA circRNA_100349 functions as a miR-218-5p sponge for suppressing the cell proliferation of gastric cancer via regulation of IGF2 expression. Clinics (Sao Paulo) 2024; 79:100492. [PMID: 39293372 PMCID: PMC11422554 DOI: 10.1016/j.clinsp.2024.100492] [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: 11/03/2023] [Revised: 04/19/2024] [Accepted: 08/25/2024] [Indexed: 09/20/2024] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) hold critical importance due to their notable function in developing Gastric Cancer (GC), which is a malignancy with the third most frequent occurrence worldwide. The aim of this study was to see if circRNA_0044516 would control GC cell proliferation and establish more effective therapeutic strategies. METHODS In GC tissues or cells, quantitative Real‑Time Polymerase Chain Reaction (qRT-PCR) was employed for the detection of the expression of circRNA_100349, Insulin-like Growth Factor II (IGF2), and miR-218-5p. CCK-8 assays were employed to gauge the proliferation of cells. A luciferase reporter was employed to establish the relationship of circRNA_100349 or IGF2 with miR-218-5p. RESULTS CircRNA_100349 was observed to undergo upregulation in GC cell lines along with tissues. GC cell proliferation was prevented by downregulating circRNA_100349. MiR-149 was targeted by CircRNA_100349, and its downregulation increased the amount of miR-218-5p in GC cells. Simultaneously silencing circRNA_100349 decreased IGF2 expression via miR-218-5p, and thus suppressed GC cell proliferation. Furthermore, in nude mice, circRNA_100349 knockdown prevented the tumor development of GC cells. CONCLUSIONS The findings furnished evidence of the critical involvement of circRNA_100349 in GC and that its downregulation impedes GC cell proliferation via the miR-218-5p/IGF2 axis.
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Affiliation(s)
- Linmei Lin
- Blood Transfusion Department, The First Hospital of Putian City, Putian, Fujian, China
| | - Jiamilan Wusiman
- Internal Medicine-Oncology, Guangzhou Royal Cancer Hospital, Guangzhou, Guangdong, China
| | - Zixu Zhang
- Department of Endoscope, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Wang Y, Zhang J, Yang Y, Liu Z, Sun S, Li R, Zhu H, Li T, Zheng J, Li J, Ma L. Circular RNAs in human diseases. MedComm (Beijing) 2024; 5:e699. [PMID: 39239069 PMCID: PMC11374765 DOI: 10.1002/mco2.699] [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: 06/20/2023] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 09/07/2024] Open
Abstract
Circular RNAs (circRNAs) are a unique class of RNA molecules formed through back-splicing rather than linear splicing. As an emerging field in molecular biology, circRNAs have garnered significant attention due to their distinct structure and potential functional implications. A comprehensive understanding of circRNAs' functions and potential clinical applications remains elusive despite accumulating evidence of their involvement in disease pathogenesis. Recent research highlights their significant roles in various human diseases, but comprehensive reviews on their functions and applications remain scarce. This review provides an in-depth examination of circRNAs, focusing first on their involvement in non-neoplastic diseases such as respiratory, endocrine, metabolic, musculoskeletal, cardiovascular, and renal disorders. We then explore their roles in tumors, with particular emphasis on exosomal circular RNAs, which are crucial for cancer initiation, progression, and resistance to treatment. By detailing their biogenesis, functions, and impact on disease mechanisms, this review underscores the potential of circRNAs as diagnostic biomarkers and therapeutic targets. The review not only enhances our understanding of circRNAs' roles in specific diseases and tumor types but also highlights their potential as novel diagnostic and therapeutic tools, thereby paving the way for future clinical investigations and potential therapeutic interventions.
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Affiliation(s)
- Yuanyong Wang
- Department of Thoracic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)The First Department of Thoracic SurgeryPeking University Cancer Hospital and InstitutePeking University School of OncologyBeijingChina
| | - Jin Zhang
- Department of Traditional Chinese MedicineTangdu HospitalAir Force Medical UniversityXi'anChina
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi ProvinceXi'anChina
| | - Yuchen Yang
- Department of Traditional Chinese MedicineTangdu HospitalAir Force Medical UniversityXi'anChina
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi ProvinceXi'anChina
| | - Zhuofeng Liu
- Department of Traditional Chinese MedicineThe Third Affiliated Hospital of Xi'an Medical UniversityXi'anChina
| | - Sijia Sun
- Department of Traditional Chinese MedicineTangdu HospitalAir Force Medical UniversityXi'anChina
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi ProvinceXi'anChina
| | - Rui Li
- Department of EpidemiologySchool of Public HealthAir Force Medical UniversityXi'anChina
| | - Hui Zhu
- Department of AnatomyMedical College of Yan'an UniversityYan'anChina
- Institute of Medical ResearchNorthwestern Polytechnical UniversityXi'anChina
| | - Tian Li
- School of Basic MedicineFourth Military Medical UniversityXi'anChina
| | - Jin Zheng
- Department of Traditional Chinese MedicineTangdu HospitalAir Force Medical UniversityXi'anChina
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi ProvinceXi'anChina
| | - Jie Li
- Department of EndocrineXijing 986 HospitalAir Force Medical UniversityXi'anChina
| | - Litian Ma
- Department of Thoracic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
- Department of Traditional Chinese MedicineTangdu HospitalAir Force Medical UniversityXi'anChina
- Key Laboratory of Integrated Traditional Chinese and Western Medicine Tumor Diagnosis and Treatment in Shaanxi ProvinceXi'anChina
- Department of GastroenterologyTangdu HospitalAir Force Medical UniversityXi'anChina
- School of MedicineNorthwest UniversityXi'anChina
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Hasoglu I, Karatug Kacar A. The therapeutic effects of exosomes the first time isolated from pancreatic islet-derived progenitor cells in the treatment of pancreatic cancer. PROTOPLASMA 2024; 261:281-291. [PMID: 37798610 DOI: 10.1007/s00709-023-01896-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 09/21/2023] [Indexed: 10/07/2023]
Abstract
Insulinoma is an excessive insulin-released beta cell tumor. Pancreas cancer is one of the deadliest malignant neoplasms. Exosomes are secreted cell membrane vesicles containing a large number of proteins, lipids, and nucleic acids. The aim of this study is to investigate the effects of exosomes on two cell lines of benign and malignant character. For the first time, exosomes were isolated from pancreatic island-derived progenitor cells (PID-PCs) and applied to INS-1 and MiaPaCa-2 cells. In addition, exosomes isolated from PID-PC, MiaPaca-2, and INS-1 cells were characterized in order to compare their sizes with other previously isolated exosomes. Alix, TSG101, CD9, and CD81 were analyzed. The size and concentration of exosomes and the cell viability were detected. The cells were marked with HSP90, HSF-1, Kaspaz-8, Active-Kaspaz-3, Beclin, and p-Bcl-2. The cell cytotoxicity and insulin levels kit were measured. Alix in all exosomes, and PID-PC, MiaPaca-2 cell lysates; TSG101 in PID-PC and MiaPaca-2 cell lysates; CD9 in INS-1 exosomes were detected. The dimensions of isolated exosomes were 103.6 ± 28.6 nm, 100.7 ± 10 nm, and 147.2 ± 12.3 nm for PID-PCs, MiaPaca-2, and INS-1 cells. The cell viability decreased and HSP90 increased in the MiaPaca-2 cells. The HSF-1 was higher in the control MiaPaca-2 cell compared to the control INS-1 cell, and the exosome-treated MiaPaca-2 cell compared to the exosome-treated INS-1 cell. Beclin and p-Bcl-2 were decreased in the exosome-treated MiaPaca-2 cells. The insulin level in the cell lysates increased compared to cell secretion in INS-1 cells. In conclusion, exosomes isolated from the PID-PC caused cell death in the MiaPaca-2 cells in a time- and dose-dependent manner. The IC50 value determined for MiaPaca-2 cells has no effect on cell viability in INS-1 cells, which best mimics pancreatic beta cells and can be used instead of healthy pancreatic beta cells. Isolated exosomes can kill cancer cells without damaging healthy cells.
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Affiliation(s)
- Imren Hasoglu
- Faculty of Science, Department of Biology, Istanbul University, Istanbul, Turkey
| | - Ayse Karatug Kacar
- Faculty of Science, Department of Biology, Istanbul University, Istanbul, Turkey.
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Xu Y, Han J, Zhang X, Zhang X, Song J, Gao Z, Qian H, Jin J, Liang Z. Exosomal circRNAs in gastrointestinal cancer: Role in occurrence, development, diagnosis and clinical application (Review). Oncol Rep 2024; 51:19. [PMID: 38099408 PMCID: PMC10777447 DOI: 10.3892/or.2023.8678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/27/2023] [Indexed: 12/18/2023] Open
Abstract
Gastrointestinal cancer is frequently detected at an advanced stage and has an undesirable prognosis due to the absence of efficient and precise biomarkers and therapeutic targets. Exosomes are small, living‑cell‑derived vesicles that serve a critical role in facilitating intercellular communication by transporting molecules from donor cells to receiver cells. circular RNAs (circRNAs) are mis‑expressed in a variety of diseases, including gastrointestinal cancer, and are promising as diagnostic biomarkers and tumor therapeutic targets for gastrointestinal cancer. The main features of exosomes and circRNAs are discussed in the present review, along with research on the biological function of exosomal circRNAs in the development and progression of gastrointestinal cancer. It also assesses the advantages and disadvantages of implementing these findings in clinical applications.
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Affiliation(s)
- Yumeng Xu
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jiayi Han
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xuan Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xinyi Zhang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jiajia Song
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Zihan Gao
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Hui Qian
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jianhua Jin
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
| | - Zhaofeng Liang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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Jiang C, Zhang J, Wang W, Shan Z, Sun F, Tan Y, Tong Y, Qiu Y. Extracellular vesicles in gastric cancer: role of exosomal lncRNA and microRNA as diagnostic and therapeutic targets. Front Physiol 2023; 14:1158839. [PMID: 37664422 PMCID: PMC10469264 DOI: 10.3389/fphys.2023.1158839] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
Extracellular vesicles (EVs), including exosomes, play a crucial role in intercellular communication and have emerged as important mediators in the development and progression of gastric cancer. This review discusses the current understanding of the role of EVs, particularly exosomal lncRNA and microRNA, in gastric cancer and their potential as diagnostic and therapeutic targets. Exosomes are small membrane-bound particles secreted by both cancer cells and stromal cells within the tumor microenvironment. They contain various ncRNA and biomolecules, which can be transferred to recipient cells to promote tumor growth and metastasis. In this review, we highlighted the importance of exosomal lncRNA and microRNA in gastric cancer. Exosomal lncRNAs have been shown to regulate gene expression by interacting with transcription factors or chromatin-modifying enzymes, which regulate gene expression by binding to target mRNAs. We also discuss the potential use of exosomal lncRNAs and microRNAs as diagnostic biomarkers for gastric cancer. Exosomes can be isolated from various bodily fluids, including blood, urine, and saliva. They contain specific molecules that reflect the molecular characteristics of the tumor, making them promising candidates for non-invasive diagnostic tests. Finally, the potential of targeting exosomal lncRNAs and microRNAs as a therapeutic strategy for gastric cancer were reviewed as wee. Inhibition of specific molecules within exosomes has been shown to suppress tumor growth and metastasis in preclinical models. In conclusion, this review article provides an overview of the current understanding of the role of exosomal lncRNA and microRNA in gastric cancer. We suggest that further research into these molecules could lead to new diagnostic tools and therapeutic strategies for this deadly disease.
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Affiliation(s)
- Chengyao Jiang
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Jianjun Zhang
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Wentao Wang
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Zexing Shan
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Fan Sun
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Yuen Tan
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Yilin Tong
- Department of Gastric Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Yue Qiu
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
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Meng X, Yang D, Zhang B, Zhao Y, Zheng Z, Zhang T. Regulatory mechanisms and clinical applications of tumor-driven exosomal circRNAs in cancers. Int J Med Sci 2023; 20:818-835. [PMID: 37213665 PMCID: PMC10198146 DOI: 10.7150/ijms.82419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/09/2023] [Indexed: 05/23/2023] Open
Abstract
Malignant tumors seriously affect people's survival and prognosis. Exosomes, as vesicle structures widely existing in human tissues and body fluids, are involved in cell-to-cell transmission. Tumor-derived exosomes were secreted from tumors and involved in the development of carcinogenesis. Circular RNA (circRNA), a novel member of endogenous noncoding RNAs, is widespread in human and play a vital role in many physiological or pathological processes. Tumor-driven exosomal circRNAs are often involved in tumorigenesis and development including the proliferation, invasion, migration and chemo-or-radiotherapy sensitivity of tumor cell by multiple regulatory mechanisms. In this review, we will elaborate the roles and functions of tumor-driven exosomal circRNAs in cancers which may be used as potential cancer biomarkers and novel therapeutic targets.
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Affiliation(s)
| | | | | | | | | | - Tao Zhang
- Department of Gastric Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital, Shenyang, Liaoning, China
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Shen X, Zhu X, Hu P, Ji T, Qin Y, Zhu J. Knockdown circZNF131 Inhibits Cell Progression and Glycolysis in Gastric Cancer Through miR-186-5p/PFKFB2 Axis. Biochem Genet 2022; 60:1567-1584. [PMID: 35059934 DOI: 10.1007/s10528-021-10165-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 12/06/2021] [Indexed: 11/02/2022]
Abstract
Gastric cancer (GC) is a prevalent and heterogeneous malignancy in the digestive system. Increasing studies have suggested that circular RNAs are implicated in GC pathogenesis. This study aimed to explore the biological role and underlying mechanism of circRNA zinc finger protein 131 (circZNF131) in GC. The expression pattern of circZNF131, microRNA-186-5p (miR-186-5p), and 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) mRNA in GC tissues and cells was detected by quantitative real-time polymerase chain reaction. The stability of circZNF131 was verified using ribonuclease R assay. Functional experiments were performed by colony formation assay for cloning ability analysis, transwell assay and wounding healing assay for cell metastasis, and flow cytometry for cell apoptosis. Glycolysis metabolism was investigated by determining the levels of glucose uptake and lactate production. The protein detection of apoptosis- or glycolysis-associated markers, PFKFB2, and Ki-67 was implemented by western blot or immunohistochemistry. Dual-luciferase reporter assay was conducted to identify the interaction between miR-186-5p and circZNF131 or PFKFB2. The role of circZNF131 on tumor growth in nude mice was investigated via xenograft tumor assay. Expression analysis indicated that circZNF131 was upregulated in GC tissues and cells in a stable structure. Functional analyses showed that circZNF131 knockdown suppressed GC cell colony formation ability, migration, invasion and glycolysis metabolism, and induced cell apoptosis. Mechanically, miR-186-5p was a target of circZNF131, and miR-186-5p could bind to PFKFB2. Rescue experiments presented that miR-186-5p inhibition reversed the effects of circZNF131 knockdown on GC cell growth and glycolysis, and PFKFB2 overexpression abolished the impacts of miR-186-5p restoration on GC cell progression. Moreover, circZNF131 could positively modulate PFKFB2 expression via sponging miR-186-5p. In vivo, circZNF131 knockdown hindered GC tumor growth by regulating the miR-186-5p/PFKFB2 axis. circZNF131 could exert an oncogenic role in GC malignant development through the miR-186-5p/PFKFB2 axis, which might provide novel targets for GC treatment.
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Affiliation(s)
- Xingjie Shen
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan City, 250013, Shandong Province, China.
| | - Xiaoyan Zhu
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan City, 250013, Shandong Province, China
| | - Peixin Hu
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan City, 250013, Shandong Province, China
| | - Tingting Ji
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan City, 250013, Shandong Province, China
| | - Ying Qin
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan City, 250013, Shandong Province, China
| | - Jingyu Zhu
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan City, 250013, Shandong Province, China
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11
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Tumor-Suppressive and Oncogenic Roles of microRNA-149-5p in Human Cancers. Int J Mol Sci 2022; 23:ijms231810823. [PMID: 36142734 PMCID: PMC9501226 DOI: 10.3390/ijms231810823] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/07/2022] [Accepted: 09/14/2022] [Indexed: 12/24/2022] Open
Abstract
Malignant tumors are always a critical threat to human health, with complex pathogenesis, numerous causative factors, and poor prognosis. The features of cancers, such as gene mutations, epigenetic alterations, and the activation and inhibition of signaling pathways in the organism, play important roles in tumorigenesis and prognosis. MicroRNA (miRNA) enables the control of various molecular mechanisms and plays a variety of roles in human cancers, such as radiation sensitivity and tumor immunity, through the regulation of target genes. MiR-149-5p participates in the process and is closely related to lipogenesis, the migration of vascular endothelial cells, and the expression of stem-cell-related proteins. In recent years, its role in cancer has dramatically increased. In this review, we summarize the regular physiological roles of miRNAs, specifically miR-149-5p, in the organism and discuss the tumor-suppressive or oncogenic roles of miR-149-5p in different human cancers with respect to signaling pathways involved in regulation. Possible clinical applications of miR-149-5p in future targeted therapies and prognosis improvement in oncology are suggested.
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12
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Circular RNA circPGD contributes to gastric cancer progression via the sponging miR-16-5p/ABL2 axis and encodes a novel PGD-219aa protein. Cell Death Dis 2022; 8:384. [PMID: 36104322 PMCID: PMC9472197 DOI: 10.1038/s41420-022-01177-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/26/2022]
Abstract
CircRNAs have critical effects on tumor development and progression. However, circPGD effect on gastric cancer (GC) is still elusive. Nuclear and cytoplasmic RNA fractionation, and RNA-FISH assay examined the localization of circPGD in MGC-803 cells. qRT-PCR was conducted to detect the expression and prognostic significance of circPGD, miR-16-5p, and ABL2 within GC tissues. Meanwhile, qRT-PCR, luciferase reporter assays, rescue, and western blotting assays confirmed the interactions between circPGD, miR-16-5p, and ABL2. Transwell, wound healing, and colony-formation assays, as well as CCK-8 and cell apoptosis assays, analyzed the functions of circPGD, miR-16-5p, ABL2, as well as PGD-219aa within GC cells. Western blotting and cell immunofluorescence experiments detected the differences in the expression of the related proteins. Finally, xenograft and metastatic mouse models were used to investigate circPGD function in vivo. Mass spectrometry was used to detect the existence of PGD-219aa in MGC-803 cells. CircPGD was localized in the cytoplasm and nucleus of MGC-803 cells. Compared with the control, circPGD and ABL2 expression increased within GC tissues and cells, and the miR-16-5p level was decreased. Functionally, circPGD promoted cell proliferation, migration and suppressed apoptosis in vitro. Mechanistically, circPGD sponged miR-16-5p for relieving miR-16-5p suppression on the corresponding target ABL2 via the SMAD2/3 and YAP signaling pathways. In addition, circPGD encodes a novel PGD-219aa protein that can enhance the growth and migration of GC cells, while inhibiting GC cells apoptosis via the SMAD2/3 and YAP signaling pathways. Furthermore, circPGD overexpression enhanced tumor aggressiveness, while circPGD knockdown inhibited tumor growth. Overall, circPGD has a novel oncogenic effect on GC cells, indicating the potential of circPGD as the tumorigenic factor and a promising diagnostic marker for GC.
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13
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Liu H, Dai W. Circular RNA 0000654 facilitates the growth of gastric cancer cells through absorbing microRNA-149-5p to up-regulate inhibin-beta A. Bioengineered 2022; 13:469-480. [PMID: 35100076 PMCID: PMC8805893 DOI: 10.1080/21655979.2021.2009414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Circular (circ) RNAs are differentially expressed in gastric cancer (GC) and participate in the biological growth of tumor cells. Given that, investigations were performed to unravel the function of circ_0000654 in GC. GC tissue and normal tissue specimens were obtained, in which circ_0000654, microRNA (miR)-149-5p, and inhibin-beta A (INHBA) levels were examined. GC cell line (BGC-823) was transfected to alter circ_0000654 and miR-149-5p expression, thereby observing cell malignancy. Stably-transfected BGC-823 cells were injected into nude mice to observe tumor growth in vivo. The interaction circ_0000654, miR-149-5p, and INHBA was validated. circ_0000654 and INHBA were up-regulated but miR-149-5p was down-regulated in GC. circ_0000654 absorbed miR-149-5p to target INHBA. Silencing circ_0000654inhibited the progress of GC cell biology. Oppositely, restoring circ_0000654 enhanced the growth of GC cells. Inhibiting miR-149-5p rescued down-regulated circ_0000654-induced anti-tumor effect on GC. circ_0000654 silence or miR-149-5p overexpression limited the growth of GC tumors in vivo. Obviously, circ_0000654 facilitates the growth of GC cells through absorbing miR-149-5p to up-regulate INHBA.
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Affiliation(s)
- Han Liu
- Department of General Medicine, The First People's Hospital of Shangqiu City, Shangqiu, Henan, China
| | - Wen Dai
- Department of Joint Surgery, The First People's Hospital of Shangqiu City, Shangqiu, Henan, China
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14
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Zheng W, Shen GL, Xu KY, Yin QQ, Hui TC, Zhou ZW, Xu CA, Wang SH, Wu WH, Shi LF, Pan HY. Lnc524369 promotes hepatocellular carcinoma progression and predicts poor survival by activating YWHAZ-RAF1 signaling. World J Gastrointest Oncol 2022; 14:253-264. [PMID: 35116115 PMCID: PMC8790426 DOI: 10.4251/wjgo.v14.i1.253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/28/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver cancer is one of the most highly malignant cancers, characterized by easy metastasis and chemoradiotherapy resistance. Emerging evidence indicates that long noncoding RNAs (LncRNAs), including Lnc524369, are highly involved in the initiation, progression, radioresistance, and chemoresistance of hepatocellular carcinoma (HCC). However, the function of Lnc524369 remains unclear.
AIM To explore the function of Lnc524369 in HCC.
METHODS To investigate the effect of Lnc524369, tissue from 41 HCC patients were analyzed using CCK8, migration, and invasion assays. Lnc524369 and YWHAZ (also named 14-3-3ζ) mRNA were detected by qPCR, and YWHAZ and RAF1 proteins were detected by western blot in liver cancer cell lines and human HCC tissues. The Cancer Cell Line Encyclopedia (CCLE) databases, STRING database, Human Protein Atlas database, and the TCGA database were used for bioinformatic analysis.
RESULTS Lnc524369 was significantly upregulated in the nucleus of liver cancer cells and human HCC tissues. Overexpression of Lnc524369 was associated with the proliferation, migration, and invasion of liver cancer cells. YWHAZ and RAF1 proteins and YWHAZ mRNA were overexpressed in liver cancer, which could be attenuated by overexpression of Lnc524369. Lnc524369 and its downstream target YWHAZ and RAF1 proteins were negatively associated with overall survival time.
CONCLUSION Lnc524369 might be a promising target of HCC as it can enhance liver cancer progression and decrease the overall survival time of HCC by activating the YWHAZ/RAF1 pathway.
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Affiliation(s)
- Wei Zheng
- Department of Clinical Medicine, Medical College of Soochow University, Suzhou 215006, Jiangsu Province, China
- Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Guo-Liang Shen
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Ke-Yang Xu
- School of Chinese Medicine, Hongkong Baptist university, Hong Kong 999777, China
| | - Qiao-Qiao Yin
- Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Tian-Chen Hui
- Department of Graduate School, Bengbu Medical College, Bengbu 233030, Anhui Province, China
| | - Zhe-Wen Zhou
- Department of Graduate School, Bengbu Medical College, Bengbu 233030, Anhui Province, China
| | - Cheng-An Xu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Shou-Hao Wang
- Medical Department of Qingdao University, Qingdao University, Qingdao 266071, Shandong, China
| | - Wen-Hao Wu
- Medical Department of Qingdao University, Qingdao University, Qingdao 266071, Shandong, China
| | - Ling-Fei Shi
- Diagnosis and Treatment Center of Osteoporosis, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hang Zhou 310014, Zhejiang Province, China
| | - Hong-Ying Pan
- Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
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15
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Yun BD, Choi YJ, Son SW, Cipolla GA, Berti FCB, Malheiros D, Oh TJ, Kuh HJ, Choi SY, Park JK. Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers. Int J Mol Sci 2022; 23:ijms23020930. [PMID: 35055115 PMCID: PMC8781283 DOI: 10.3390/ijms23020930] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell-cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.
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Affiliation(s)
- Ba Da Yun
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Ye Ji Choi
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Seung Wan Son
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Gabriel Adelman Cipolla
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Fernanda Costa Brandão Berti
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Danielle Malheiros
- Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba 81531-990, Brazil; (G.A.C.); (F.C.B.B.); (D.M.)
| | - Tae-Jin Oh
- Department of Pharmaceutical Engineering and Biotechnology, SunMoon University, 70 Sunmoon-ro 221, Tangjeong-myeon, Asan-si 31460, Korea;
- Genome-Based BioIT Convergence Institute, 70 Sunmoon-ro 221, Tangjeong-myeon, Asan-si 31460, Korea
| | - Hyo Jeong Kuh
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Soo Young Choi
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
| | - Jong Kook Park
- Department of Biomedical Science and Research, Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (B.D.Y.); (Y.J.C.); (S.W.S.); (S.Y.C.)
- Correspondence: ; Tel.: +82-33-248-2114
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16
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A Review on the Role of miR-149-5p in the Carcinogenesis. Int J Mol Sci 2021; 23:ijms23010415. [PMID: 35008841 PMCID: PMC8745060 DOI: 10.3390/ijms23010415] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
miR-149 is an miRNA with essential roles in carcinogenesis. This miRNA is encoded by the MIR149 gene on 2q37.3. The miR-149 hairpin produces miR-149-5p and miR-149-3p, which are the “guide” and the sister “passenger” strands, respectively. Deep sequencing experiments have shown higher prevalence of miR-149-5p compared with miR-149-3p. Notably, both oncogenic and tumor suppressive roles have been reported for miR-149-5p. In this review, we summarize the impact of miR-149-5p in the tumorigenesis and elaborate mechanisms of its involvement in this process in a variety of neoplastic conditions based on three lines of evidence, i.e., in vitro, in vivo and clinical settings.
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17
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Circular RNA circDNA2 upregulates CCDC6 expression to promote the progression of gastric cancer via miR-149-5p suppression. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:360-373. [PMID: 34552818 PMCID: PMC8426470 DOI: 10.1016/j.omtn.2021.05.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 05/26/2021] [Indexed: 02/06/2023]
Abstract
Circular (circ)RNAs are widely involved in gastric cancer (GC) pathogenesis, and coiled-coil domain containing 6 (CCDC6) is a fused partner of multiple oncogenes; however, the underlying mechanisms of how circRNAs regulate CCDC6 expression in the progression and prognosis of GC remain unclear. Here, we discovered the circRNA derived from the DNA2 gene locus (circDNA2) through RNA sequencing. By performing quantitative real-time PCR and fluorescence in situ hybridization (FISH) assays with a human tissue microarray, circDNA2 was found to be highly expressed in GC tissues and associated with lymphatic invasion of GC patients. Knockdown of circDNA2 expression suppressed the proliferation of GC cells by reducing CCDC6 expression. Mechanistically, circDNA2 acted as a microRNA (miR)-149-5p sponge, which was confirmed to target CCDC6 by RNA pulldown and dual-luciferase reporter assays and rescue experiments. Both low miR-149-5p expression and high CCDC6 expression were related to unfavorable prognosis in GC patients. Moreover, GC patients with low miR-149-5p expression had shorter overall survival and a higher risk of chemotherapy resistance than those with high miR-149-5p expression. In summary, circDNA2 contributes to the growth and lymphatic metastasis of GC by upregulating CCDC6 expression by sponging miR-149-5p. The circDNA2/miR-149-5p/CCDC6 axis might be developed as a therapeutic target and prognostic indicator for GC.
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18
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Wang J, Yang K, Cao J, Li L. Knockdown of circular RNA septin 9 inhibits the malignant progression of breast cancer by reducing the expression of solute carrier family 1 member 5 in a microRNA-149-5p-dependent manner. Bioengineered 2021; 12:10624-10637. [PMID: 34738502 PMCID: PMC8809977 DOI: 10.1080/21655979.2021.2000731] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer in women. Increasing evidence suggests that circular RNA (circRNA) exerts critical functions in BC progression. However, the roles of circRNA septin 9 (circSEPT9) in BC development and the underneath mechanism remain largely unclear so far. In this work, the RNA levels of circSEPT9, microRNA-149-5p (miR-149-5p) and solute carrier family 1 member 5 (SLC1A5) were detected by quantitative real-time polymerase chain reaction. Western blot was performed to check protein expression. Glutamine uptake, cell proliferation and cell apoptosis were investigated by glutamine uptake, cell counting kit-8, cell colony formation, 5-Ethynyl-29-deoxyuridine, flow cytometry analysis or DNA content quantitation assay. The interactions of miR-149-5p with circSEPT9 and SLC1A5 were identified by a dual-luciferase reporter assay. Mouse model assay was carried out to analyze the effect of circSEPT9 on tumor formation in vivo. Results showed that circSEPT9 and SLC1A5 expression were significantly upregulated, while miR-149-5p was downregulated in BC tissues and cells as compared with paracancerous normal breast tissues and human normal breast cells. Knockdown of circSEPT9 or SLC1A5 inhibited glutamine uptake and cell proliferation, but induced cell apoptosis in BC cells. SLC1A5 overexpression relieved circSEPT9 silencing-induced repression of BC cell malignancy. In mechanism, circSEPT9 regulated SLC1A5 expression by sponging miR-149-5p. In support, circSEPT9 knockdown led to delayed tumor tumorigenesis in vivo. In summary, these results indicates that circSEPT9 may act an oncogenic role in BC malignant progression by regulating miR-149-5p/SLC1A5 pathway, providing a novel mechanism responsible for BC development.
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Affiliation(s)
- Jianjun Wang
- Department of Breast and Thyroid Tumors Surgery, The First People’s Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Yunnan, China
| | - Kunxian Yang
- Department of Breast and Thyroid Tumors Surgery, The First People’s Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Yunnan, China
| | - Junyu Cao
- Department of Breast and Thyroid Tumors Surgery, The First People’s Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Yunnan, China
| | - Li Li
- Department of Breast and Thyroid Tumors Surgery, The First People’s Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Yunnan, China
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19
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Li C, Ni YQ, Xu H, Xiang QY, Zhao Y, Zhan JK, He JY, Li S, Liu YS. Roles and mechanisms of exosomal non-coding RNAs in human health and diseases. Signal Transduct Target Ther 2021; 6:383. [PMID: 34753929 PMCID: PMC8578673 DOI: 10.1038/s41392-021-00779-x] [Citation(s) in RCA: 217] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 09/23/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023] Open
Abstract
Exosomes play a role as mediators of cell-to-cell communication, thus exhibiting pleiotropic activities to homeostasis regulation. Exosomal non-coding RNAs (ncRNAs), mainly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are closely related to a variety of biological and functional aspects of human health. When the exosomal ncRNAs undergo tissue-specific changes due to diverse internal or external disorders, they can cause tissue dysfunction, aging, and diseases. In this review, we comprehensively discuss the underlying regulatory mechanisms of exosomes in human diseases. In addition, we explore the current knowledge on the roles of exosomal miRNAs, lncRNAs, and circRNAs in human health and diseases, including cancers, metabolic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and infectious diseases, to determine their potential implication in biomarker identification and therapeutic exploration.
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Affiliation(s)
- Chen Li
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China
| | - Yu-Qing Ni
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China
| | - Hui Xu
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China
| | - Qun-Yan Xiang
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China
| | - Yan Zhao
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China
| | - Jun-Kun Zhan
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China
| | - Jie-Yu He
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China
| | - Shuang Li
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China
| | - You-Shuo Liu
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, Hunan, 410011, China.
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20
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Lu L, Fang S, Zhang Y, Jin L, Xu W, Liang Z. Exosomes and Exosomal circRNAs: The Rising Stars in the Progression, Diagnosis and Prognosis of Gastric Cancer. Cancer Manag Res 2021; 13:8121-8129. [PMID: 34737640 PMCID: PMC8558314 DOI: 10.2147/cmar.s331221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/14/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is a common malignant tumor affecting human health, with occult onset and poor prognosis. Exosomes are extracellular vesicles secreted by almost all cells, which can reflect the state of source cells or tissues. It is reported that exosomes are involved in almost all processes of GC. Exosomes provided a window to understand changes in cell or tissue states by carrying active components such as circular RNAs (circRNAs). CircRNAs are a naturally occurring class of endogenous noncoding RNAs and abnormal expression during the occurrence and development of GC. Exosomal circRNAs are those circRNAs stably existing in exosomes and having high clinical values as novel potential diagnosis and prognosis biomarkers of GC, which have the characteristics of abnormal expression, tissue specificity and development stage specificity. Herein, we briefly summarize the functions and roles and the current research progress of exosomes and exosomal circRNAs in GC with a focus on the potential application for GC progression, diagnosis and prognosis. We also prospected the clinical application of exosomes and exosomal circRNAs in the future.
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Affiliation(s)
- Ling Lu
- Child Healthcare Department, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Shikun Fang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People’s Republic of China
| | - Yue Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People’s Republic of China
| | - Longtao Jin
- Child Healthcare Department, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People’s Republic of China
| | - Zhaofeng Liang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People’s Republic of China
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21
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Ren FJ, Yao Y, Cai XY, Cai YT, Su Q, Fang GY. MiR-149-5p: An Important miRNA Regulated by Competing Endogenous RNAs in Diverse Human Cancers. Front Oncol 2021; 11:743077. [PMID: 34722295 PMCID: PMC8554335 DOI: 10.3389/fonc.2021.743077] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 10/01/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) consist of a large family of small, non-coding RNAs with the ability to result in gene silencing post-transcriptionally. With recent advances in research technology over the past several years, the physiological and pathological potentials of miRNAs have been gradually uncovered. MiR-149-5p, a conserved miRNA, was found to regulate physiological processes, such as inflammatory response, adipogenesis and cell proliferation. Notably, increasing studies indicate miR-149-5p may act as an important regulator in solid tumors, especially cancers in reproductive system and digestive system. It has been acknowledged that miR-149-5p can function as an oncogene or tumor suppressor in different cancers, which is achieved by controlling a variety of genes expression and adjusting downstream signaling pathway. Moreover, the levels of miR-149-5p are influenced by several newly discovered long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). However, there is blank about systematic function and mechanism of miR-149-5p in human cancers. In this review, we firstly summarize the present comprehension of miR-149-5p at the molecular level, its vital role in tumor initiation and progression, as well as its potential roles in monitoring diverse reproductive and digestive malignancies.
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Affiliation(s)
- Fu-jia Ren
- Department of Pharmacy, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Yao Yao
- Department of Pharmacy, Women’s Hospital School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao-yu Cai
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu-ting Cai
- Department of Pharmacy, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Qian Su
- Department of Pharmacy, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Guo-ying Fang
- Department of Pharmacy, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
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Zhang H, Yang M, Wu X, Li Q, Li X, Zhao Y, Du F, Chen Y, Wu Z, Xiao Z, Shen J, Wen Q, Hu W, Cho CH, Chen M, Zhou Y, Li M. The distinct roles of exosomes in tumor-stroma crosstalk within gastric tumor microenvironment. Pharmacol Res 2021; 171:105785. [PMID: 34311072 DOI: 10.1016/j.phrs.2021.105785] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/19/2021] [Accepted: 07/22/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) development is a complex process displaying polytropic cell and molecular landscape within gastric tumor microenvironment (TME). Stromal cells in TME, including fibroblasts, endothelial cells, mesenchymal stem cells, and various immune cells, support tumor growth, metastasis, and recurrence, functioning as the soil for gastric tumorigenesis. Importantly, exosomes secreted by either stromal cells or tumor cells during tumor-stroma crosstalk perform as crucial transporter of agents including RNAs and proteins for cell-cell communication in GC pathogenesis. Therefore, given the distinct roles of exosomes secreted by various cell types in GC TME, increasing evidence has indicated that exosomes present as new biomarkers for GC diagnosis and prognosis and shed light on novel approaches for GC treatment.
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Affiliation(s)
- Hanyu Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; Nanchong Key Laboratory of Individualized Drug Therapy, Department of Pharmacy, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong 637000, Sichuan, China
| | - Min Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qianxiu Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Xin Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Zhigui Wu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, Guangzhou, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Yejiang Zhou
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.
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23
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Chen H, Zhang Y, Wu K, Qiu X. circVAPA promotes the proliferation, migration and invasion of oral cancer cells through the miR-132/HOXA7 axis. J Int Med Res 2021; 49:3000605211013207. [PMID: 34102907 PMCID: PMC8193665 DOI: 10.1177/03000605211013207] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Objective To study the relationship between the circular RNA vesicle-associated membrane protein-associated protein A (circVAPA) and the pathogenesis of oral squamous cell carcinoma. Methods The expression of circVAPA was detected by RT-qPCR. In vitro loss-of-function experiments were performed in Cal-27 cells. The malignant phenotype of cells was evaluated by cell counting kit-8, clone formation and transwell assays. Luciferase reporter assays were used to assess the circVAPA/miR-132/homeobox A (HOXA) regulatory axis. Results circVAPA expression was significantly increased in oral cancer tissues and cells. The overall survival and progression-free survival of patients with oral cancer who exhibited high circVAPA expression were significantly shorter compared with those with low expression. circVAPA expression was closely related to tumor size, TNM stage and distant metastasis. circVAPA knockdown reduced the proliferation, invasion and migration of Cal-27 cells. MiR-132 was identified as a target of circVAPA in Cal-27 cells. Cotransfection with si-circVAPA and miR-132 inhibitor reversed the inhibitory effect of circVAPA knockdown on cell malignant phenotypes. HOXA7 was further identified as a downstream target of miR-132. Conclusion circVAPA is highly expressed in oral cancer, and its abnormal expression might affect the proliferation, invasion and migration of oral cancer cells by modulating the miR-132/HOXA7 signaling axis.
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Affiliation(s)
- Hao Chen
- Department of Stomatology, the Wuhan Sixth Hospital, Wuhan, China
| | - Ye Zhang
- Department of Stomatology, the First Affiliated Hospital of Jinan University, Jinan, China.,School of Stomatology, Jinan University, Jinan, China
| | - Kankui Wu
- Department of Stomatology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoyong Qiu
- Department of Stomatology, the Wuhan Sixth Hospital, Wuhan, China
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24
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Wu H, Fu M, Liu J, Chong W, Fang Z, Du F, Liu Y, Shang L, Li L. The role and application of small extracellular vesicles in gastric cancer. Mol Cancer 2021; 20:71. [PMID: 33926452 PMCID: PMC8081769 DOI: 10.1186/s12943-021-01365-z] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/19/2021] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer (GC) is a common tumour that affects humans worldwide, is highly malignant and has a poor prognosis. Small extracellular vesicles (sEVs), especially exosomes, are nanoscale vesicles released by various cells that deliver bioactive molecules to recipient cells, affecting their biological characteristics, changing the tumour microenvironment and producing long-distance effects. In recent years, many studies have clarified the mechanisms by which sEVs function with regard to the initiation, progression, angiogenesis, metastasis and chemoresistance of GC. These molecules can function as mediators of cell-cell communication in the tumour microenvironment and might affect the efficacy of immunotherapy. Due to their unique physiochemical characteristics, sEVs show potential as effective antitumour vaccines as well as drug carriers. In this review, we summarize the roles of sEVs in GC and highlight the clinical application prospects in the future.
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Affiliation(s)
- Hao Wu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Mengdi Fu
- Department of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Jin Liu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Wei Chong
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.,Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan, 250021, Shandong, China
| | - Zhen Fang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.,Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan, 250021, Shandong, China
| | - Fengying Du
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Yang Liu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Liang Shang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. .,Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan, 250021, Shandong, China.
| | - Leping Li
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. .,Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan, 250021, Shandong, China.
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