|
1
|
Huang CJ, Choo KB. Frequent dysregulation of multiple circular RNA isoforms with diverse regulatory mechanisms in cancer - Insights from circFNDC3B and beyond: Why unique circular RNA identifiers matter. Biochem Biophys Res Commun 2025; 758:151627. [PMID: 40112536 DOI: 10.1016/j.bbrc.2025.151627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/09/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
Circular RNAs (circRNAs) are post-transcriptional regulators generated through backsplicing of pre-mRNAs, primarily comprising exons of host genes. A single host gene may produce multiple circRNA isoforms with distinct structures and sequences. Dysregulated circRNA expression has been implicated in tumorigenesis. This review aims to investigate the selection and regulatory roles of circRNA isoforms in cancer using the extensively studied hsa_circFNDC3B and thirteen other circRNAs as study models. Interrogation of literature and databases, particularly the circBase, confirms that host genes generate a plethora of circRNA isoforms; however, only a small subset of isoforms is validated as dysregulated in tumor tissues. Notably, two or more isoforms of the same circRNA are frequently dysregulated in cancer. Structurally, short isoforms retaining 5'-proximal exons are preferentially selected, but for long host genes, circRNAs may arise from mid- or 3'-regions. We identify dysregulation of seven circFNDC3B isoforms across twelve cancer types and multi-isoforms in nine of the other thirteen circRNAs also in multiple cancers. MicroRNA sponging appears to be the major regulatory mechanism, but possible biased study designs raise concerns. Using circFNDC3B and circZFR as examples, we show inconsistency and inadequacy in circRNA nomenclature in different databases and the literature, underscoring the urgent need for a universally accepted standardized central circRNA database. As an interim measure, we propose guidelines for circRNA nomenclature in journal publications. Our findings caution against indiscriminate clinical use of specific circRNA isoforms as biomarkers or therapeutic targets without further validation.
Collapse
Affiliation(s)
- Chiu-Jung Huang
- Department of Animal Science & Graduate Institute of Biotechnology, College of Environmental Planning & Bioresources (former School of Agriculture), Chinese Culture University, Taipei, 111114, Taiwan.
| | - Kong Bung Choo
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.
| |
Collapse
|
|
2
|
Palcau AC, Pulito C, De Pascale V, Casadei L, Valerio M, Sacconi A, Canu V, Rutigliano D, Donzelli S, Sardo FL, Auciello FR, Pimpinelli F, Muti P, Botti C, Strano S, Blandino G. CircPVT1 weakens miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer. J Exp Clin Cancer Res 2025; 44:100. [PMID: 40114244 PMCID: PMC11924866 DOI: 10.1186/s13046-025-03355-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/04/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Altered metabolism is one of the cancer hallmarks. The role of circRNAs in cancer metabolism is poorly studied. Specifically, the impact of circPVT1, a well-known oncogenic circRNA on triple negative breast cancer metabolism is mechanistically underexplored. METHODS The clinical significance of circPVT1 expression levels was assessed in human breast cancer samples using digital PCR and the cancer genome atlas (TCGA) dataset. The oncogenic activity of circPVT1 was assessed in TNBC cell lines and in MCF-10 A breast cell line by either ectopic expression or depletion of circPVT1 molecule. CircPVT1 mediated metabolic perturbation was assessed by 1 H-NMR spectroscopy metabolic profiling. The binding of circPVT1 to miR-33a-5p and c-Myc recruitment onto the Glutaminase gene promoter were assessed by RNA immunoprecipitation and chromatin immunoprecipitation assays, respectively. The circPVT1/miR-33a-5p/Myc/GLS1 axis was functionally validated in breast cancer patients derived organoids. The viability of 2D and PDO cell models was assessed by ATP light assay and Opera Phenix plus high content screening. RESULTS We initially found that the expression of circPVT1 was significantly higher in tumoral tissues than in non-tumoral breast tissues. Basal like breast cancer patients with higher levels of circPVT1 exhibited shorter disease-free survival compared to those with lower expression. CircPVT1 ectopic expression rendered fully transformed MCF-10 A immortalized breast cells and increased tumorigenicity of TNBC cell lines. Depletion of endogenous circPVT1 reduced tumorigenicity of SUM-159PT and MDA-MB-468 cells. 1 H-NMR spectroscopy metabolic profiling of circPVT1 depleted breast cancer cell lines revealed reduced glycolysis and glutaminolitic fluxes. Conversely, MCF-10 A cells stably overexpressing circPVT1 exhibited increased glutaminolysis. Mechanistically, circPVT1 sponges miR-33a-5p, a well know metabolic microRNA, which in turn releases c-MYC activity promoting transcriptionally glutaminase. This activity facilitates the conversion of glutamine to glutamate. CircPVT1 depletion synergizes with GLS1 inhibitors BPTES or CB839 to reduce cell viability of breast cancer cell lines and breast cancer-derived organoids. CONCLUSIONS In aggregate, our findings unveil the circPVT1/miR-33a-5p/Myc/GLS1 axis as a pro-tumorigenic metabolic event sustaining breast cancer transformation with potential therapeutic implications.
Collapse
Affiliation(s)
- Alina Catalina Palcau
- Microbiology and Virology Unit, San Gallicano Dermatological Institute IRCSS, Rome, 00144, Italy
| | - Claudio Pulito
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Valentina De Pascale
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Luca Casadei
- Department of Chemistry, "Sapienza" University of Rome, Piazzale A. Moro 2, Rome, 00185, Italy
- VLC Biochem Solutions, Chieti, 66100, Italy
| | - Mariacristina Valerio
- Department of Chemistry, "Sapienza" University of Rome, Piazzale A. Moro 2, Rome, 00185, Italy
- VLC Biochem Solutions, Chieti, 66100, Italy
| | - Andrea Sacconi
- Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, Rome, 00144, Italy
| | - Valeria Canu
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Daniela Rutigliano
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Sara Donzelli
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Federica Lo Sardo
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | | | - Fulvia Pimpinelli
- Microbiology and Virology Unit, San Gallicano Dermatological Institute IRCSS, Rome, 00144, Italy
| | - Paola Muti
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Claudio Botti
- Department of Surgery, IRCCS, Regina Elena National Cancer Institute, Rome, 00144, Italy
| | - Sabrina Strano
- SAFU Laboratory, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
| | - Giovanni Blandino
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy.
| |
Collapse
|
|
3
|
Han Z, Yu X, Wang C, Song X, Zhong X, Guo R, Yu W, Luo C. Circular RNA circHSPA8 Aggravates Metastasis by Acting as a Competitive Inhibitor of miR-195-5p to Upregulate WNT3A Expression in Breast Cancer. J Cell Mol Med 2025; 29:e70499. [PMID: 40099939 PMCID: PMC11915588 DOI: 10.1111/jcmm.70499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 03/09/2025] [Accepted: 03/10/2025] [Indexed: 03/20/2025] Open
Abstract
Circular RNA (circRNA) plays a vital role in the tumorigenicity and progression of cancer by regulating various biological behaviours. It acts as a microRNA sponge, disrupting transcription and the abnormal expression of oncogenes. Hsa_circ_0024715, a circRNA generated from cyclization at specific sites of the HSPA8 gene, has been found to be highly expressed in breast cancer (BC) tissue based on non-coding RNA high-throughput sequencing. However, its functions remain poorly understood. In this study, we performed qPCR to evaluate the expression of circHSPA8 in BC tissues. Survival analysis in a prospective cohort revealed that high expression of circHSPA8 is associated with poor prognosis and lymphoid node metastasis. Overexpression of circHSPA8 in MCF-7 cells significantly enhanced their proliferative and invasive abilities, whereas knockdown of circHSPA8 in MDA-MB-231 cells significantly reduced their proliferative and invasive abilities. We found that circHSPA8 can promote epithelial-mesenchymal transition (EMT) in BC cells, primarily by upregulating the expression of WNT3A. This process depends on the sponging and inhibition of miR-195-5p, which suppresses the proliferation, invasion, and metastasis of BC cells. In vivo experiments further confirmed that circHSPA8 can promote the intravasation and extravasation of BC cells as well as the formation of metastatic lesions in the lungs. In summary, these data demonstrate that circHSPA8 promotes EMT by acting as a competitive inhibitor of miR-195-5p to upregulate the expression of WNT3A in BC, suggesting that dysregulation of circRNA in BC might be a pathological factor and potential therapeutic target.
Collapse
Affiliation(s)
- Zhuoying Han
- Department of Central LaboratoryThe Affiliated Huaian No. 1 People's Hospital, Nanjing Medical UniversityHuai'anChina
| | - Xiaojuan Yu
- Department of Clinical OncologyThe Affiliated Huaian No. 1 People's Hospital, Nanjing Medical UniversityHuai'anChina
| | - Chenlong Wang
- Department of Central LaboratoryThe Affiliated Huaian No. 1 People's Hospital, Nanjing Medical UniversityHuai'anChina
| | - Xiaoyu Song
- Department of Central LaboratoryThe Affiliated Huaian No. 1 People's Hospital, Nanjing Medical UniversityHuai'anChina
| | - Xiaomin Zhong
- Department of Clinical OncologyThe Affiliated Huaian No. 1 People's Hospital, Nanjing Medical UniversityHuai'anChina
| | - Renhua Guo
- Department of Clinical OncologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Weiyong Yu
- Department of Clinical OncologyThe Affiliated Huaian No. 1 People's Hospital, Nanjing Medical UniversityHuai'anChina
| | - Chao Luo
- Department of Central LaboratoryThe Affiliated Huaian No. 1 People's Hospital, Nanjing Medical UniversityHuai'anChina
- Biological Sample BankThe Affiliated Huaian No. 1 People's Hospital, Nanjing Medical UniversityHuai'anChina
| |
Collapse
|
|
4
|
Wang J, Lv ZY, Li P, Zhang Y, Li X, Shen DF. Lnc PVT1 facilitates TGF-β1-induced human cardiac fibroblast activation in vitro and ISO-induced myocardial fibrosis in vivo through regulating MYC. Mol Cell Biochem 2025; 480:1611-1625. [PMID: 38997507 DOI: 10.1007/s11010-024-05060-7] [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: 09/20/2023] [Accepted: 06/29/2024] [Indexed: 07/14/2024]
Abstract
Cardiac fibrosis is a commonly seen pathophysiological process in various cardiovascular disorders, such as coronary heart disorder, hypertension, and cardiomyopathy. Cardiac fibroblast trans-differentiation into myofibroblasts (MFs) is a key link in myocardial fibrosis. LncRNA PVT1 participates in fibrotic diseases in multiple organs; however, its role and mechanism in cardiac fibrosis remain largely unknown. Human cardiac fibroblasts (HCFs) were stimulated with TGF-β1 to induce myofibroblast; Immunofluorescent staining, Immunoblotting, and fluorescence in situ hybridization were used to detect the myofibroblasts phenotypes and lnc PVT1 expression. Cell biological phenotypes induced by lnc PVT1 knockdown or overexpression were detected by CCK-8, flow cytometry, and Immunoblotting. A mouse model of myocardial fibrosis was induced using isoproterenol (ISO), and the cardiac functions were examined by echocardiography measurements, cardiac tissues by H&E, and Masson trichrome staining. In this study, TGF-β1 induced HCF transformation into myofibroblasts, as manifested as significantly increased levels of α-SMA, vimentin, collagen I, and collagen III; the expression level of lnc PVT1 expression showed to be significantly increased by TGF-β1 stimulation. The protein levels of TGF-β1, TGFBR1, and TGFBR2 were also decreased by lnc PVT1 knockdown. Under TGF-β1 stimulation, lnc PVT1 knockdown decreased FN1, α-SMA, collagen I, and collagen III protein contents, inhibited HCF cell viability and enhanced cell apoptosis, and inhibited Smad2/3 phosphorylation. Lnc PVT1 positively regulated MYC expression with or without TGF-β1 stimulation; MYC overexpression in TGF-β1-stimulated HCFs significantly attenuated the effects of lnc PVT1 knockdown on HCF proliferation and trans-differentiation to MFs. In the ISO-induced myocardial fibrosis model, lnc PVT1 knockdown partially reduced fibrotic area, improved cardiac functions, and decreased the levels of fibrotic markers. In addition, lnc PVT1 knockdown decreased MYC and CDK4 levels but increased E-cadherin in mice heart tissues. lnc PVT1 is up-regulated in cardiac fibrosis and TGF-β1-stimulated HCFs. Lnc PVT1 knockdown partially ameliorates TGF-β1-induced HCF activation and trans-differentiation into MFs in vitro and ISO-induced myocardial fibrosis in vivo, potentially through interacting with MYC and up-regulating MYC.
Collapse
Affiliation(s)
- Juan Wang
- The Second Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, China
| | - Zhong-Yin Lv
- The Fifth Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, China
| | - Peng Li
- The Fifth Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, China
| | - Yin Zhang
- The Fifth Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, China
| | - Xia Li
- The Fifth Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang, China.
- Department of Cardiology, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumchi, 830001, Xinjiang, China.
| | - Di-Fei Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| |
Collapse
|
|
5
|
Liu W, Niu J, Huo Y, Zhang L, Han L, Zhang N, Yang M. Role of circular RNAs in cancer therapy resistance. Mol Cancer 2025; 24:55. [PMID: 39994791 PMCID: PMC11854110 DOI: 10.1186/s12943-025-02254-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 01/30/2025] [Indexed: 02/26/2025] Open
Abstract
Over the past decade, circular RNAs (circRNAs) have gained recognition as a novel class of genetic molecules, many of which are implicated in cancer pathogenesis via different mechanisms, including drug resistance, immune escape, and radio-resistance. ExosomalcircRNAs, in particular, facilitatecommunication between tumour cells and micro-environmental cells, including immune cells, fibroblasts, and other components. Notably, micro-environmental cells can reportedly influence tumour progression and treatment resistance by releasing exosomalcircRNAs. circRNAs often exhibit tissue- and cancer-specific expression patterns, and growing evidence highlights their potential clinical relevance and utility. These molecules show strong promise as potential biomarkers and therapeutic targets for cancer diagnosis and treatment. Therefore, this review aimed to briefly discuss the latest findings on the roles and resistance mechanisms of key circRNAs in the treatment of various malignancies, including lung, breast, liver, colorectal, and gastric cancers, as well as haematological malignancies and neuroblastoma.This review will contribute to the identification of new circRNA biomarkers for the early diagnosis as well as therapeutic targets for the treatment of cancer.
Collapse
Affiliation(s)
- Wenjuan Liu
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Jiling Niu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Yanfei Huo
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Long Zhang
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Ming Yang
- Shandong Provincial Key Laboratory of Precision Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
- School of Life Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, Shandong Province, China.
| |
Collapse
|
|
6
|
Molaei P, Mahdavinezhad A, Najafi R, Hashemi M, Tapak L, Afshar S. Role of hsa_Circ_0001821 in Colorectal Cancer Pathogenesis and Response to 5-Fluorouracil through miR-203a-3p/FGF-2 Axis. IRANIAN BIOMEDICAL JOURNAL 2025; 29:82-89. [PMID: 40231340 PMCID: PMC12040633 DOI: 10.61186/ibj.4942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 12/22/2024] [Indexed: 04/20/2025]
Abstract
Background Chemoresistance, the primary cause of disease relapse and treatment failure, poses a significant challenge in the treatment of colorectal cancer (CRC). Understanding the molecular mechanisms that underlie the pathogenesis and chemoresistance of colorectal tumor cells, as well as identifying novel therapeutic strategies, would be crucial. This study aimed to evaluate the role of hsa_Circ_0001821 in response to 5-fluorouracil (5-FU) in CRC, a topic that has not been examined to date. Methods The current study investigated the effect of hsa_Circ_0001821 suppression using interfering RNAs on the response of colorectal tumor cells to 5-FU. The expression levels of hsa_Circ_0001821, hsa-miR-203a-3p, BAX, BCL-2, and FGF-2 were determined via quantitative RT-PCR. Cell survival, migration rate, and apoptosis induction of colorectal tumor cells subjected to 5-FU treatment were assessed using the MTT test, scratch assay, and flow cytometry analysis, respectively. Results Knockdown of hsa_Circ_0001821 with siRNA increased the expression level of hsa-miR-203a-3p and decreased the expression level of FGF-2. Additionally, the knockdown of hsa_Circ_0001821 enhanced the sensitivity of colorectal tumor cells to 5-FU. This circRNA significantly affected the viability, apoptosis, and migration of tumor cells. Conclusion Our study reveals the potential role of hsa_Circ_0001821 in controlling the tumor cell viability and response to 5-FU by targeting the hsa-miR-203a-3p/FGF-2 axis. These findings enhance our understanding of the molecular mechanisms that influence chemotherapy response in CRC, paving the way for the identification of more effective treatments for this disease.
Collapse
Affiliation(s)
- Pejman Molaei
- Department of molecular medicine, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, Institute of cancer, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Mahdavinezhad
- Department of molecular medicine, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, Institute of cancer, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rezvan Najafi
- Department of molecular medicine, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, Institute of cancer, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Leili Tapak
- Modeling of Noncommunicable Diseases Research Center, Institute of Health Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Biostatistics, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Saeid Afshar
- Cancer Research Center, Institute of cancer, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
| |
Collapse
|
|
7
|
Wu S, Hu Y, Lei X, Yang X. The Emerging Roles of CircPVT1 in Cancer Progression. Curr Pharm Biotechnol 2025; 26:1-8. [PMID: 38454774 DOI: 10.2174/0113892010282141240226112253] [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: 10/17/2023] [Revised: 01/27/2024] [Accepted: 02/15/2024] [Indexed: 03/09/2024]
Abstract
CircRNA is stable due to its ring structure and is abundant in humans, which not only exists in various tissues and biofluids steadily but also plays a significant role in the physiology and pathology of human beings. CircPVT1, an endogenous circRNA, has recently been identified from the PVT1 gene located in the cancer risk region 8q24. CircPVT1 is reported to be highly expressed in many different tumors, where it affects tumor cell proliferation, apoptosis, invasion, and migration. We summarize the biosynthesis and biological functions of circPVT1 and analyze the relationship between circPVT1 and tumors as well as its significance to tumors. Further, it's noteworthy for the diagnosis, treatment, and prognosis of cancer patients. Therefore, circPVT1 is likely to become an innovative tumor marker.
Collapse
Affiliation(s)
- Shijie Wu
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, People's Republic of China
| | - Yan Hu
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, People's Republic of China
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, People's Republic of China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, Hunan, 421001, People's Republic of China
| | - Xiaoyan Yang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, People's Republic of China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, Hunan, 421001, People's Republic of China
| |
Collapse
|
|
8
|
Chen Y, Du C, Tang J, Zhao Y, Xie H, Zheng S, Tu Z. Super-enhancer-associated circPVT1 promotes malignancy of hepatocellular carcinoma via YBX1-mediated RRM2 activation. Cancer Lett 2024; 611:217395. [PMID: 39694225 DOI: 10.1016/j.canlet.2024.217395] [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: 02/08/2024] [Revised: 12/08/2024] [Accepted: 12/14/2024] [Indexed: 12/20/2024]
Abstract
Circular RNAs (circRNAs), the essential members of epigenetic reprogramming, are emerging as an appealing layer in hepatocellular carcinoma (HCC). Super-enhancers (SEs) are large clusters of transcriptional enhancers with the tremendous gene activation potential and are extensively investigated in cancer research. The present study explores and uncovers an SE-related circRNA circPVT1, identifying its biological functions and downstream mechanisms in HCC. CircPVT1 is upregulated in HCC, serving as an independent prognostic factor for patients with HCC. Enrichment of H3K27ac and H3K4me1 modifications has been confirmed at the genomic loci of circPVT1's host gene, and the expression of circPVT1 is triggered by SEs. Functionally, circPVT1 enhances cell propagation and mobility capabilities in vitro, and facilitates tumour growth and metastasis in vivo. Mechanistically, circPVT1 recruits YBX1 into the cell nucleus, promoting the transcription of RRM2. Dysregulation of the circPVT1-RRM2 axis advances HCC malignancy, while inhibition of RRM2 or SE alleviates the effects of circPVT1 overexpression. In conclusion, our work demonstrates that circPVT1 is driven by super-enhancers. CircPVT1 promotes HCC progression via YBX1-mediated transcriptional activation of RRM2. These findings provide constructive insights into exploring the pathogenesis of HCC.
Collapse
Affiliation(s)
- Yunhao Chen
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang Province, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China.
| | - Chengli Du
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
| | - Jie Tang
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
| | - Yanchun Zhao
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
| | - Haiyang Xie
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang Province, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
| | - Shusen Zheng
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Zhejiang Province, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
| | - Zhengliang Tu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
| |
Collapse
|
|
9
|
Abohassan M, Khaleel AQ, Pallathadka H, Kumar A, Allela OQB, Hjazi A, Pramanik A, Mustafa YF, Hamzah HF, Mohammed BA. Circular RNA as a Biomarker for Diagnosis, Prognosis and Therapeutic Target in Acute and Chronic Lymphoid Leukemia. Cell Biochem Biophys 2024; 82:1979-1991. [PMID: 39136839 DOI: 10.1007/s12013-024-01404-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2024] [Indexed: 10/02/2024]
Abstract
Circular RNAs (circRNAs) are single-stranded RNAs that have received much attention in recent years. CircRNAs lack a 5' head and a 3' poly-A tail. The structure of this type of RNAs make them resistant to digestion by exonucleases. CircRNAs are expressed in different cells and have various functions. The function of circRNAs is done by sponging miRNAs, changing gene expression, and protein production. The expression of circRNAs changes in different types of cancers, which causes changes in cell growth, proliferation, differentiation, and apoptosis. Changes in the expression of circRNAs can cause the invasion and progression of tumors. Studies have shown that changes in the expression of circRNAs can be seen in acute lymphoid leukemia (ALL) and chronic lymphoid leukemia (CLL). The conducted studies aim to identify circRNAs whose expression has changed in these leukemias and their more precise function so that these circRNAs can be identified as biomarkers, prediction of patient prognosis, and treatment targets for ALL and CLL patients. In this study, we review the studies conducted on the role and function of circRNAs in ALL and CLL patients. The results of the studies show that there is a possibility of using circRNAs as biomarkers in the identification and treatment of patients in the future.
Collapse
MESH Headings
- Humans
- RNA, Circular/genetics
- RNA, Circular/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Prognosis
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy
- RNA/metabolism
- RNA/genetics
- MicroRNAs/genetics
- MicroRNAs/metabolism
Collapse
Affiliation(s)
- Mohammad Abohassan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Abdulrahman Qais Khaleel
- Department of Medical Instruments Engineering, Al-Maarif University College, Al Anbar, 31001, Iraq.
| | | | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka, 560069, India
- Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | | | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Ivison of Research and Innovation Uttaranchal University, Dehradun, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Hamza Fadhel Hamzah
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | | |
Collapse
|
|
10
|
Shakerian N, Darzi-Eslam E, Afsharnoori F, Bana N, Noorabad Ghahroodi F, Tarin M, Mard-Soltani M, Khalesi B, Hashemi ZS, Khalili S. Therapeutic and diagnostic applications of exosomes in colorectal cancer. Med Oncol 2024; 41:203. [PMID: 39031221 DOI: 10.1007/s12032-024-02440-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 06/26/2024] [Indexed: 07/22/2024]
Abstract
Exosomes play a key role in colorectal cancer (CRC) related processes. This review explores the various functions of exosomes in CRC and their potential as diagnostic markers, therapeutic targets, and drug delivery vehicles. Exosomal long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) significantly influence CRC progression. Specific exosomal lncRNAs are linked to drug resistance and tumor growth, respectively, highlighting their therapeutic potential. Similarly, miRNAs like miR-21, miR-10b, and miR-92a-3p, carried by exosomes, contribute to chemotherapy resistance by altering signaling pathways and gene expression in CRC cells. The review also discusses exosomes' utility in CRC diagnosis. Exosomes from cancer cells have distinct molecular signatures compared to healthy cells, making them reliable biomarkers. Specific exosomal lncRNAs (e.g., CRNDE-h) and miRNAs (e.g., miR-17-92a) have shown effectiveness in early CRC detection and monitoring of treatment responses. Furthermore, exosomes show promise as vehicles for targeted drug delivery. The potential of mesenchymal stem cell (MSC)-derived exosomes in CRC treatment is also noted, with their role varying from promoting to inhibiting tumor progression. The application of multi-omics approaches to exosome research is highlighted, emphasizing the potential for discovering novel CRC biomarkers through comprehensive genomic, transcriptomic, proteomic, and metabolomic analyses. The review also explores the emerging field of exosome-based vaccines, which utilize exosomes' natural properties to elicit strong immune responses. In conclusion, exosomes represent a promising frontier in CRC research, offering new avenues for diagnosis, treatment, and prevention. Their unique properties and versatile functions underscore the need for continued investigation into their clinical applications and underlying mechanisms.
Collapse
Affiliation(s)
- Neda Shakerian
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran
| | - Elham Darzi-Eslam
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Afsharnoori
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nikoo Bana
- Kish International Campus, University of Teheran, Tehran, Iran
| | - Faezeh Noorabad Ghahroodi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mojtaba Tarin
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Maysam Mard-Soltani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Education and Extension Organization, Razi Vaccine and Serum Research Institute, Agricultural Research, Karaj, 3197619751, Iran
| | - Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran.
| |
Collapse
|
|
11
|
Li LG, Peng XC, Yang ZY, Han N, Gou CL, Shi J, Yu LL, Chen NN, Yu TT, Li TF, Li XY, Hu J. Dihydroartemisinin-driven selective anti-lung cancer proliferation by binding to EGFR and inhibition of NRAS signaling pathway-induced DNA damage. Sci Rep 2024; 14:11704. [PMID: 38778121 PMCID: PMC11111767 DOI: 10.1038/s41598-024-62126-8] [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: 11/23/2023] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Chemotherapeutic agents can inhibit the proliferation of malignant cells due to their cytotoxicity, which is limited by collateral damage. Dihydroartemisinin (DHA), has a selective anti-cancer effect, whose target and mechanism remain uncovered. The present work aims to examine the selective inhibitory effect of DHA as well as the mechanisms involved. The findings revealed that the Lewis cell line (LLC) and A549 cell line (A549) had an extremely rapid proliferation rate compared with the 16HBE cell line (16HBE). LLC and A549 showed an increased expression of NRAS compared with 16HBE. Interestingly, DHA was found to inhibit the proliferation and facilitate the apoptosis of LLC and A549 with significant anti-cancer efficacy and down-regulation of NRAS. Results from molecular docking and cellular thermal shift assay revealed that DHA could bind to epidermal growth factor receptor (EGFR) molecules, attenuating the EGF binding and thus driving the suppressive effect. LLC and A549 also exhibited obvious DNA damage in response to DHA. Further results demonstrated that over-expression of NRAS abated DHA-induced blockage of NRAS. Moreover, not only the DNA damage was impaired, but the proliferation of lung cancer cells was also revitalized while NRAS was over-expression. Taken together, DHA could induce selective anti-lung cancer efficacy through binding to EGFR and thereby abolishing the NRAS signaling pathway, thus leading to DNA damage, which provides a novel theoretical basis for phytomedicine molecular therapy of malignant tumors.
Collapse
Grants
- YC2022027, YC2023009 Innovative Research Program for Graduates of Hubei University of Medicine
- YC2022027, YC2023009 Innovative Research Program for Graduates of Hubei University of Medicine
- 202213249001, 202210929001, S202210929004, S202210929007, S202210929010 National Training Program of Innovation and Entrepreneurship for Undergraduates
- Q20222107, B2022128 Natural Science Foundation of Hubei Provincial Department of Education
- Q20222107, B2022128 Natural Science Foundation of Hubei Provincial Department of Education
- 2021-2025, 2023XKQT2 Advantages Discipline Group (Medicine) Project in Higher Education of Hubei Province
- 2023AFB837, 2022CFB994 Natural Science Foundation of Hubei Province
- 2020QDJZR002, 2021QDJZR015, 2019QDJZR02, 2021QDJZR007, 2020QDJZR020 Cultivating Project for Young Scholar at Hubei University of Medicine
Collapse
Affiliation(s)
- Liu-Gen Li
- Shiyan Key Laboratory of Natural Medicine Nanoformulation ResearchHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China
| | - Xing-Chun Peng
- Department of Pathology, Shenzhen Pingle Orthopedic Hospital (Shenzhen Pingshan Traditional Chinese Medicine Hospital), Shenzhen, 518118, Guangzhou Province, People's Republic of China
- Department of Pathology, Sinopharm DongFeng General Hospital, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China
| | - Zi-Yi Yang
- Shiyan Key Laboratory of Natural Medicine Nanoformulation ResearchHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China
| | - Ning Han
- Shiyan Key Laboratory of Natural Medicine Nanoformulation ResearchHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China
| | - Chang-Long Gou
- Department of Ultrasound Medicine, Taihe Hospital of Shiyan, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China
| | - Jun Shi
- Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, 518000, People's Republic of China
| | - Li-Li Yu
- Traditional Chinese Medicine Hospital, Dianjiang, Chongqing, 408300, People's Republic of China
| | - Nan-Nan Chen
- Shiyan Key Laboratory of Natural Medicine Nanoformulation ResearchHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China
| | - Ting-Ting Yu
- Shiyan Key Laboratory of Natural Medicine Nanoformulation ResearchHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China
| | - Tong-Fei Li
- Shiyan Key Laboratory of Natural Medicine Nanoformulation ResearchHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China.
| | - Xian-Yu Li
- Shiyan Key Laboratory of Natural Medicine Nanoformulation ResearchHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China.
| | - Jun Hu
- Shiyan Key Laboratory of Natural Medicine Nanoformulation ResearchHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, 442000, Hubei, People's Republic of China.
| |
Collapse
|
|
12
|
Wang T, He M, Zhang X, Guo Z, Wang P, Long F. Deciphering the impact of circRNA-mediated autophagy on tumor therapeutic resistance: a novel perspective. Cell Mol Biol Lett 2024; 29:60. [PMID: 38671354 PMCID: PMC11046940 DOI: 10.1186/s11658-024-00571-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
Cancer therapeutic resistance remains a significant challenge in the pursuit of effective treatment strategies. Circular RNAs (circRNAs), a class of non-coding RNAs, have recently emerged as key regulators of various biological processes, including cancer progression and drug resistance. This review highlights the emerging role of circRNAs-mediated autophagy in cancer therapeutic resistance, a cellular process that plays a dual role in cancer by promoting both cell survival and death. Increasing evidence suggests that circRNAs can modulate autophagy pathways, thereby influencing the response of cancer cells to therapeutic agents. In this context, the intricate interplay between circRNAs, autophagy, and therapeutic resistance is explored. Various mechanisms are discussed through which circRNAs can impact autophagy, including direct interactions with autophagy-related genes, modulation of signaling pathways, and cross-talk with other non-coding RNAs. Furthermore, the review delves into specific examples of how circRNA-mediated autophagy regulation can contribute to resistance against chemotherapy and radiotherapy. Understanding these intricate molecular interactions provides valuable insights into potential strategies for overcoming therapeutic resistance in cancer. Exploiting circRNAs as therapeutic targets or utilizing them as diagnostic and predictive biomarkers opens new avenues for developing personalized treatment approaches. In summary, this review underscores the importance of circRNA-mediated autophagy in cancer therapeutic resistance and proposes future directions for research in this exciting and rapidly evolving field.
Collapse
Affiliation(s)
- Ting Wang
- Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Mengjie He
- Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610041, China
| | - Xudong Zhang
- Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Zhixun Guo
- Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Pinghan Wang
- Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610041, China.
| | - Fangyi Long
- Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610041, China.
| |
Collapse
|
|
13
|
Cheng B, Li L, Luo T, Wang Q, Luo Y, Bai S, Li K, Lai Y, Huang H. Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway. J Exp Clin Cancer Res 2024; 43:67. [PMID: 38429845 PMCID: PMC10905933 DOI: 10.1186/s13046-024-02962-8] [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: 11/20/2023] [Accepted: 01/19/2024] [Indexed: 03/03/2024] Open
Abstract
BACKGROUND Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC. METHODS Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity. RESULTS Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity. CONCLUSION Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer.
Collapse
Affiliation(s)
- Bisheng Cheng
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Urology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Lingfeng Li
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Tianlong Luo
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qiong Wang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 511430, China
| | - Yong Luo
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Shoumin Bai
- Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Kaiwen Li
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
| | - Yiming Lai
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
| | - Hai Huang
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
- Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
- Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, China.
| |
Collapse
|
|
14
|
Zhao X, van den Berg A, Winkle M, Koerts J, Seitz A, de Jong D, Rutgers B, van der Sluis T, Bakker E, Kluiver J. Proliferation-promoting roles of linear and circular PVT1 are independent of their ability to bind miRNAs in B-cell lymphoma. Int J Biol Macromol 2023; 253:126744. [PMID: 37689284 DOI: 10.1016/j.ijbiomac.2023.126744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 08/01/2023] [Accepted: 08/27/2023] [Indexed: 09/11/2023]
Abstract
Plasmacytoma Variant Translocation 1 (PVT1) is a long non-coding RNA located at 8q24.21 immediately downstream of MYC. Both the linear and circular PVT1 transcripts contribute to cancer pathogenesis by binding microRNAs. However, little is known about their roles in B-cell lymphoma. Here we studied their expression patterns, role in growth, and ability to bind miRNAs in B-cell lymphoma. Linear PVT1 transcripts were downregulated in B-cell cell lymphoma lines compared to germinal center B cells, while circPVT1 levels were increased. Two Hodgkin lymphoma cell lines had a homozygous deletion including the 5' region of the PVT1 locus, resulting in a complete lack of circPVT1 and 5' linear PVT1 transcripts. Inhibition of both linear and circular PVT1 decreased growth of Burkitt lymphoma, while the effects on Hodgkin lymphoma and diffuse large B cell lymphoma were less pronounced. Overexpression of circPVT1 promoted growth of B-cell lymphoma lacking or having low endogenous circPVT1 levels. Contrary to other types of cancer, linear and circular PVT1 transcripts did not interact with miRNAs in B-cell lymphoma. Overall, we showed an opposite expression pattern of linear and circular PVT1 in B-cell lymphoma. Their effect on growth was independent of their ability to bind miRNAs.
Collapse
Affiliation(s)
- Xing Zhao
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
| | - Melanie Winkle
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Jasper Koerts
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Annika Seitz
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Bea Rutgers
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Tineke van der Sluis
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Emke Bakker
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
| |
Collapse
|
|
15
|
Almalki WH. Beyond the genome: lncRNAs as regulators of the PI3K/AKT pathway in lung cancer. Pathol Res Pract 2023; 251:154852. [PMID: 37837857 DOI: 10.1016/j.prp.2023.154852] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/18/2023] [Accepted: 10/02/2023] [Indexed: 10/16/2023]
Abstract
Lung cancer is a prevalent and devastating disease, representing a significant global health burden. Despite advancements in therapeutic strategies, the molecular mechanisms underlying its pathogenesis remain incompletely understood. Lung cancer typically displays the deregulated activity of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, which is vital for cell proliferation, survival, and metastasis. Emerging evidence suggests that long non-coding RNA (lncRNAs) can modulate the PI3K/AKT pathway, offering new insights into lung cancer biology and potential therapeutic opportunities. These lncRNA act as either oncogenes, promoting pathway activation, or tumour suppressors, attenuating pathway signalling. The dysregulation of lncRNA is associated with various cellular processes, including apoptosis, cell cycle control, epithelial-mesenchymal transition (EMT), and angiogenesis, ultimately influencing lung cancer growth and metastasis. The development of novel therapeutic strategies, such as small interfering RNAs (siRNAs), antisense oligonucleotides, and CRISPR/Cas9-mediated gene editing, holds promise for restoring lncRNAs dysregulation and re-establishing the equilibrium of the PI3K/AKT pathway. The emerging role of lncRNAs as regulators of the PI3K/AKT pathway sheds new light on the complex molecular landscape of lung cancer. Understanding the interplay between lncRNA and the PI3K/AKT pathway could lead to the identification of novel biomarkers for prognosis and therapeutic targets for precision medicine. The potential of lncRNAs-based therapeutics may pave the way for more effective and personalized treatment approaches in lung cancer and potentially other malignancies with dysregulated PI3K/AKT signalling. This review aims to explore the emerging role of lncRNAs as key regulators of the PI3K/AKT pathway in lung cancer.
Collapse
Affiliation(s)
- Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
| |
Collapse
|
|
16
|
Palcau AC, Brandi R, Mehterov NH, Botti C, Blandino G, Pulito C. Exploiting Long Non-Coding RNAs and Circular RNAs as Pharmacological Targets in Triple-Negative Breast Cancer Treatment. Cancers (Basel) 2023; 15:4181. [PMID: 37627209 PMCID: PMC10453179 DOI: 10.3390/cancers15164181] [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: 07/04/2023] [Revised: 08/13/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer is one of the most frequent causes of cancer death among women worldwide. In particular, triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype because it is characterized by the absence of molecular targets, thus making it an orphan type of malignancy. The discovery of new molecular druggable targets is mandatory to improve treatment success. In that context, non-coding RNAs represent an opportunity for modulation of cancer. They are RNA molecules with apparently no protein coding potential, which have been already demonstrated to play pivotal roles within cells, being involved in different processes, such as proliferation, cell cycle regulation, apoptosis, migration, and diseases, including cancer. Accordingly, they could be used as targets for future TNBC personalized therapy. Moreover, the peculiar characteristics of non-coding RNAs make them reliable biomarkers to monitor cancer treatment, thus, to monitor recurrence or chemoresistance, which are the most challenging aspects in TNBC. In the present review, we focused on the oncogenic or oncosuppressor role of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) mostly involved in TNBC, highlighting their mode of action and depicting their potential role as a biomarker and/or as targets of new non-coding RNA-based therapeutics.
Collapse
Affiliation(s)
- Alina Catalina Palcau
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (A.C.P.); (R.B.); (G.B.)
| | - Renata Brandi
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (A.C.P.); (R.B.); (G.B.)
| | - Nikolay Hristov Mehterov
- Department of Medical Biology, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria;
- Research Institute, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria
| | - Claudio Botti
- Breast Surgery Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Giovanni Blandino
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (A.C.P.); (R.B.); (G.B.)
| | - Claudio Pulito
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (A.C.P.); (R.B.); (G.B.)
| |
Collapse
|
|
17
|
RezaSoltani M, Forouzesh F, Salehi Z, Zabihi MR, Rejali L, Nazemalhosseini-Mojarad E. Identification of LncPVT1 and CircPVT1 as prognostic biomarkers in human colorectal polyps. Sci Rep 2023; 13:13113. [PMID: 37573419 PMCID: PMC10423217 DOI: 10.1038/s41598-023-40288-1] [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] [Received: 04/27/2023] [Accepted: 08/08/2023] [Indexed: 08/14/2023] Open
Abstract
LncPVT1 and CircPVT1 are isoforms for the PVT1 gene and are associated with cancer progression and carcinogenesis. Our study investigated the expression of LncPVT1 and CircPVT1 in colon adenoma polyps. 40 tissues of colorectal polyps and 40 normal-adjacent tissues (NATs) were taken. The expression of LncPVT1 and CircPVT1 was evaluated through qRael-Time PCR. The relation between expression and features of clinicopathological was explored. The ceRNA network was constructed by LncPVT1 and CircPVT1 and predicted miRNAs and miRNAs targets. Further, hub nodes in this network were determined using the cytoHubba package. Over-expressed LncPVT1 and CircPVT1 were differentiated in polyp and NATs. The expression level of LncPVT1 and CircPVT1 were significantly higher in adenoma polyps than in hyperplastic polyps. The area under the curve of the ROC estimate for the LncPVT1 and CircPVT1 was 0.74 and 0.77, respectively. A positive correlation was observed between the LncPVT1 expression and CircPVT1. Three miRNAs, including hsa-miR-484, hsa-miR-24-3p, hsa-miR-423-5p, and CircPVT1, were detected as ceRNA hub nodes. In this study, expression profiles of LncPVT1 and CircPVT1 were significantly higher in precancerous polyps. In addition, based on our in silico analysis, LncPVT1, CircPVT1/miR-484, miR-24-3p, miR-423-5p/PLAGL2 axis might be involved in colon cancer development. LncPVT1 and CircPVT1 can be prescribed as warning problems as potential prognostic biomarkers in patients with pre-CRC colon polyps.
Collapse
Affiliation(s)
- Mahsa RezaSoltani
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Flora Forouzesh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, P.O. Box: 193951495, Tehran, Iran.
| | - Zahra Salehi
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Zabihi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Leili Rejali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Department of Cancer, Gastroenterology and Liver Disease Research center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
18
|
Blandino G, Dinami R, Marcia M, Anastasiadou E, Ryan BM, Palcau AC, Fattore L, Regazzo G, Sestito R, Loria R, Díaz Méndez AB, Cappelletto MC, Pulito C, Monteonofrio L, Calin GA, Sozzi G, Cheong JK, Aharonov R, Ciliberto G. The new world of RNA diagnostics and therapeutics. J Exp Clin Cancer Res 2023; 42:189. [PMID: 37507791 PMCID: PMC10386627 DOI: 10.1186/s13046-023-02752-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
The 5th Workshop IRE on Translational Oncology was held in Rome (Italy) on 27-28 March at the IRCCS Regina Elena National Cancer Institute. This meeting entitled "The New World of RNA diagnostics and therapeutics" highlightes the significant progress in the RNA field made over the last years. Research moved from pure discovery towards the development of diagnostic biomarkers or RNA-base targeted therapies seeking validation in several clinical trials. Non-coding RNAs in particular have been the focus of this workshop due to their unique properties that make them attractive tools for the diagnosis and therapy of cancer.This report collected the presentations of many scientists from different institutions that discussed recent oncology research providing an excellent overview and representative examples for each possible application of RNA as biomarker, for therapy or to increase the number of patients that can benefit from precision oncology treatment.In particular, the meeting specifically emphasized two key features of RNA applications: RNA diagnostic (Blandino, Palcau, Sestito, Díaz Méndez, Cappelletto, Pulito, Monteonofrio, Calin, Sozzi, Cheong) and RNA therapeutics (Dinami, Marcia, Anastasiadou, Ryan, Fattore, Regazzo, Loria, Aharonov).
Collapse
Affiliation(s)
- Giovanni Blandino
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy.
| | - Roberto Dinami
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | | | - Eleni Anastasiadou
- Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy
| | | | - Alina Catalina Palcau
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Luigi Fattore
- SAFU Laboratory, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giulia Regazzo
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Rosanna Sestito
- Preclinical models and new therapeutic agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Rossella Loria
- Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Ana Belén Díaz Méndez
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Maria Chiara Cappelletto
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Claudio Pulito
- Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Laura Monteonofrio
- Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | | | | | - Jit Kong Cheong
- National University of Singapore Yong Loo Lin School of Medicine, NUS Centre for Cancer Research and Mirxes Lab Pte Ltd, Singapore, Singapore
| | | | - Gennaro Ciliberto
- Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| |
Collapse
|
|
19
|
Uppaluri KR, Challa HJ, Gaur A, Jain R, Krishna Vardhani K, Geddam A, Natya K, Aswini K, Palasamudram K, K SM. Unlocking the potential of non-coding RNAs in cancer research and therapy. Transl Oncol 2023; 35:101730. [PMID: 37406550 PMCID: PMC10366642 DOI: 10.1016/j.tranon.2023.101730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/30/2023] [Accepted: 06/21/2023] [Indexed: 07/07/2023] Open
Abstract
Non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, with growing evidence implicating their involvement in cancer development and progression. The potential of ncRNAs as diagnostic and prognostic biomarkers for cancer is promising, with emphasis on their use in liquid biopsy and tissue-based diagnostics. In a nutshell, the review comprehensively summarizes the diverse classes of ncRNAs implicated in cancer, including microRNAs, long non-coding RNAs, and circular RNAs, and their functions and mechanisms of action. Furthermore, we describe the potential therapeutic applications of ncRNAs, including anti-miRNA oligonucleotides, siRNAs, and other RNA-based therapeutics in cancer treatment. However, significant challenges remain in developing effective ncRNA-based diagnostics and therapeutics, including the lack of specificity, limited understanding of mechanisms, and delivery challenges. This review also covers the current state-of-the-art non-coding RNA research technologies and bioinformatic analysis tools. Lastly, we outline future research directions in non-coding RNA research in cancer, including developing novel biomarkers, therapeutic targets, and modalities. In summary, this review provides a comprehensive understanding of non-coding RNAs in cancer and their potential clinical applications, highlighting both the opportunities and challenges in this rapidly evolving field.
Collapse
Affiliation(s)
- Kalyan Ram Uppaluri
- GenepoweRx, Uppaluri K&H Personalized Medicine Clinic, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana 500033, India.
| | - Hima J Challa
- GenepoweRx, Uppaluri K&H Personalized Medicine Clinic, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana 500033, India
| | - Ashish Gaur
- Department of Biotechnology, GLA University, Mathura, India
| | - Rajul Jain
- Dayalbagh Educational Institute, Agra, India
| | - K Krishna Vardhani
- GenepoweRx, Uppaluri K&H Personalized Medicine Clinic, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana 500033, India
| | - Anusha Geddam
- GenepoweRx, Uppaluri K&H Personalized Medicine Clinic, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana 500033, India
| | - K Natya
- GenepoweRx, Uppaluri K&H Personalized Medicine Clinic, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana 500033, India
| | - K Aswini
- GenepoweRx, Uppaluri K&H Personalized Medicine Clinic, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana 500033, India
| | - Kalyani Palasamudram
- GenepoweRx, Uppaluri K&H Personalized Medicine Clinic, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana 500033, India
| | - Sri Manjari K
- GenepoweRx, Uppaluri K&H Personalized Medicine Clinic, Suit #2B, Plot No. 240, Nirvana, Road No. 36, Jawahar Colony, Jubilee Hills, Hyderabad, Telangana 500033, India.
| |
Collapse
|
|
20
|
Yi J, Wang L, Hu G, Zhang Y, Du J, Ding J, Ji X, Shen H, Huang H, Ye F, Liu W. CircPVT1 promotes ER-positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS. EMBO J 2023; 42:e112408. [PMID: 37009655 PMCID: PMC10183818 DOI: 10.15252/embj.2022112408] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 02/06/2023] [Accepted: 03/02/2023] [Indexed: 04/04/2023] Open
Abstract
The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we report that circPVT1, a circular RNA generated from the lncRNA PVT1, is highly expressed in ERα-positive breast cancer cell lines and tumor samples and is functionally important in promoting ERα-positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR-181a-2-3p, promoting the expression of ESR1 and downstream ERα-target genes and breast cancer cell growth. Furthermore, circPVT1 directly interacts with MAVS protein to disrupt the RIGI-MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti-tumor immunity. Anti-sense oligonucleotide (ASO)-targeting circPVT1 inhibits ERα-positive breast cancer cell and tumor growth, re-sensitizing tamoxifen-resistant ERα-positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffolding mechanisms to promote cancer. Thus, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERα-positive breast cancer in the clinic.
Collapse
Affiliation(s)
- Jia Yi
- Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation ResearchThe First Affiliated Hospital of Xiamen UniversityXiamenChina
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Lei Wang
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Guo‐sheng Hu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Yue‐ying Zhang
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Jiao Du
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Jian‐cheng Ding
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Xiang Ji
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Hai‐feng Shen
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| | - Hai‐hua Huang
- Department of Pathology, The Second Affiliated HospitalShantou University Medical CollegeShantouChina
| | - Feng Ye
- Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation ResearchThe First Affiliated Hospital of Xiamen UniversityXiamenChina
| | - Wen Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical SciencesXiamen UniversityXiamenChina
| |
Collapse
|
|
21
|
Muftuoglu C, Mert U, Akagunduz OO, Tavlayan E, Al-Omar A, Asadi M, Caner A. Profiling of circRNA expressions in radiation-treated head and neck cancer cells and the potential role of circPVT1. Arch Oral Biol 2023; 150:105690. [PMID: 37027893 DOI: 10.1016/j.archoralbio.2023.105690] [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: 01/11/2023] [Revised: 03/20/2023] [Accepted: 03/26/2023] [Indexed: 03/30/2023]
Abstract
OBJECTIVE Radiotherapy is an indispensable treatment modality for head and neck cancers (HNCs). Due to their stable structure, circular RNAs (circRNA) have been implicated as potential biomarkers for clinical use in cancers. The purpose of this study was profiling the circRNA in radiation-treated head and neck cancer cells to identify potential differentially expressed circRNAs. DESIGN The effects of radiation on the expression level of circRNAs were investigated in HNCs cells, compared to healthy cell lines. To predict the potential role of circRNAs in HNC patients, tissue expression levels, survival analyses of circRNAs, and circRNA-miRNA network were evaluated using TCGA/CPTAC datasets. Based on expression level in irradiated cells, circPVT1 (plasmacytoma variant translocation 1) was further investigated by sequence analysis. RESULTS The study revealed the characterization of differentially expressed circRNAs in cancer cells and that irradiation made significant changes in the expression of circRNAs. These findings suggest that certain circRNAs, especially circPVT1, may be potential biomarkers to monitor radiotherapy effects in patients with HNCs. CONCLUSIONS CircRNAs may be promising molecules for improving and understanding radiotherapy efficacy in HNCs.
Collapse
Affiliation(s)
- Can Muftuoglu
- Institute of Health Sciences, Department of Basic Oncology, Ege University, Izmir, Turkey; Translational Pulmonary Research Center (EGESAM), Ege University, Izmir, Turkey
| | - Ufuk Mert
- Institute of Health Sciences, Department of Basic Oncology, Ege University, Izmir, Turkey; Translational Pulmonary Research Center (EGESAM), Ege University, Izmir, Turkey; Atatürk Health Care Vocational School, Ege University, Izmir, Turkey
| | | | - Emin Tavlayan
- Department of Radiation Oncology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Ahmed Al-Omar
- Institute of Health Sciences, Department of Basic Oncology, Ege University, Izmir, Turkey
| | - Milad Asadi
- Institute of Health Sciences, Department of Basic Oncology, Ege University, Izmir, Turkey
| | - Ayse Caner
- Institute of Health Sciences, Department of Basic Oncology, Ege University, Izmir, Turkey; Translational Pulmonary Research Center (EGESAM), Ege University, Izmir, Turkey; Department of Parasitology, Faculty of Medicine, Ege University, Izmir, Turkey.
| |
Collapse
|
|
22
|
Zhu C, Jiang J, Feng G, Fan S. The exciting encounter between lncRNAs and radiosensitivity in IR-induced DNA damage events. Mol Biol Rep 2023; 50:1829-1843. [PMID: 36507968 DOI: 10.1007/s11033-022-07966-1] [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: 01/08/2022] [Accepted: 09/22/2022] [Indexed: 12/14/2022]
Abstract
Radiation therapy is a commonly used tool in cancer management due to its ability to destroy malignant tumors. Mechanically, the efficacy of radiotherapy mainly depends on the inherent radiosensitivity of cancer cells and surrounding normal tissues, which mostly accounts for molecular dynamics associated with radiation-induced DNA damage. However, the relationship between radiosensitivity and DNA damage mechanism deserves to be further probed. As the well-established RNA regulators or effectors, long noncoding RNAs (lncRNAs) dominate vital roles in modulating ionizing radiation response by targeting crucial molecular pathways, including DNA damage repair. Recently, emerging evidence has constantly confirmed that overexpression or inhibition of lncRNAs can greatly influence the sensitivity of radiotherapy for many kinds of cancers, by driving a diverse array of DNA damage-associated signaling cascades. In conclusion, this review critically summarizes the recent progress in the molecular mechanism of IR-responsive lncRNAs in the context of radiation-induced DNA damage. The different response of lncRNAs when IR exposure. IR exposure can trigger the changes in expression pattern and subcellular localization of lncRNAs that influences the different radiology processes.
Collapse
Affiliation(s)
- Changchun Zhu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, 300192, Tianjin, PR China
| | - Jin Jiang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, 300192, Tianjin, PR China
| | - Guoxing Feng
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, 300192, Tianjin, PR China.
| | - Saijun Fan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, 300192, Tianjin, PR China.
| |
Collapse
|
|
23
|
Fontemaggi G. Non-coding RNA regulatory networks in post-transcriptional regulation of VEGFA in cancer. IUBMB Life 2023; 75:30-39. [PMID: 35467790 PMCID: PMC10084289 DOI: 10.1002/iub.2620] [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: 02/15/2022] [Accepted: 04/10/2022] [Indexed: 12/29/2022]
Abstract
The switch from the normal quiescent vasculature to angiogenesis in tumors is induced by a variety of growth factors, released from cancer and stromal cells upon oxygen and nutrients deprivation. Vascular endothelial growth factor A (VEGF-A) is a potent-secreted mitogen and the only growth factor specific to endothelial cells that is observed almost ubiquitously at sites of angiogenesis. Expression of VEGF-A in cancer cells is controlled through transcriptional and post-transcriptional mechanisms. Post-transcriptional regulation of VEGF-A occurs at multiple levels, through the control of splicing, mRNA stability and translation rate, enabling a fine-tuned expression and release of VEGF-A. Mounting evidence is highlighting the important role played by microRNAs (miRNAs) in the control of VEGF-A mRNA stability and translation in cancer. Moreover, non-coding RNAs, as long non-coding RNAs and circular RNAs, are emerging as crucial modulators of VEGF-A-targeting miRNAs, with consequent ability to modulate VEGF-A expression. This review discusses the recent progress on the ncRNA-related networks controlling VEGF-A expression in cancer cells and provides insights into the complexity of VEGF-A post-transcriptional regulation.
Collapse
Affiliation(s)
- Giulia Fontemaggi
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| |
Collapse
|
|
24
|
Tolomeo D, Traversa D, Venuto S, Ebbesen KK, García Rodríguez JL, Tamma G, Ranieri M, Simonetti G, Ghetti M, Paganelli M, Visci G, Liso A, Kok K, Muscarella LA, Fabrizio FP, Frassanito MA, Lamanuzzi A, Saltarella I, Solimando AG, Fatica A, Ianniello Z, Marsano RM, Palazzo A, Azzariti A, Longo V, Tommasi S, Galetta D, Catino A, Zito A, Mazza T, Napoli A, Martinelli G, Kjems J, Kristensen LS, Vacca A, Storlazzi CT. circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer. Genes Chromosomes Cancer 2022; 62:377-391. [PMID: 36562080 DOI: 10.1002/gcc.23121] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/06/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.
Collapse
Affiliation(s)
- Doron Tolomeo
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Debora Traversa
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Santina Venuto
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Karoline K Ebbesen
- Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Aarhus, Denmark
| | | | - Grazia Tamma
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Marianna Ranieri
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Giorgia Simonetti
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola (FC), Italy
| | - Martina Ghetti
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola (FC), Italy
| | - Matteo Paganelli
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola (FC), Italy
| | - Grazia Visci
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Arcangelo Liso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Klaas Kok
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lucia Anna Muscarella
- Laboratory of Oncology, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy
| | - Federico Pio Fabrizio
- Laboratory of Oncology, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy
| | - Maria Antonia Frassanito
- Department of Precision and Regenerative Medicine and Ionian Area - (DiMePRe-J), School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Aurelia Lamanuzzi
- Department of Precision and Regenerative Medicine and Ionian Area - (DiMePRe-J), School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Ilaria Saltarella
- Department of Precision and Regenerative Medicine and Ionian Area - (DiMePRe-J), School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Antonio Giovanni Solimando
- Department of Precision and Regenerative Medicine and Ionian Area - (DiMePRe-J), School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Alessandro Fatica
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Zaira Ianniello
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | | | - Antonio Palazzo
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Amalia Azzariti
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Vito Longo
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Stefania Tommasi
- Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Domenico Galetta
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Annamaria Catino
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Alfredo Zito
- Pathology Unit, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Tommaso Mazza
- Bioinformatics Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy
| | - Alessandro Napoli
- Bioinformatics Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy
| | - Giovanni Martinelli
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola (FC), Italy
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Aarhus, Denmark
| | | | - Angelo Vacca
- Department of Precision and Regenerative Medicine and Ionian Area - (DiMePRe-J), School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Clelia Tiziana Storlazzi
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| |
Collapse
|
|
25
|
Myc-mediated circular RNA circMcph1/miR-370-3p/Irak2 axis is a progressive regulator in hepatic fibrosis. Life Sci 2022; 312:121182. [PMID: 36435226 DOI: 10.1016/j.lfs.2022.121182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/30/2022] [Accepted: 11/08/2022] [Indexed: 11/27/2022]
Abstract
AIMS Treating hepatic fibrosis (HF) is a major challenge worldwide. However, the biological functions and regulatory mechanisms of circular RNAs (circRNAs) remain unclear in HF. The present study aimed to elucidate the novel role of circMcph1 in HF. MAIN METHODS HF mouse model was established by injecting CCl4 intraperitoneally and validated using hematoxylin and eosin staining, immunohistochemistry, and serological tests in vivo. RAW264.7 cells were treated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) in vitro inflammatory damage model. Gel electrophoresis, DNA sequencing, RNase R and actinomycin D treatment, random 6 primers and oligo dT primers assay, nuclear and cytoplasmic fractionation assay, and fluorescence in situ hybridization were performed to identify the characteristics of circMcph1. Functional assays such as ELISA, flow cytometry, and adeno-associated virus administration in vivo and liposome delivery gene therapy in vitro were used to determine the functional effects of circMcph1/miR-370-3p/interleukin-1 receptor-associated kinase 2 (Irak2) axis. Mechanistic assays such as luciferase reporter analysis, and chromatin immunoprecipitation revealed the molecular mechanism of the Myc/circMcph1/miR-370-3p/Irak2 axis in HF. KEY FINDINGS CircMcph1 expression was upregulated in liver tissues and primary Kupffer cells of CCl4-induced HF mice, as well as in LPS and IFN-γ-treated RAW264.7 cells. Knockdown of circMcph1 ameliorated liver fibrogenesis and inflammatory damage in HF mice and reduced the inflammatory response in LPS and IFN-γ-treated RAW264.7 cells. Mechanically, circMcph1 mediated by Myc regulated the expression of Irak2 by sponging miR-370-3p in HF. SIGNIFICANCE The study findings suggested that the Myc/circMcph1/miR-370-3p/Irak2 axis might be a novel identifier and therapeutic target for HF.
Collapse
|
|
26
|
Guo H, Zhuang K, Ding N, Hua R, Tang H, Wu Y, Yuan Z, Li T, He S. High-fat diet induced cyclophilin B enhances STAT3/lncRNA-PVT1 feedforward loop and promotes growth and metastasis in colorectal cancer. Cell Death Dis 2022; 13:883. [PMID: 36266267 PMCID: PMC9584950 DOI: 10.1038/s41419-022-05328-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/28/2022] [Accepted: 10/06/2022] [Indexed: 01/23/2023]
Abstract
High-fat diet (HFD) has been implicated to promote colorectal cancer (CRC). Recently, oncogene Cyclophilin B (CypB) is reported to be induced by cholesterol. However, the role of CypB in CRC carcinogenesis and metastasis associated with HFD remains unknown. In the present study, we showed that HFD-induced CypB enhances proliferation and metastasis through an inflammation-driven circuit, including Signal Transducer and Activator of Transcription 3 (STAT3)-triggered transcription of lncRNA-PVT1, and its binding with CypB that promotes activation of STAT3. CypB was found to be upregulated in CRC, which was correlated with elevated body mass index and poor prognosis. HFD induced CypB expression and proinflammatory cytokines in colon of mice. Besides, CypB restoration facilitated growth, invasion and metastasis in CRC cells both in vitro and in vivo. Moreover, RIP sequencing data identified lncRNA-PVT1 as a functional binding partner of CypB. Mechanistically, PVT1 increased the phosphorylation and nuclear translocation of STAT3 in response to IL-6, through directly interaction with CypB, which impedes the binding of Suppressors Of Cytokine Signalling 3 (SOCS3) to STAT3. Furthermore, STAT3 in turn activated PVT1 transcription through binding to its promoter, forming a regulatory loop. Finally, this CypB/STAT3/PVT1 axis was verified in TCGA datasets and CRC tissue arrays. Our data revealed that CypB linked HFD and CRC malignancy by enhancing the CypB/STAT3/PVT1 feedforward axis and activation of STAT3.
Collapse
Affiliation(s)
- Hanqing Guo
- grid.43169.390000 0001 0599 1243First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China ,grid.43169.390000 0001 0599 1243Department of Gastroenterology, Xi’an Central Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Kun Zhuang
- grid.43169.390000 0001 0599 1243Department of Gastroenterology, Xi’an Central Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Ning Ding
- grid.43169.390000 0001 0599 1243First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Rui Hua
- grid.43169.390000 0001 0599 1243First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Hailing Tang
- grid.43169.390000 0001 0599 1243Department of Gastroenterology, Xi’an Central Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Yue Wu
- grid.43169.390000 0001 0599 1243First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China ,grid.452438.c0000 0004 1760 8119Department of Cardiovascular Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zuyi Yuan
- grid.43169.390000 0001 0599 1243First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China ,grid.452438.c0000 0004 1760 8119Department of Cardiovascular Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ting Li
- grid.43169.390000 0001 0599 1243First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China ,grid.452438.c0000 0004 1760 8119Department of Cardiovascular Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shuixiang He
- grid.43169.390000 0001 0599 1243First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| |
Collapse
|
|
27
|
Li R, Wang X, Zhu C, Wang K. lncRNA PVT1: a novel oncogene in multiple cancers. Cell Mol Biol Lett 2022; 27:84. [PMID: 36195846 PMCID: PMC9533616 DOI: 10.1186/s11658-022-00385-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 09/07/2022] [Indexed: 12/01/2022] Open
Abstract
Long noncoding RNAs are involved in epigenetic gene modification, including binding to the chromatin rearrangement complex in pre-transcriptional regulation and to gene promoters in gene expression regulation, as well as acting as microRNA sponges to control messenger RNA levels in post-transcriptional regulation. An increasing number of studies have found that long noncoding RNA plasmacytoma variant translocation 1 (PVT1) plays an important role in cancer development. In this review of a large number of studies on PVT1, we found that PVT1 is closely related to tumor onset, proliferation, invasion, epithelial–mesenchymal transformation, and apoptosis, as well as poor prognosis and radiotherapy and chemotherapy resistance in some cancers. This review comprehensively describes PVT1 expression in various cancers and presents novel approaches to the diagnosis and treatment of cancer.
Collapse
Affiliation(s)
- Ruiming Li
- Department of Urology, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Chunming Zhu
- Department of Family Medicine, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
| |
Collapse
|
|
28
|
CircSEMA4B inhibits the progression of breast cancer by encoding a novel protein SEMA4B-211aa and regulating AKT phosphorylation. Cell Death Dis 2022; 13:794. [PMID: 36115854 PMCID: PMC9482637 DOI: 10.1038/s41419-022-05246-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 01/22/2023]
Abstract
PI3K/AKT signaling pathway plays an important role in regulating the tumorigenesis, recurrence, and metastasis of breast cancer (BC). In this study, we discovered a circRNA with protein-coding potential, which we named circSEMA4B. CircSEMA4B could encode a novel protein, SEMA4B-211aa. Both circSEMA4B and SEMA4B-211aa were remarkably downregulated in BC tissues and cell lines. Low expression of circSEMA4B was positively associated with TNM stage, tumor size, lymph node metastasis, and distant metastasis of BC patients. The functional investigation showed that circSEMA4B and SEMA4B-211aa could significantly inhibit the proliferation and migration of BC in vivo and in vitro. Of note, SEMA4B-211aa inhibited the generation of PIP3 by binding to p85, thereby inhibiting the phosphorylation of AKT (Thr308). CircSEMA4B inhibited the phosphorylation of AKT (Ser473) through miR-330-3p/PDCD4 axis. Taken together, circSEMA4B is a novel negative regulator of PI3K/AKT signaling pathway, providing novel mechanistic insights into the underlying mechanisms of BC.
Collapse
|
|
29
|
Zhang Q, Qin S, Peng C, Liu Y, Huang Y, Ju S. Circulating circular RNA hsa_circ_0023179 acts as a diagnostic biomarker for non-small-cell lung cancer detection. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04254-0. [PMID: 35972691 DOI: 10.1007/s00432-022-04254-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 08/02/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Lung cancer, the most prevalent cancer-related death worldwide, still lacks the means for early diagnosis. Because of the unique properties of the loop that make it stable in body fluids, circular RNAs (circRNAs) as a biomarker becomes a possibility. This research purposed to explore whether hsa_circ_0023179 can be applied as a possible biomarker for the early diagnosis and prognosis of non-small cell lung cancer (NSCLC). METHODS hsa_circ_0023179 was screened by high-throughput sequencing of three pairs of NSCLC tissues and their surrounding tissues. Agarose gel electrophoresis (AGE), Sanger sequencing, exonuclease digestion assay, and actinomycin D were used to affirm the molecular properties of circRNA. Precision determination was performed by placement at room temperature and multiple freeze-thawing test for methodological evaluation. The expression of hsa_circ_0023179 in tissues, serum, and cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR) to establish the receiver operating characteristic (ROC) curve to assess the diagnostic efficacy of hsa_circ_0023179. RESULTS hsa_circ_0023179 conforms to the basic properties of circRNA, and the detection method of hsa_circ_0023179 has good stability and repeatability. Its expression was connected to histological type, TNM stage, lymph node metastasis, and distal metastasis in NSCLC tissues, serum, and cells. Compared with traditional tumor markers with higher sensitivity and specificity. A combined diagnosis can significantly improve the diagnostic value. The decrease in postoperative expression level suggests some potential for dynamic monitoring. CONCLUSION hsa_circ_0023179 might be a promising novel serum marker for the detection and prediction of NSCLC.
Collapse
Affiliation(s)
- Qi Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Shiyi Qin
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Chunlei Peng
- Department of Medical Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Yupeng Liu
- Department of Thoracic Surgery, Affiliated Tumor Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Yuejiao Huang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China. .,Department of Medical Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, 226001, Jiangsu, China. .,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
| |
Collapse
|
|
30
|
Role of circular RNAs in disease progression and diagnosis of cancers: An overview of recent advanced insights. Int J Biol Macromol 2022; 220:973-984. [PMID: 35977596 DOI: 10.1016/j.ijbiomac.2022.08.085] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/19/2022] [Accepted: 08/11/2022] [Indexed: 02/07/2023]
Abstract
Tumor microenvironment (TME) is a crucial regulator of tumor progression and cells in the TME release a number of molecules that are responsible for anaplasticity, invasion, metastasis of tumor, establishing stem cell niches, up-regulation and down-regulation of various pathways in cancer cells, interfering with immune surveillance and immune escape. Moreover, they can serve as diagnostic markers, and determine effective therapies. Among them, CircRNAs have gained special attention due to their involvement in mutated pathways in cancers. By functioning as a molecular sponge for miRNAs, binding with proteins, and directing selective splicing. CircRNAs modify the immunological environment of cancers to promote their growth. Besides of critical role in tumor growth, circRNAs are emerging as potential candidates as biomarkers for diagnosis cancer therapy. Also, circRNAs vaccination even offers a novel approach to tumor immunotherapy. Over the recent years, studies are advocating that circRNAs have tissue specific tumor specific expression patterns, which indicates their potential clinical utility. Especially, circRNAs have emerged as potential predictive and prognostic biomarkers. Although, there has been significant progress in deciphering the role of circRNA in cancers, literature lacks comprehensive overview on this topic. Keeping in view of these significant discoveries, this review systematically discusses circRNA and their role in the tumor in different dimensions.
Collapse
|
|
31
|
Li–Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment. Cancers (Basel) 2022; 14:cancers14153664. [PMID: 35954327 PMCID: PMC9367397 DOI: 10.3390/cancers14153664] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/23/2022] [Accepted: 07/26/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Li–Fraumeni Syndrome (LFS) is a rare tumor predisposition syndrome in which the tumor suppressor TP53 gene is mutated in the germ cell population. LFS patients develop a broad spectrum of cancers in their lifetime. The risk to develop these tumors is not decreased by any type of treatment and if the analysis of the TP53 mutational status in the family members was not possible, tumors are often diagnosed in already advanced stages. This review aims to report the evidence for novel mechanisms of tumor onset related to germline TP53 mutations and possible treatments. Abstract Li–Fraumeni syndrome (LFS) is a rare familial tumor predisposition syndrome with autosomal dominant inheritance, involving germline mutations of the TP53 tumor suppressor gene. The most frequent tumors that arise in patients under the age of 45 are osteosarcomas, soft-tissue sarcomas, breast tumors in young women, leukemias/lymphomas, brain tumors, and tumors of the adrenal cortex. To date, no other gene mutations have been associated with LFS. The diagnosis is usually confirmed by genetic testing for the identification of TP53 mutations; therefore, these mutations are considered the biomarkers associated with the tumor spectrum of LFS. Here, we aim to review novel molecular mechanisms involved in the oncogenic functions of mutant p53 in LFS and to discuss recent new diagnostic and therapeutic approaches exploiting TP53 mutations as biomarkers and druggable targets.
Collapse
|
|
32
|
Du J, Jia F, Wang L. Advances in the Study of circRNAs in Hematological Malignancies. Front Oncol 2022; 12:900374. [PMID: 35795049 PMCID: PMC9250989 DOI: 10.3389/fonc.2022.900374] [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: 03/20/2022] [Accepted: 05/23/2022] [Indexed: 11/26/2022] Open
Abstract
Circular RNAs (circRNAs) are non–protein-coding RNAs that have a circular structure and do not possess a 5` cap or 3` poly-A tail. Their structure is more stable than that of linear RNAs, and they are difficult to deform via hydrolysis. Advancements in measurement technology such as RNA sequencing have enabled the detection of circRNAs in various eukaryotes in both in vitro and in vivo studies. The main function of circRNAs involves sponging of microRNAs (MiRNAs) and interaction with proteins associated with physiological and pathological processes, while some circRNAs are involved in translation. circRNAs act as tumor suppressors or oncogenes during the development of many tumors and are emerging as new diagnostic and prognostic biomarkers. They also affect resistance to certain chemotherapy drugs such as imatinib. The objective of this review is to investigate the expression and clinical significance of circRNAs in hematological malignancies. We will also explore the effect of circRNAs on proliferation and apoptosis in hematological malignancy cells and their possible use as biomarkers or targets to determine prognoses. The current literature indicates that circRNAs may provide new therapeutic strategies for patients with hematologic malignancies.
Collapse
Affiliation(s)
- Jingyi Du
- School of Clinical Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Central Laboratory, Linyi People’s Hospital, Linyi, China
| | - Feiyu Jia
- Department of Education and Teaching, Linyi People’s Hospital, Linyi, China
- *Correspondence: Lijuan Wang, ; Feiyu Jia,
| | - Lijuan Wang
- Central Laboratory, Linyi People’s Hospital, Linyi, China
- Linyi Key Laboratory of Tumor Biology, Linyi, China
- *Correspondence: Lijuan Wang, ; Feiyu Jia,
| |
Collapse
|