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Sheng S, Guo J, Lu C, Hu X. Non-coding RNAs in thoracic disease: Barrett's esophagus and esophageal adenocarcinoma. Clin Chim Acta 2025; 571:120242. [PMID: 40074193 DOI: 10.1016/j.cca.2025.120242] [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: 01/31/2025] [Revised: 03/08/2025] [Accepted: 03/09/2025] [Indexed: 03/14/2025]
Abstract
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy with increasing incidence and poor survival rates, primarily due to late-stage diagnosis. This cancer often develops from Barrett's Esophagus (BE), a precancerous condition linked to chronic gastroesophageal reflux disease (GERD). The transition from BE to EAC is a complex multistep process involving numerous genetic, epigenetic, and molecular changes that lead to the malignant transformation of the esophageal epithelium. Despite advancements in understanding the molecular mechanisms underlying EAC, early detection and effective treatment options remain limited, highlighting an urgent need for innovative diagnostic and therapeutic strategies. Recent research has focused on non-coding RNAs (ncRNAs), which play crucial roles in regulating gene expression and cellular processes relevant to cancer progression. Various types of ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have been implicated in the development of BE and EAC by modulating key signaling pathways such as Wnt/β-catenin and NF-κB. Additionally, ncRNAs are stable in biological fluids, presenting opportunities for their use as non-invasive biomarkers for early detection and monitoring of EAC. This review aims to elucidate the involvement of ncRNAs in the progression from BE to EAC, their potential as therapeutic targets, and their emerging roles in intercellular communication. We will also discuss the challenges in translating ncRNA research into clinical applications, emphasizing their promise in revolutionizing early detection and treatment strategies for EAC.
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Affiliation(s)
- Siyuan Sheng
- Department of Medicine, Hunan University of Arts and Science, Changde, Hunan Province 415000, China.
| | - Jianhui Guo
- Spine Surgery of Changde Second People's Hospital, Changde, Hunan Province 415000, China
| | - Chuangang Lu
- Sanya Central Hospital, Sanya, Hainan Province 572000, China
| | - Xia Hu
- Department of Medicine, Hunan University of Arts and Science, Changde, Hunan Province 415000, China
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2
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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.
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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.
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3
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Liu Y, Lan S, Duan Z. circ-TTC17 Promotes Esophagus Squamous Cell Carcinoma Cell Growth, Metastasis, and Inhibits Autophagy-Mediated Radiosensitivity Through miR-145-5p/SIRT1 Axis. Thorac Cancer 2025; 16:e15494. [PMID: 39621506 PMCID: PMC11729993 DOI: 10.1111/1759-7714.15494] [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: 08/21/2024] [Revised: 10/22/2024] [Accepted: 11/11/2024] [Indexed: 01/15/2025] Open
Abstract
BACKGROUND Circular RNA (circRNA) plays a significant role in esophagus squamous cell carcinoma (ESCC) progression. Nevertheless, circ-TTC17 roles in ESCC have not fully understood. METHODS The levels of circ-TTC17, miR-145-5p and sirtuin 1 (SIRT1) were determined using qRT-PCR. ESCC cell functions were examined by CCK8 assay, flow cytometry, transwell assay and colony formation assay. The relative protein levels of autophagy marker and SIRT1 were determined by western blot (WB). The interactions among circ-TTC17, miR-145-5p, and SIRT1 were verified by dual-luciferase reporter assay and RIP assay. RESULTS circ-TTC17 was overexpressed and miR-145-5p was underexpressed in ESCC. circ-TTC17 knockdown restrained ESCC cell proliferation and metastasis, while enhance apoptosis and autophagy-mediated radiosensitivity. Circ-TTC17 could sponge miR-145-5p, and its inhibitor reversed the inhibitory effect of circ-TTC17 knockdown on ESCC cell progression. Additionally, SIRT1 was targeted by miR-145-5p, and SIRT1 overexpression abolished miR-145-5p-mediated the suppressive effect on ESCC cell progression. Also, circ-TTC17 interference reduced ESCC tumor growth via miR-145-5p/SIRT1 axis. CONCLUSION circ-TTC17 promoted ESCC cell growth, metastasis and inhibited autophagy-mediated radiosensitivity by miR-145-5p/SIRT1 axis.
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Affiliation(s)
- Ying Liu
- Department of Head and Neck Radiotherapy CombinedShanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanChina
| | - Shengmin Lan
- Department of Head and Neck Radiotherapy CombinedShanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanChina
| | - Zhihui Duan
- Department of Thoracic SurgeryShanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanChina
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Wang H, Wang H, Liu Z, Wu P, Dai R, Hong D, Nakamura T, Ren W. MiR-490-3p promotes cell apoptosis and cell-cycle arrest in osteosarcoma via the modulation of CDCA8/ATF3 by targeting NUSAP1. Transl Pediatr 2024; 13:2242-2253. [PMID: 39823004 PMCID: PMC11732628 DOI: 10.21037/tp-2024-529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 12/21/2024] [Indexed: 01/19/2025] Open
Abstract
Background Micro RNA-490-3p (miR-490-3p) is associated with a variety of malignancies. However, the role of miR-490-3p in osteosarcoma and its underlying mechanism are not yet fully understood. This study aimed to explore the role and the mechanism of miR-490-3p in osteosarcoma. Methods MiR-490-3p and nucleolar and spindle-associated protein 1 (NUSAP1) expression in osteosarcoma was detected using real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8), wound-healing, and transwell assays were used to detect cell proliferation, migration and invasion. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot were used to evaluate the cell apoptosis. Flow cytometry was used to assess the cell cycle. In addition, luciferase reporter assay was used to confirm the binding of miR-490-3p and NUSAP1. Western blot and RT-qPCR was used to examine cell division cycle associated 8 (CDCA8) and activating transcription factor 3 (ATF3) expression. Results MiR-490-3p expression was significantly decreased in the osteosarcoma cells. Following the transfection with miR-490-3p mimic, it was found that 143B cell proliferation, migration, and invasion were inhibited, while the cell apoptotic levels and cell-cycle arrest were promoted, accompanied with decreased B cell lymphoma protein-2 (Bcl-2) protein expression, and increased protein expressions of Bcl-2-associated X (Bax), cleaved caspase-3, and cleaved caspase-9. In addition, miR-490-3p was found to bind to NUSAP1, and negatively regulate NUSAP1 expression. NUSAP1 upregulation reversed the inhibitory effects of miR-490-3p overexpression on cell proliferation, migration, and invasion, and the promoting effects on cell apoptosis and cell-cycle arrest in osteosarcoma. Moreover, miR-490-3p was identified to mediate CDCA8/ATF3 by targeting NUSAP1. Conclusions MiR-490-3p upregulation inhibited cell proliferation and metastasis but promoted the cell apoptosis and cell-cycle arrest in osteosarcoma via the regulation of CDCA8/ATF3 by targeting NUSAP1. Thus, miR-490-3p might be a potential therapeutic target for the treatment of osteosarcoma.
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Affiliation(s)
- Haoran Wang
- Department of Orthopedics, Hangzhou Children’s Hospital, Hangzhou, China
| | - Hanqing Wang
- Department of Orthopedics, Hangzhou Children’s Hospital, Hangzhou, China
| | - Zixiang Liu
- Department of Orthopedics, Hangzhou Children’s Hospital, Hangzhou, China
| | - Peng Wu
- Department of Orthopedics, Hangzhou Children’s Hospital, Hangzhou, China
| | - Rongdan Dai
- Department of Orthopedics, Hangzhou Children’s Hospital, Hangzhou, China
| | - Dongsheng Hong
- Department of Orthopedics, Hangzhou Children’s Hospital, Hangzhou, China
| | - Tomoki Nakamura
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan
| | - Weiwei Ren
- Department of Gynecology, Hangzhou Children’s Hospital, Hangzhou, China
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Sun Q, Lei X, Yang X. CircRNAs as upstream regulators of miRNA//HMGA2 axis in human cancer. Pharmacol Ther 2024; 263:108711. [PMID: 39222752 DOI: 10.1016/j.pharmthera.2024.108711] [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: 05/22/2024] [Revised: 07/21/2024] [Accepted: 08/30/2024] [Indexed: 09/04/2024]
Abstract
High mobility group protein A2 (HMGA2) is widely recognized as a chromatin-binding protein, whose overexpression is observed in nearly all human cancers. It exerts its oncogenic effects by influencing various cellular processes such as the epithelial-mesenchymal transition, cell differentiation, and DNA damage repair. MicroRNA (miRNA) serves as a pivotal gene expression regulator, concurrently modulating multiple genes implicated in cancer progression, including HMGA2. It also serves as a significant biomarker for cancer. Circular RNA (circRNA) plays a crucial role in gene regulation primarily by sequestering miRNAs and impeding their ability to enhance the expression of other genes, including HMGA2. Increasingly, studies have underscored the vital role of miRNA/HMGA2 interactions in cancer. Given the significance of circRNA as an upstream regulatory mediator and the complexity of regulatory mechanisms, we hereby present a comprehensive overview of the pivotal role of circRNAs as upstream regulators of the miRNA//HMGA2 axis in human cancers. This insight may herald a novel direction for future cancer research.
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Affiliation(s)
- Qiqi Sun
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China
| | - Xiaoyan Yang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China.
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Li Y, Ma L, Li P. Circ_FNDC3B Promotes Cell Proliferation and Metastasis in Esophageal Squamous Cell Carcinoma via Regulating MAPK1 by Binding to miR-136-5p. Biochem Genet 2024; 62:3803-3820. [PMID: 38228844 DOI: 10.1007/s10528-023-10585-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 11/01/2023] [Indexed: 01/18/2024]
Abstract
A handful of circular RNAs (circRNAs) associated with cancer progression have been indicated in esophageal squamous cell carcinoma (ESCC). The current study aimed to investigate the functional mechanism of circular RNA Fibronectin type III domain containing 3B (circ_FNDC3B) in ESCC. Circ_FNDC3B, FNDC3B, microRNA-136-5p (miR-136-5p) and mitogen-activated protein kinase 1 (MAPK1) were examined via the quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) and colony formation assays. Transwell assay was performed to measure cell migration and invasion. Protein analysis was implemented by western blot. Cell apoptosis was assessed via flow cytometry. Target interaction was affirmed using dual-luciferase reporter assay. The function analysis of circ_FNDC3B in vivo was explored by xenograft models. The upregulation of circ_FNDC3B was detected in ESCC tissues and cells. Functionally, ESCC cell proliferation and metastasis were repressed but apoptosis was promoted by circ_FNDC3B knockdown. Besides, circ_FNDC3B silence inhibited ESCC progression through MAPK1 downregulation. Further target analysis identified miR-136-5p as a target of circ_FNDC3B and an upstream control of MAPK1. Additionally, the regulation of si-circ_FNDC3B in ESCC was also dependent on targeting miR-136-5p. Moreover, circ_FNDC3B targeted miR-136-5p to affect MAPK1 level. Tumorigenesis in vivo was also suppressed by downregulating circ_FNDC3B to regulate miR-136-5p/MAPK1 axis. Circ_FNDC3B downregulation impeded the development of ESCC via the mediation of miR-136-5p/MAPK1 axis. This report afforded a novel insight into the functional mechanism of circ_FNDC3B in ESCC.
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Affiliation(s)
- Yuwei Li
- Center of Medical Genetics, Northwest Women's and Children's Hospital, Xi'an, People's Republic of China
| | - Lieting Ma
- Department of Laboratory, First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
| | - Peng Li
- Department of Laboratory, First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
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7
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Wu G, Hou Q, Liu Z, Pu Z, Wu L. N 6-methyladenosine-modified circ_0006168 promotes epithelial mesenchymal transition via miR-384/STAT3/Snail axis in esophageal squamous cell carcinoma. J Cancer 2024; 15:4939-4954. [PMID: 39132166 PMCID: PMC11310886 DOI: 10.7150/jca.97533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 07/01/2024] [Indexed: 08/13/2024] Open
Abstract
Circular RNAs (circRNAs) are involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC). This study aimed to explore the mechanisms of aberrant expression and functions of circ_0006168 in ESCC. In this study, real-time qPCR and fluorescence in situ hybridization (FISH) are adopted to estimate the expression and localization of circ_0006168 in cancer tissues and cells. Methylated RNA immunoprecipitation (MeRIP) was performed to detect the N6-methyladenosine (m6A) modification of circ_0006168. Gain- and loss-of-functions of circ_0006168 were performed to identify its role in ESCC progression. RNA-binding protein immunoprecipitation (RIP) was used to detect the interaction of circ_0006168 with IGF2BP2. Luciferase reporter assay and RIP are used to confirm the circ_0006168/miR-384/STAT3 ceRNA network. Our results showed that the expression of circ_0006168 was upregulated in ESCC tissues and cells. METTL3-mediated m6A modification increased the expression of circ_0006168 via IGF2BP2-dependent way in TE-1 cells. Circ_0006168 promoted cell proliferation, migration, invasion, cell cycle progression and inhibited cell apoptosis, while knockdown of circ_0006168 had the reverse effects. Mechanistically, circ_0006168 acted its functions via miR-384/STAT3/Snail axis in TE-1 cells. In conclusion, circ_0006168 is upregulated in ESCC and m6A methylation increased its expression via IGF2BP2. CircRNA_0006168 promotes cell migration, invasion by regulating EMT via miR-384/STAT3/Snail axis in ESCC.
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Affiliation(s)
- Guandi Wu
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg 69120, Germany
| | - Qin Hou
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Zhe Liu
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Zejin Pu
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Lingfei Wu
- Department of Gastroenterology, Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
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Najibi K, Moghanibashi M, Naeimi S. Association of deletion polymorphism rs10573247 in the HMGA2 gene with the risk of breast cancer: bioinformatic and experimental analyses. World J Surg Oncol 2024; 22:142. [PMID: 38802807 PMCID: PMC11131319 DOI: 10.1186/s12957-024-03415-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 05/20/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND The high mobility group A2 (HMGA2) gene is expressed extensively during early embryonic development but is inactivated in adulthood, and it is also reactivated in various benign and malignant tumors, including breast cancer. We first assessed the potential functional significance of the unstudied deletion polymorphism rs10573247 at the 3'UTR of HMGA2 on miRNA binding using bioinformatic tools, and subsequently, the association between this polymorphism and breast cancer susceptibility was investigated. MATERIALS AND METHODS We applied the RNAhybrid tool to predict the functional effects of polymorphism rs10573247 located within the 3' UTR of the HMGA2 gene on miRNA binding. Then, following DNA extraction, 141 breast cancer patients and 123 healthy controls were genotyped for polymorphism rs10573247 using RFLP-PCR with the restriction enzyme Eam1104I. RESULTS Our bioinformatic data have shown that polymorphism rs10573247 is located in the region that serves as a potential target site for eight miRNAs binding. Among them, miR-3125 exhibited decreased binding affinity for the allele delTT (MFE = -21.8) when compared to the allele TT (MFE = -23.9), but miR-4476 increased binding affinity for the allele delTT (MFE = -22.4) compared to the allele TT (MFE = -22.2). In addition, our results showed that the genotype TT/delTT (p = 0.005) and the genotype delTT/delTT (p = 0.029) were significantly associated with an increased risk of developing breast cancer compared to the genotype TT/TT using RFLP-PCR. DISCUSSION AND CONCLUSION Our findings suggest that polymorphism rs10573247 may contribute to the risk of breast cancer through the functional effect of this polymorphism on miRNA binding.
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Affiliation(s)
- Kolsoom Najibi
- Department of Biology, Faculty of Basic Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran
| | - Mehdi Moghanibashi
- Department of Genetics, Faculty of Medicine, Kazerun Branch, Islamic Azad University, P.O. Box: 73135-168, Kazerun, Iran.
| | - Sirous Naeimi
- Department of Biology, Faculty of Basic Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran
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Wei QY, Jin F, Wang ZY, Li BJ, Cao WB, Sun ZY, Mo SJ. MicroRNAs: A novel signature in the metastasis of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:1497-1523. [PMID: 38617454 PMCID: PMC11008420 DOI: 10.3748/wjg.v30.i11.1497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/12/2024] [Accepted: 03/01/2024] [Indexed: 03/21/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.
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Affiliation(s)
- Qi-Ying Wei
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Feng Jin
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhong-Yu Wang
- Department of Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bing-Jie Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Wen-Bo Cao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhi-Yan Sun
- Division of Special Service, Department of Basic Oncology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Sai-Jun Mo
- Department of Basic Science of Oncology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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Gao H, Sun M, Gao Z, Song J, Tang D, Liu R. Hsa_circ_0001707 regulates endothelial-mesenchymal transition in esophageal squamous cell carcinoma via miR-203a-3p/Snail2 pathway. ENVIRONMENTAL TOXICOLOGY 2024; 39:1210-1220. [PMID: 37921085 DOI: 10.1002/tox.23998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/02/2023] [Accepted: 10/07/2023] [Indexed: 11/04/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with high mortality and poor prognosis. Despite intensive research focused on tumor suppression, the 5-year survival rate of ESCC is lower than 15%. Therefore, investigate fundamental mechanisms involved in ESCC is on-demand crucial for diagnostics and developing targeted therapeutic drugs. Circular RNAs (circRNAs), as an emerging class of non-coding RNA, have been elucidated that circRNAs participated in regulating a variety of pathological processes and tumorigenesis. Nevertheless, the functional role of circRNAs in the occurrence and development of ESCC remains unclear. We identify a novel circRNA (hsa_circ_0001707), which was highly expressed in ESCC patients' tissues and cell lines. Furthermore, gain- and loss-of-function assays were performed and found that overexpression of hsa_circ_0001707 significantly promote tumor proliferation, metastasis, and invasion. By functioning as a competing endogenous RNA (ceRNA), the dual-luciferase activity assay verified that hsa_circ_0001707 can endogenously bind with miR-203a-3p and regulate its downstream gene Snail2. Rescue assay further confirms that hsa_circ_0001707 downregulation could partially attenuate the facilitation effect of miR-203a-3p, thereby inhibiting the endothelial-mesenchymal transition (EMT) process of ESCC. Our results suggested that hsa_circ_0001707 play an oncogenic role in the pathogenesis of ESCC, which might be a potential biomarker for diagnostics and targeting therapy.
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Affiliation(s)
- Han Gao
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Mingjun Sun
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Zhikui Gao
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Jing Song
- Institute of Nephrology, Zhongda Hospital Southeast University, Nanjing, China
| | - Derong Tang
- Department of Thoracic Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
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11
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Liang H, Che W, Peng F, Chen H, Xie X, Wu B. Triptolide inhibits esophageal squamous cell carcinoma progression by regulating the circNOX4/miR-153-3p/SATB1 signaling pathway. Thorac Cancer 2024; 15:538-549. [PMID: 38268309 PMCID: PMC10912528 DOI: 10.1111/1759-7714.15215] [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: 11/21/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND To explore the role and mechanism of triptolide in regulating esophageal squamous cell carcinoma (ESCC) progression by mediating the circular RNA (circRNA)-related pathway. METHODS The expression levels of circNOX4, miR-153-3p and special AT-rich sequence binding protein-1 (SATB1) were measured by qRT-PCR. Cell proliferation was confirmed by cell counting kit-8 assay and colony formation assay. Flow cytometry was employed to measure cell apoptosis and cell cycle process. Moreover, cell migration and invasion were detected using transwell assay. The protein levels of epithelial-mesenchymal transformation markers and SATB1 were determined by western blot analysis. Furthermore, dual-luciferase reporter assay and RIP assay were performed to confirm the interaction between miR-153-3p and circNOX4 or SATB1. Xenograft tumor models were built to verify the effects of triptolide and circNOX4 on ESCC tumor growth. RESULTS CircNOX4 was highly expressed in ESCC tissues and cells, and its expression could be reduced by triptolide. Triptolide could inhibit ESCC proliferation, cell cycle process, migration, invasion, EMT process, and promote apoptosis, while these effects were reversed by circNOX4 overexpression. MiR-153-3p could be sponged by circNOX4, and the promotion effect of circNOX4 on the progression of triptolide-treated ESCC cells was abolished by miR-153-3p overexpression. SATB1 was a target of miR-153-3p. Also, SATB1 knockdown reversed the enhancing effect of miR-153-3p inhibitor on the progression of triptolide-treated ESCC cells. Triptolide reduced ESCC tumor growth by regulating the circNOX4/miR-153-3p/SATB1 axis. CONCLUSION Triptolide could hinder ESCC progression, which was mainly achieved by regulating the circNOX4/miR-153-3p/SATB1 axis.
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Affiliation(s)
- Hanping Liang
- Department of thoracic surgeryGaozhou people's HospitalGaozhouChina
| | - Weibi Che
- Department of thoracic surgeryGaozhou people's HospitalGaozhouChina
| | - Fengyuan Peng
- Department of thoracic surgeryGaozhou people's HospitalGaozhouChina
| | - Huilong Chen
- Department of thoracic surgeryGaozhou people's HospitalGaozhouChina
| | - Xihao Xie
- Department of thoracic surgeryGaozhou people's HospitalGaozhouChina
| | - Bomeng Wu
- Department of thoracic surgeryGaozhou people's HospitalGaozhouChina
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Du L, Yang J, Qin S, Ding S, Guo Y, Wang J. Appraising the value of CircRNAs for the diagnosis and prognosis of esophageal squamous cell cancer: An updated meta-analysis. Pathol Res Pract 2024; 254:155074. [PMID: 38246036 DOI: 10.1016/j.prp.2023.155074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024]
Abstract
OBJECTIVE The purpose of this study was to thoroughly assess the relevance of circular RNAs (circRNAs) in the diagnosis and prognosis of esophageal squamous cell carcinoma (ESCC)， and design a systematic review and meta-analysis. METHODS Using Stata 14.0 software, a meta-analysis was carried out by looking for pertinent studies up to February 20, 2023, in the online databases PubMed, Embase, Web of Science, and CNKI. The clinicopathologic and prognostic data were evaluated using the combined advantage ratio (OR) and combined hazard ratio (HR), respectively. The threshold effects and publication bias were quantified using Spearman's correlation and the Deeks funnel plot asymmetry tests, respectively. RESULTS A total of 36 pertinent studies with a literature quality score of 7 or above were included in this study. Of them, 22 papers dealt with clinicopathological characterization, 15 dealt with prognostic analysis, and 13 dealt with diagnostic analysis. The findings demonstrated that high expression of upregulated circRNAs was associated with worse clinicopathological features (tumor size: OR=3.61, 95% CI:1.45-5.78; TNM stage: OR=2.12, 95% CI:1.41-2.83; lymph node metastasis: OR=2.87, 95% CI:1.67-4.07) and worse OS (HR=1.49, 95% CI:1.26-1.77). High downregulated circRNAs expression was linked to improved clinicopathologic characteristics (TNM staging: OR=0.35, 95% CI:0.13- 0.95) and longer survival (HR=0.48, 95% CI:0.27-0.84); combined sensitivity was 0.77 (95% CI: 0.71-0.82), specificity was 0.80 (95% CI:0.74-0.86), and area under the subject operating characteristic curve (AUC) was 0.86 (95% CI:0.82- 0.88). CONCLUSION CircRNAs are useful for ESCC patient diagnosis and prognosis, and they are anticipated to be unique potential biomarkers for ESCC clinical diagnosis.
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Affiliation(s)
- Lihong Du
- Changzhi Medical College Affiliated Heping Hospital, Changzhi, Shanxi Province, 046000, China; Department of Pathology, Changzhi Medical College, Changzhi, Shanxi Province 046000, China; First Clinical College of Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Jianzhou Yang
- Department of Public Health and Preventive Medicine, Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Shaoze Qin
- First Clinical College of Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Shuyu Ding
- First Clinical College of Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Yuwei Guo
- First Clinical College of Changzhi Medical College, Changzhi, Shanxi Province 046000, China
| | - Jinsheng Wang
- Changzhi Medical College Affiliated Heping Hospital, Changzhi, Shanxi Province, 046000, China; Department of Pathology, Changzhi Medical College, Changzhi, Shanxi Province 046000, China; Key Laboratory of Shanxi Provincial Health Commission, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi Province 046000, China.
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13
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Ma Q, Ye S, Liu H, Zhao Y, Mao Y, Zhang W. HMGA2 promotes cancer metastasis by regulating epithelial-mesenchymal transition. Front Oncol 2024; 14:1320887. [PMID: 38361784 PMCID: PMC10867147 DOI: 10.3389/fonc.2024.1320887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/09/2024] [Indexed: 02/17/2024] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a complex physiological process that transforms polarized epithelial cells into moving mesenchymal cells. Dysfunction of EMT promotes the invasion and metastasis of cancer. The architectural transcription factor high mobility group AT-hook 2 (HMGA2) is highly overexpressed in various types of cancer (e.g., colorectal cancer, liver cancer, breast cancer, uterine leiomyomas) and significantly correlated with poor survival rates. Evidence indicated that HMGA2 overexpression markedly decreased the expression of epithelial marker E-cadherin (CDH1) and increased that of vimentin (VIM), Snail, N-cadherin (CDH2), and zinc finger E-box binding homeobox 1 (ZEB1) by targeting the transforming growth factor beta/SMAD (TGFβ/SMAD), mitogen-activated protein kinase (MAPK), and WNT/beta-catenin (WNT/β-catenin) signaling pathways. Furthermore, a new class of non-coding RNAs (miRNAs, circular RNAs, and long non-coding RNAs) plays an essential role in the process of HMGA2-induced metastasis and invasion of cancer by accelerating the EMT process. In this review, we discuss alterations in the expression of HMGA2 in various types of cancer. Furthermore, we highlight the role of HMGA2-induced EMT in promoting tumor growth, migration, and invasion. More importantly, we discuss extensively the mechanism through which HMGA2 regulates the EMT process and invasion in most cancers, including signaling pathways and the interacting RNA signaling axis. Thus, the elucidation of molecular mechanisms that underlie the effects of HMGA2 on cancer invasion and patient survival by mediating EMT may offer new therapeutic methods for preventing cancer progression.
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Affiliation(s)
- Qing Ma
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Sisi Ye
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Hong Liu
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Yu Zhao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Yan Mao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Wei Zhang
- Emergency Department of West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
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14
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Wang J, Yao W, Li J, Zhang Q, Wei L. Circ_0001944 depletion inhibits glycolysis and esophageal cancer progression by binding to miR-338-5p to reduce PDK1 expression. J Bioenerg Biomembr 2024; 56:73-85. [PMID: 37999809 DOI: 10.1007/s10863-023-09988-1] [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: 06/28/2023] [Accepted: 10/05/2023] [Indexed: 11/25/2023]
Abstract
Circular RNA (circRNA) plays multiple roles in the development of esophageal cancer (EC). Herein, we investigate the function of circ_0001944 in EC progression and the related mechanism. Expression of circ_0001944, microRNA-338-5p (miR-338-5p), pyruvate dehydrogenase kinase 1 (PDK1), E-cadherin and N-cadherin was analyzed by quantitative real-time polymerase chain reaction, Western blotting or immunohistochemistry assay. Cell viability, proliferation, apoptosis, invasion and migration were investigated by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell invasion and wound-healing assays, respectively. Glucose consumption was detected by Glucose Assay Kit. Lactate production was analyzed by Lactate Assay Kit. ATP/ADP ratio was determined by ADP/ATP ratio Assay Kit. The associations among circ_0001944, miR-338-5p and PDK1 were identified by dual-luciferase reporter and RNA pull-down assays. Xenograft mouse model assay was used to explore the role of circ_0001944 on tumor tumorigenesis in vivo. Circ_0001944 and PDK1 expression were significantly upregulated, while miR-338-5p was downregulated in EC tissues and cells in contrast with normal esophageal tissues and cells. Circ_0001944 knockdown inhibited EC cell proliferation, invasion, migration and glycolysis but induced apoptosis. Meanwhile, circ_0001944 depletion suppressed tumor tumorigenesis in vivo. Mechanistically, circ_0001944 bound to miR-338-5p, and miR-338-5p targeted PDK1. In addition, miR-338-5p inhibitors attenuated circ_0001944 depletion-induced effects in EC cells. The regulation of miR-338-5p on EC progression involved the downregulation of PDK1. Further, circ_0001944 controlled PDK1 expression through miR-338-5p. Circ_0001944 knockdown inhibited EC development and glycolysis by regulating the miR-338-5p/PDK1 pathway, providing a promising target for EC therapy.
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Affiliation(s)
- Jianjun Wang
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China
| | - Wenjian Yao
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China
| | - Jiwei Li
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China
| | - Quan Zhang
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China
| | - Li Wei
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou City, Henan, 450003, China.
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15
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Ahuja P, Yadav R, Goyal S, Yadav C, Ranga S, Kadian L. Targeting epigenetic deregulations for the management of esophageal carcinoma: recent advances and emerging approaches. Cell Biol Toxicol 2023; 39:2437-2465. [PMID: 37338772 DOI: 10.1007/s10565-023-09818-5] [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: 03/16/2023] [Accepted: 06/08/2023] [Indexed: 06/21/2023]
Abstract
Ranking from seventh in incidence to sixth in mortality, esophageal carcinoma is considered a severe malignancy of food pipe. Later-stage diagnosis, drug resistance, and a high mortality rate contribute to its lethality. Esophageal squamous cell carcinoma and esophageal adenocarcinoma are the two main histological subtypes of esophageal carcinoma, with squamous cell carcinoma alone accounting for more than eighty percent of its cases. While genetic anomalies are well known in esophageal cancer, accountability of epigenetic deregulations is also being explored for the recent two decades. DNA methylation, histone modifications, and functional non-coding RNAs are the crucial epigenetic players involved in the modulation of different malignancies, including esophageal carcinoma. Targeting these epigenetic aberrations will provide new insights into the development of biomarker tools for risk stratification, early diagnosis, and effective therapeutic intervention. This review discusses different epigenetic alterations, emphasizing the most significant developments in esophageal cancer epigenetics and their potential implication for the detection, prognosis, and treatment of esophageal carcinoma. Further, the preclinical and clinical status of various epigenetic drugs has also been reviewed.
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Affiliation(s)
- Parul Ahuja
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Ritu Yadav
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India.
| | - Sandeep Goyal
- Department of Internal Medicine, Pt. B.D, Sharma University of Health Sciences, (Haryana), Rohtak, 124001, India
| | - Chetna Yadav
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Shalu Ranga
- Department of Genetics, Maharshi Dayanand University, (Haryana), Rohtak, 124001, India
| | - Lokesh Kadian
- Department of Dermatology, School of Medicine, Indiana University, Indianapolis, Indiana, 46202, USA
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Luo Q, Li J, Miao H, Su S, Chen Y, Xu C, Zhao C, Huang J, Ling K, Lin C, Yan H, Zhang S. circSSPO boosts growth of esophageal squamous cell carcinoma through upregulation of micrRNA-6820-5p-mediated KLK8 and PKD1 expression. Cell Biol Toxicol 2023; 39:3219-3234. [PMID: 37812360 DOI: 10.1007/s10565-023-09828-3] [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: 01/31/2023] [Accepted: 08/13/2023] [Indexed: 10/10/2023]
Abstract
Investigation on a competitive endogenous RNA (ceRNA) network attracted lots of attention due its function in cancer regulation. Here, we probed into the possible molecular mechanism of circSSPO/microRNA-6820-5p (miR-6820-5p)/kallikrein-related peptidase 8 (KLK8)/PKD1 network in the esophageal squamous cell carcinoma (ESCC). Following whole-transcriptome sequencing and differential analysis in collected ESCC tissue samples, circRNA-miRNA-mRNA regulatory network affecting ESCC was investigated. After interaction measurement among circSSPO/miR-6820-5p/KLK8/PKD1, their regulatory roles in ESCC cell functions in vitro and xenograft tumor growth and lung metastasis in vivo were analyzed. The bioinformatics prediction and sequencing results screened that circSSPO, miR-6820-5p, KLK8, and PKD1 were associated with ESCC development. In ESCC, miR-6820-5p was expressed at very low levels, while circSSPO, KLK8, and PKD1 were highly expressed. In vitro cell experiments further proved that circSSPO competitively inhibited miR-6820-5p to induce ESCC cell malignant properties. Moreover, knockdown of KLK8 or PKD1 inhibited ESCC cell malignant properties. circSSPO also promoted the tumorigenic and metastasis of ESCC through the upregulation of KLK8 and PKD1 expression in vivo. We found that circSSPO was an oncogenic circRNA that was significantly abundant in ESCC tissues and circSSPO exhibited an oncogenic activity in ESCC by elevating expression of KLK8 and PKD1 through suppressing miR-6820-5p expression.
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Affiliation(s)
- Qianhua Luo
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Junzheng Li
- Department of Otolaryngology-Head and Neck Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou, 510280, China
| | - Haixiong Miao
- Department of Orthopaedics, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, 510220, People's Republic of China
| | - Siman Su
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China
| | - Yun Chen
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Chengcheng Xu
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Chengkuan Zhao
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Jianxiang Huang
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China
| | - Kai Ling
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China
| | - Chaoxian Lin
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China.
- Shantou Chaonan Minsheng Hospital, Shantou, 515144, People's Republic of China.
| | - Hongfei Yan
- Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, 515031, People's Republic of China.
| | - Shuyao Zhang
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, 515041, People's Republic of China.
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396, Tongfuzhong Road, Haizhu District, Guangzhou, 510220, People's Republic of China.
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Yang Y, Zhu B, Ning Z, Wang X, Li Z, Zhang C, Wen L. Circ_0058063 regulates cell vitality and proliferation in oesophageal squamous-cell carcinomas. J Biochem Mol Toxicol 2023; 37:e23470. [PMID: 37477183 DOI: 10.1002/jbt.23470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 07/03/2023] [Accepted: 07/08/2023] [Indexed: 07/22/2023]
Abstract
Oesophageal squamous-cell carcinoma (ESCC) is a malignant tumor of the digestive system with a poor prognosis. Recent studies have shown the promoting effect of hsa_circ_0058063 (circ_0058063) on ESCC, but the potential regulatory mechanisms of circ_0058063 in ESCC remain largely unclear. The levels of circ_0058063, microRNA-4319 (miR-4319) and mRNA of thrombospondin-1 (THBS1) were indicated by quantitative real-time polymerase chain reaction in ESCC tissues and cells. Meanwhile, the level of THBS1 was quantified by western blot analysis. In addition, the cell functions were examined by CCK8 assay, Edu assay, flow cytometry assay and transwell assay. Furthermore, the interplay between miR-4319 and circ_0058063 or THBS1 was detected by dual-luciferase reporter assay. Finally, an in vivo experiment was implemented to confirm the effect of circ_0058063. The level of circ_0058063 and THBS1 were increased, and the miR-4319 level was decreased in ESCC tissues in contrast to that in normal tissues and cells. For functional analysis, circ_0058063 deficiency inhibited cell vitality, cell proliferation, migration and invasion in ESCC cells, whereas promoted cell apoptosis. Moreover, miR-4319 was confirmed to repress the progression of ESCC cells by suppressing THBS1. In mechanism, circ_0058063 acted as a miR-4319 sponge to regulate the level of THBS1. Besides, circ_0058063 knockdown also attenuated tumour growth in vivo. Circ_0058063 facilitates the development of ESCC through increasing THBS1 expression by regulating miR-4319, which also offered an underlying targeted therapy for ESCC treatment.
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Affiliation(s)
- Yixuan Yang
- Department of Health Care, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Bing Zhu
- Department of Thoracic Surgery, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, Hubei, China
| | - Zhaofeng Ning
- Department of Radiotherapy, Tai'an Tumor Hospital, Tai'an, Shandong, China
| | - Xiaodong Wang
- Department of Cardiothoracic Surgery, Air Force Hospital in Western War Zone, Chengdu, Sichuan, China
| | - Zhaoxia Li
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Chunxia Zhang
- Department of Gastroenterology, Inner Mongolia Forestry General Hospital, Yakeshi, Inner Mongolia, China
| | - Linchun Wen
- Department of Oncology, Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu, China
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Li R, Chai L, Lei L, Guo R, Wen X. MiR-671-5p sponging activity of circMMP1 promotes esophageal squamous cancer progression. Thorac Cancer 2023; 14:2924-2933. [PMID: 37635445 PMCID: PMC10569906 DOI: 10.1111/1759-7714.15078] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/01/2023] [Accepted: 08/05/2023] [Indexed: 08/29/2023] Open
Abstract
BACKGROUND The aim of this study was to explore the function and mechanism of circular RNA (circRNA) matrix metallopeptidase 1 (circMMP1) in the progression of esophageal squamous cell carcinoma (ESCC). METHODS CircMMP1 expression was detected by quantitative real-time PCR (qRT-PCR), and its relationship with the prognosis of ESCC patients was evaluated by Kaplan-Meier analysis. Cells were transfected using corresponding plasmids, and the cell proliferation activity, migration and invasion capabilities in vitro were assessed. The protein level in tissues and cells was analyzed using western blotting. RNA pulldown, dual-luciferase reporter assay and RNA immunoprecipitation assay were performed in ESCC cells to detect the interaction between circMMP1 and miR-671-5p, or the correlation between miR-671-5p and ANO1. Xenograft tumor experiment was carried out to uncover the function of circMMP1 in vivo. RESULTS The high level of circMMP1 in tumor tissues was associated with poor prognoses of ESCC patients. Knockdown of circMMP1 suppressed ESCC cell proliferation, migration and invasion in vitro. MiR-671-5p was the target of circMMP1 and mediated the inhibition effect of circMMP1 on ESCC cells. CircMMP1 targeted miR-671-5p to regulate ANO1 expression, which was downstream of miR-671-5p. Overexpression of ANO1 weakened tumor-repressive function of circMMP1 knockdown in ESCC cells. Moreover, silencing of circMMP1 impeded ESCC tumor growth in vivo. CONCLUSION Our study provided novel evidence that circMMP1 accelerated ESCC progression by acting as a miR-671-5p sponge to enhance ANO1 expression.
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Affiliation(s)
- Rong Li
- Department of RadiotherapyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Linyan Chai
- Department of RadiotherapyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Lei Lei
- Department of CardiologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Rong Guo
- Department of Nuclear MedicineThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Xiulin Wen
- Department of NursingThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
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Cui Y, Wu Y, Zhu Y, Liu W, Huang L, Hong Z, Zhang M, Zheng X, Sun G. The possible molecular mechanism underlying the involvement of the variable shear factor QKI in the epithelial-mesenchymal transformation of oesophageal cancer. PLoS One 2023; 18:e0288403. [PMID: 37428781 DOI: 10.1371/journal.pone.0288403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 06/26/2023] [Indexed: 07/12/2023] Open
Abstract
OBJECTIVE Based on the GEO, TCGA and GTEx databases, we reveal the possible molecular mechanism of the variable shear factor QKI in epithelial mesenchymal transformation (EMT) of oesophageal cancer. METHODS Based on the TCGA and GTEx databases, the differential expression of the variable shear factor QKI in oesophageal cancer samples was analysed, and functional enrichment analysis of QKI was performed based on the TCGA-ESCA dataset. The percent-spliced in (PSI) data of oesophageal cancer samples were downloaded from the TCGASpliceSeq database, and the genes and variable splicing types that were significantly related to the expression of the variable splicing factor QKI were screened out. We further identified the significantly upregulated circRNAs and their corresponding coding genes in oesophageal cancer, screened the EMT-related genes that were significantly positively correlated with QKI expression, predicted the circRNA-miRNA binding relationship through the circBank database, predicted the miRNA-mRNA binding relationship through the TargetScan database, and finally obtained the circRNA-miRNA-mRNA network through which QKI promoted the EMT process. RESULTS Compared with normal control tissue, QKI expression was significantly upregulated in tumour tissue samples of oesophageal cancer patients. High expression of QKI may promote the EMT process in oesophageal cancer. QKI promotes hsa_circ_0006646 and hsa_circ_0061395 generation by regulating the variable shear of BACH1 and PTK2. In oesophageal cancer, QKI may promote the production of the above two circRNAs by regulating variable splicing, and these circRNAs further competitively bind miRNAs to relieve the targeted inhibition of IL-11, MFAP2, MMP10, and MMP1 and finally promote the EMT process. CONCLUSION Variable shear factor QKI promotes hsa_circ_0006646 and hsa_circ_0061395 generation, and downstream related miRNAs can relieve the targeted inhibition of EMT-related genes (IL11, MFAP2, MMP10, MMP1) and promote the occurrence and development of oesophageal cancer, providing a new theoretical basis for screening prognostic markers of oesophageal cancer patients.
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Affiliation(s)
- Yishuang Cui
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
| | - Yanan Wu
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
| | - Yingze Zhu
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
- School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei Province, China
- Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Wei Liu
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
- School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei Province, China
- Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Lanxiang Huang
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
- School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei Province, China
- Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Ziqian Hong
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
| | - Mengshi Zhang
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
| | - Xuan Zheng
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
| | - Guogui Sun
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
- Department of Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, Tangshan, Hebei Province, China
- School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei Province, China
- Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei Province, China
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Li J, Song Y, Cai H, Zhou B, Ma J. Roles of circRNA dysregulation in esophageal squamous cell carcinoma tumor microenvironment. Front Oncol 2023; 13:1153207. [PMID: 37384299 PMCID: PMC10299836 DOI: 10.3389/fonc.2023.1153207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most prevalent histological esophageal cancer characterized by advanced diagnosis, metastasis, resistance to treatment, and frequent recurrence. In recent years, numerous human disorders such as ESCC, have been linked to abnormal expression of circular RNAs (circRNAs), suggesting that they are fundamental to the intricate system of gene regulation that governs ESCC formation. The tumor microenvironment (TME), referring to the area surrounding the tumor cells, is composed of multiple components, including stromal cells, immune cells, the vascular system, extracellular matrix (ECM), and numerous signaling molecules. In this review, we briefly described the biological purposes and mechanisms of aberrant circRNA expression in the TME of ESCC, including the immune microenvironment, angiogenesis, epithelial-to-mesenchymal transition, hypoxia, metabolism, and radiotherapy resistance. As in-depth research into the processes of circRNAs in the TME of ESCC continues, circRNAs are promising therapeutic targets or delivery systems for cancer therapy and diagnostic and prognostic indicators for ESCC.
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Affiliation(s)
- Jingyi Li
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuxia Song
- Department of Reproductive Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Huihong Cai
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bo Zhou
- Medical Research Center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jun Ma
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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21
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Lyu Y, Tan B, Li L, Liang R, Lei K, Wang K, Wu D, Lin H, Wang M. A novel protein encoded by circUBE4B promotes progression of esophageal squamous cell carcinoma by augmenting MAPK/ERK signaling. Cell Death Dis 2023; 14:346. [PMID: 37264022 DOI: 10.1038/s41419-023-05865-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 04/23/2023] [Accepted: 05/16/2023] [Indexed: 06/03/2023]
Abstract
Esophageal squamous carcinoma (ESCC) is a common malignant cancer. Although the non-coding roles of circRNAs in the pathogenesis of human tumors have been well studied, whether circRNAs participate in the progression of ESCC by encoding novel proteins remains unclear. In this study, we identified an overexpression circRNA with protein-coding ability in ESCC tissues, called circUBE4B, whose expression level is correlated with tumor size and tumor differentiation level of ESCC patients. Moreover, a higher level of circUBE4B in ESCC patients is correlated with a worse prognosis. Functionally, we found that circUBE4B promoted the proliferation of ESCC cells by encoding a novel cancer-promoting protein, circUBE4B-173aa. Mechanistically, the circUBE4B-173aa protein interacts with MAPK1 and promotes the phosphorylation level of MAPK1 to eventually activate MAPK/ERK signaling pathway. The xenograft model revealed that overexpression of circUBE4B-173aa in ESCC cells significantly promoted the growth of grafts. Our study provides new insights into the mechanism of circRNA in the development of ESCC and circUBE4B-173aa has the potential to serve as a biomarker and a novel therapeutic target for ESCC therapy.
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Affiliation(s)
- Yingcheng Lyu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
- Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Binghua Tan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
- Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Lin Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
- Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Ruihao Liang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
- Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Kai Lei
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
- Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Kefeng Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
- Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Duoguang Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
- Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Huayue Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China.
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China.
| | - Minghui Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China.
- Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China.
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22
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Mahmoudian RA, Akhlaghipour I, Lotfi M, Shahidsales S, Moghbeli M. Circular RNAs as the pivotal regulators of epithelial-mesenchymal transition in gastrointestinal tumor cells. Pathol Res Pract 2023; 245:154472. [PMID: 37087995 DOI: 10.1016/j.prp.2023.154472] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/11/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023]
Abstract
Gastrointestinal (GI) cancers, as the most common human malignancies are always considered one of the most important health challenges in the world. Late diagnosis in advanced tumor stages is one of the main reasons for the high mortality rate and treatment failure in these patients. Therefore, investigating the molecular pathways involved in GI tumor progression is required to introduce the efficient markers for the early tumor diagnosis. Epithelial-mesenchymal transition (EMT) is one of the main cellular mechanisms involved in the GI tumor metastasis. Non-coding RNAs (ncRNAs) are one of the main regulatory factors in EMT process. Circular RNAs (circRNAs) are a group of covalently closed loop ncRNAs that have higher stability in body fluids compared with other ncRNAs. Considering the importance of circRNAs in regulation of EMT process, in the present review we discussed the role of circRNAs in EMT process during GI tumor invasion. It has been reported that circRNAs mainly affect the EMT process through the regulation of EMT-specific transcription factors and signaling pathways such as WNT, PI3K/AKT, TGF-β, and MAPK. This review can be an effective step in introducing a circRNA/EMT based diagnostic panel marker for the early tumor detection among GI cancer patients.
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Affiliation(s)
- Reihaneh Alsadat Mahmoudian
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Lotfi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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23
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Hashemi M, Rashidi M, Hushmandi K, Ten Hagen TLM, Salimimoghadam S, Taheriazam A, Entezari M, Falahati M. HMGA2 regulation by miRNAs in cancer: affecting cancer hallmarks and therapy response. Pharmacol Res 2023; 190:106732. [PMID: 36931542 DOI: 10.1016/j.phrs.2023.106732] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 03/17/2023]
Abstract
High mobility group A 2 (HMGA2) is a protein that modulates the structure of chromatin in the nucleus. Importantly, aberrant expression of HMGA2 occurs during carcinogenesis, and this protein is an upstream mediator of cancer hallmarks including evasion of apoptosis, proliferation, invasion, metastasis, and therapy resistance. HMGA2 targets critical signaling pathways such as Wnt/β-catenin and mTOR in cancer cells. Therefore, suppression of HMGA2 function notably decreases cancer progression and improves outcome in patients. As HMGA2 is mainly oncogenic, targeting expression by non-coding RNAs (ncRNAs) is crucial to take into consideration since it affects HMGA2 function. MicroRNAs (miRNAs) belong to ncRNAs and are master regulators of vital cell processes, which affect all aspects of cancer hallmarks. Long ncRNAs (lncRNAs) and circular RNAs (circRNAs), other members of ncRNAs, are upstream mediators of miRNAs. The current review intends to discuss the importance of the miRNA/HMGA2 axis in modulation of various types of cancer, and mentions lncRNAs and circRNAs, which regulate this axis as upstream mediators. Finally, we discuss the effect of miRNAs and HMGA2 interactions on the response of cancer cells to therapy. Regarding the critical role of HMGA2 in regulation of critical signaling pathways in cancer cells, and considering the confirmed interaction between HMGA2 and one of the master regulators of cancer, miRNAs, targeting miRNA/HMGA2 axis in cancer therapy is promising and this could be the subject of future clinical trial experiments.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran.
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Timo L M Ten Hagen
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands.
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mojtaba Falahati
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands.
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24
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Yao W, Jia X, Zhu L, Xu L, Zhang Q, Xia T, Wei L. Exosomal circ_0026611 contributes to lymphangiogenesis by reducing PROX1 acetylation and ubiquitination in human lymphatic endothelial cells (HLECs). Cell Mol Biol Lett 2023; 28:13. [PMID: 36803975 PMCID: PMC9936748 DOI: 10.1186/s11658-022-00410-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 11/24/2022] [Indexed: 02/19/2023] Open
Abstract
BACKGROUND Esophageal squamous carcinoma (ESCC) is a common malignancy that originates in the digestive tract. Lymph node metastasis (LNM) is a complicated process, and tumor lymphangiogenesis has been reported to be associated with the spread of tumor cells to lymph nodes (LNs), including in ESCC. However, little is currently known about the mechanisms involved in lymphangiogenesis in ESCC tumors. According to previous literature, we know that hsa_circ_0026611 expresses at a high level in serum exosomes of patients with ESCC and shows a close association with LNM and poor prognosis. However, details on the functions of circ_0026611 in ESCC remain unclear. We aim to explore the effects of circ_0026611 in ESCC cell-derived exosomes on lymphangiogenesis and its potential molecular mechanism. METHODS We firstly examined how circ_0026611 may express in ESCC cells and exosomes by quantitative reverse transcription real-time polymerase chain reaction (RT-qPCR). The potential effects circ_0026611 may exert on lymphangiogenesis in ESCC cell-derived exosomes were assessed afterward via mechanism experiments. RESULTS circ_0026611 high expression pattern was confirmed in ESCC cells and exosomes. ESCC cell-derived exosomes promoted lymphangiogenesis by transferring circ_0026611. Besides, circ_0026611 interacted with N-α-acetyltransferase 10 (NAA10) to inhibit NAA10-mediated prospero homeobox 1 (PROX1) acetylation with subsequent ubiquitination and degradation. Furthermore, circ_0026611 was verified to promote lymphangiogenesis in a PROX1-mediated manner. CONCLUSIONS Exosomal circ_0026611 inhibited PROX1 acetylation and ubiquitination to promote lymphangiogenesis in ESCC.
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Affiliation(s)
- Wenjian Yao
- grid.256922.80000 0000 9139 560XDepartment of Thoracic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No.7, Weiwu Road, Jinshui District, Zhengzhou, 450003 Henan China
| | - Xiangbo Jia
- grid.256922.80000 0000 9139 560XDepartment of Thoracic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No.7, Weiwu Road, Jinshui District, Zhengzhou, 450003 Henan China
| | - Li Zhu
- grid.414011.10000 0004 1808 090XDepartment of Thoracic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003 Henan China
| | - Lei Xu
- grid.256922.80000 0000 9139 560XDepartment of Thoracic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No.7, Weiwu Road, Jinshui District, Zhengzhou, 450003 Henan China
| | - Quan Zhang
- grid.256922.80000 0000 9139 560XDepartment of Thoracic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No.7, Weiwu Road, Jinshui District, Zhengzhou, 450003 Henan China
| | - Tian Xia
- grid.256922.80000 0000 9139 560XDepartment of Thoracic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No.7, Weiwu Road, Jinshui District, Zhengzhou, 450003 Henan China
| | - Li Wei
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No.7, Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, China.
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25
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Circular RNA circ-AGFG1 contributes to esophageal squamous cell carcinoma progression and glutamine catabolism by targeting microRNA-497-5p/solute carrier family 1 member 5 axis. Anticancer Drugs 2023; 34:195-206. [PMID: 36206112 DOI: 10.1097/cad.0000000000001400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Circular RNAs (circRNAs) have been shown to play important regulatory roles in human malignancies. However, the role of circRNA ArfGAP with FG repeats 1 (circ-AGFG1) in esophageal squamous cell carcinoma (ESCC) progression and its associated mechanism are still largely undefined. Cell proliferation was analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-ethynyl-2'-deoxyuridine assay. Cell apoptosis was assessed by flow cytometry analysis. Transwell assay and wound healing assay were used to analyze cell invasion and migration abilities. The uptake of glutamine and the production of α-ketoglutarate and glutamate were analyzed using Glutamine Determination Kit, α-ketoglutarate Assay Kit and Glutamate Determination Kit. A xenograft tumor model was used to analyze the biological role of circ-AGFG1 in vivo . The interaction between microRNA-497-5p (miR-497-5p) and circ-AGFG1 or solute carrier family 1 member 5 (SLC1A5) was verified by dual-luciferase reporter assay. Circ-AGFG1 expression was upregulated in ESCC tissues and cell lines. Circ-AGFG1 silencing suppressed the proliferation, migration, invasion and glutaminolysis and triggered the apoptosis of ESCC cells. Circ-AGFG1 knockdown significantly slowed down tumor growth in vivo . Circ-AGFG1 acted as a sponge for miR-497-5p, and miR-497-5p interacted with the 3' untranslated region (3'UTR) of SLC1A5. miR-497-5p silencing largely abolished circ-AGFG1 silencing-induced effects in ESCC cells. miR-497-5p overexpression-mediated influences in ESCC cells were largely reversed by the addition of SLC1A5 expressing plasmid. Circ-AGFG1 could upregulate SLC1A5 expression by sponging miR-497-5p. In summary, circ-AGFG1 acted as an oncogene to elevate the malignant potential and promote the glutamine catabolism of ESCC cells by targeting the miR-497-5p/SLC1A5 axis.
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26
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Non-coding RNAs in EMT regulation: Association with tumor progression and therapy response. Eur J Pharmacol 2022; 932:175212. [DOI: 10.1016/j.ejphar.2022.175212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/03/2022] [Accepted: 08/11/2022] [Indexed: 12/12/2022]
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Wang J, Li X, Duan C, Jia Y. CircFNDC3B
knockdown restrains the progression of esophageal squamous cell carcinoma through
miR
‐214‐3p/
CDC25A
axis. Clin Exp Pharmacol Physiol 2022; 49:1209-1220. [DOI: 10.1111/1440-1681.13707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/01/2022] [Accepted: 07/27/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Jiawei Wang
- Department of Thoracic Surgery Affiliated Hospital of Jiangnan University Wuxi China
| | - Xiaolin Li
- Department of Thoracic Surgery Affiliated Hospital of Jiangnan University Wuxi China
| | - Chao Duan
- Department of Thoracic Surgery Affiliated Hospital of Jiangnan University Wuxi China
| | - Yifei Jia
- Department of Thoracic Surgery Affiliated Hospital of Jiangnan University Wuxi China
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28
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circRNA: A New Biomarker and Therapeutic Target for Esophageal Cancer. Biomedicines 2022; 10:biomedicines10071643. [PMID: 35884948 PMCID: PMC9313320 DOI: 10.3390/biomedicines10071643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 12/19/2022] Open
Abstract
Circular RNAs (circRNAs) comprise a large class of endogenous non-coding RNA with covalently closed loops and have independent functions as linear transcripts transcribed from identical genes. circRNAs are generated by a “back-splicing” process regulated by regulatory elements in cis and associating proteins in trans. Many studies have shown that circRNAs play important roles in multiple processes, including splicing, transcription, chromatin modification, miRNA sponges, and protein decoys. circRNAs are highly stable because of their closed ring structure, which prevents them from degradation by exonucleases, and are more abundant in terminally differentiated cells, such as brains. Recently, it was demonstrated that numerous circRNAs are differentially expressed in cancer cells, and their dysfunction is involved in tumorigenesis and metastasis. However, the crucial functions of these circRNAs and the dysregulation of circRNAs in cancer are still unknown. In this review, we summarize the recent reports on the biogenesis and biology of circRNAs and then catalog the advances in using circRNAs as biomarkers and therapeutic targets for cancer therapy, particularly esophageal cancer.
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Luo C, Zhao X, Wang Y, Li Y, Wang T, Li S. A novel circ_0000654/miR-375/E2F3 ceRNA network in esophageal squamous cell carcinoma. Thorac Cancer 2022; 13:2223-2234. [PMID: 35790503 PMCID: PMC9346169 DOI: 10.1111/1759-7714.14550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 11/29/2022] Open
Abstract
Background The competing endogenous RNA (ceRNA) activity of circular RNAs (circRNAs) has been implicated in the pathogenesis of cancers, including esophageal squamous cell carcinoma (ESCC). Here, we identified the ceRNA mechanism of circ_0000654 regulation in ESCC. Methods The levels of circ_0000654, E2F transcription factor 3 (E2F3), and microRNA (miR)‐375 were gauged by quantitative real‐time PCR (qRT‐PCR) and western blot. Cell proliferation was assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium (MTS) and 5‐ethynyl‐2′‐deoxyuridine (EdU) assays. Cell apoptosis was detected by flow cytometry. Cell colony formation was tested by colony formation assay. Dual‐luciferase reporter, RNA pull‐down and RNA immunoprecipitation (RIP) assays were performed to confirm the direct relationship between miR‐375 and circ_0000654 or E2F3. Xenograft model assays were used to evaluate the effect of circ_0000654 in vivo. Results Circ_0000654 and E2F3 were upregulated in ESCC. Circ_0000654 depletion enhanced cell apoptosis and hindered cell proliferation and glycolysis in vitro, as well as weakened tumor growth in vivo. Increased expression of E2F3 counteracted the effects of circ_0000654 depletion. Mechanistically, E2F3 was a target of miR‐375, and circ_0000654 modulated E2F3 expression through sequestering miR‐375. Furthermore, miR‐375 upregulation phenocopied circ_0000654 knockdown in inhibiting ESCC progression. Conclusion Our findings identify a new circ_0000654/miR‐375/E2F3 ceRNA crosstalk for the oncogenic role of circ_0000654 in ESCC and establish a notion that targeting circ_0000654 and its pathways may have the potential to improve ESCC outcome.
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Affiliation(s)
- Chunyu Luo
- Department of Clinical Laboratory, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Xiaowei Zhao
- Department of Clinical Laboratory, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Yuan Wang
- Department of Clinical Laboratory, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Yanqiu Li
- Department of Clinical Laboratory, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Tuo Wang
- Department of Clinical Laboratory, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Shumin Li
- Department of Clinical Laboratory, Affiliated Hospital of Chifeng University, Chifeng, China
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30
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Circular RNA circ_0006948 Promotes Esophageal Squamous Cell Carcinoma Progression by Regulating microRNA-3612/LASP1 Axis. Dig Dis Sci 2022; 67:2158-2172. [PMID: 34024023 DOI: 10.1007/s10620-021-07057-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 05/11/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is the most prevalent malignancy worldwide. Circular RNAs (circRNAs) circ_0006948 is reported to be upregulated in ESCC cells. AIMS This study is designed to explore the role and mechanism of circ_0006948 in ESCC progression. METHODS Circ_0006948, linear FNDC3B, microRNA-3612 (miR-3612), and LIM and SH3 protein 1 (LASP1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, colony number, migration, invasion, and apoptosis were examined by Cell Counting Kit-8 (CCK-8), colony formation, transwell, and flow cytometry assays, severally. Glucose consumption, lactate production, and ATP level were measured by the corresponding kits. Protein levels of hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA), and LASP1 were assessed by western blot assay. The cytoplasmic localization of circ_0006948 was identified by the subcellular fractionation assay. The binding relationship between miR-3612 and circ_0006948 or LASP1 was predicted by starBase or TargetScan and then verified by a dual-luciferase reporter assay. The biological role of circ_0006948 on ESCC tumor growth was examined by the xenograft tumor model in vivo. RESULTS Circ_0006948 and LASP1 were increased, and miR-3612 was decreased in ESCC tissues and cells. Furthermore, circ_0006948 knockdown could suppress cell viability, colony number, migration, invasion, glycolysis, and boost apoptosis in ESCC cells. Mechanically, circ_0006948 could act as a sponge of miR-3612 to regulate LASP1 expression. In addition, circ_0006948 silencing inhibited ESCC tumor growth in vivo. CONCLUSION Circ_0006948 boosted ESCC progression partly by regulating the miR-3612/LASP1 axis, providing an underlying therapeutic target for the ESCC treatment.
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circRNA TCFL5 Promote Esophageal Cancer Progression by Modulating M2 Macrophage Polarization via the miR-543-FMNL2 Axis. JOURNAL OF ONCOLOGY 2022; 2022:5075615. [PMID: 35646112 PMCID: PMC9132701 DOI: 10.1155/2022/5075615] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/19/2022] [Indexed: 11/18/2022]
Abstract
Objective The mechanism of circRNA on M2 macrophage polarization, which contributes to esophageal cancer, remains unclear. This study is aimed at clarifying the mechanism of circRNA on esophageal cancer by regulating M2 macrophage polarization. Methods The expression of circRNA TCFL5 and miR-543 was detected by qRT-PCR. Western blot was used to detect the expression of FMNL2 and CD163. CCK-8 and transwell assay was used to detect the proliferation, migration, and invasion of Eca109 and KYSE150, respectively. Flow cytometry was used to detect the CD163 positive cells. The contents of IL-10, TGF-β, TNF-α, IL-6, and IL-1β were detected by ELISA. A dual-luciferase reporter system was used to detect the regulation of miR-543 to circRNA TCFL5 and FMNL2. Results 156 upregulated circRNAs and 91 downregulated circRNAs in esophageal cancer tissues were identified, and the expression of circRNA TCFL5 showed the most significant upregulation. Overexpression of circRNA TCFL5 promotes proliferation, invasion, and migration of Eca109 and KYSE150 and promotes tumor growth in vivo. circRNA TCFL5 served as a sponge of miR-543, and FMNL2 was a downstream target gene of miR-543. circRNA TCFL5 promotes cell proliferation, migration, and invasion of Eca109 and KYSE150 by modulating the miR-543/FMNL2 axis. Macrophage M2 polarization promoted proliferation, invasion, and migration of Eca109 and KYSE150 cells, and circRNA TCFL5 mediated macrophage M2 polarization by regulating the FMNL2/miR-543 axis. Conclusion In the present study, we identified that circRNA TCFL5 was dramatically upregulated in esophageal cancer, and circRNA TCFL5 promotes esophageal cancer progression by modulating M2 macrophage polarization via the miR-543-FMNL2 axis, which provides a potential target for the treatment of esophageal cancer.
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32
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Wu B, Chen Y, Chen Y, Xie X, Liang H, Peng F, Che W. Circ_0001273 downregulation inhibits the growth, migration and glutamine metabolism of esophageal cancer cells via targeting the miR-622/SLC1A5 signaling axis. Thorac Cancer 2022; 13:1795-1805. [PMID: 35567340 PMCID: PMC9200876 DOI: 10.1111/1759-7714.14458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/20/2022] [Accepted: 04/22/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Esophageal cancer is a relatively rare cancer. However, its death rate is not to be taken lightly. Accumulating evidence indicates circular RNA (circRNA) is implicated in cancer development. The objective of this study was to unveil the role of circ_0001273 in esophageal cancer (EC). METHODS For expression analysis of circ_0001273, miR-622 and solute carrier family 1 member 5 (SLC1A5), quantitative real-time PCR (qPCR) and Western blot were conducted. Cell proliferation was evaluated by cell counting kit-8 (CCK-8), EdU and colony formation assays. Cell apoptosis and cell migration were investigated using flow cytometry assay and wound healing assay. Glutamine metabolism was assessed by glutamine consumption and glutamate production using matched kits. The predicted binding relationship between miR-622 and circ_0001273 or SLC1A5 was validated by dual-luciferase reporter assay. An in vivo xenograft model was established to determine the role of circ_0001273 on tumor growth. RESULTS Circ_0001273 was upregulated in EC tumor tissues and cells. Knockdown of circ_0001273 repressed EC cell proliferation, migration, epithelial-mesenchymal transition (EMT) and glutamine metabolism. Circ_0001273 knockdown also blocked tumor development in animal models. MiR-622 was targeted by circ_0001273, and its inhibition reversed the functional effects of circ_0001273 knockdown. SLC1A5 was a target gene of miR-622, and circ_0001273 targeted miR-622 to positively regulate SLC1A5 expression. The inhibitory effects of miR-622 enrichment on EC cell proliferation, migration, EMT and glutamine metabolism were recovered by SLC1A5 overexpression. CONCLUSION Circ_0001273 high expression contributed to EC progression via modulating the miR-622/SLC1A5 signaling axis.
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Affiliation(s)
- Bomeng Wu
- Department of Thoracic Surgery, Gaozhou People's Hospital, Gaozhou City, Guangdong Province, China
| | - Ying Chen
- Department of Thoracic Surgery, Gaozhou People's Hospital, Gaozhou City, Guangdong Province, China
| | - Ying Chen
- Department of Thoracic Surgery, Gaozhou People's Hospital, Gaozhou City, Guangdong Province, China
| | - Xihao Xie
- Department of Thoracic Surgery, Gaozhou People's Hospital, Gaozhou City, Guangdong Province, China
| | - Hanping Liang
- Department of Thoracic Surgery, Gaozhou People's Hospital, Gaozhou City, Guangdong Province, China
| | - Fengyuan Peng
- Department of Thoracic Surgery, Gaozhou People's Hospital, Gaozhou City, Guangdong Province, China
| | - Weibi Che
- Department of Thoracic Surgery, Gaozhou People's Hospital, Gaozhou City, Guangdong Province, China
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Liang W, Wang C, Wang J, Zhang M. Hsa_circ_0023984 Regulates Cell Proliferation, Migration, and Invasion in Esophageal Squamous Cancer via Regulating miR-1294/PI3K/Akt/c-Myc Pathway. Appl Biochem Biotechnol 2022; 194:1-16. [PMID: 35522362 DOI: 10.1007/s12010-022-03935-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2022] [Indexed: 11/02/2022]
Abstract
Circular RNAs (circRNAs) exert an essential function in the tumorigenesis and progression of esophageal squamous cancer (ESCC). Nonetheless, the role and potential mechanism of circ_0023984 in ESCC are blurred. circRNA expression profile data from Gene Expression Omnibus (GEO) database was applied to analyze circRNAs that were differentially expressed between ESCC tissues and paracancerous tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to analyze circ_0023984 expression and miR-1294 expression in ESCC tissues and cells. Then a series of functional experiments were executed to validate the role of circ_0023984 and miR-1294 in modulating the proliferation, migration, invasion, and cell cycle progression of ESCC cells. Luciferase reporter experiment was performed to confirm the targeting relationship between circ_0023984 and miR-1294. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were carried out with DAVID database. Western blot assay was utilized to detect phosphorylated-Akt (p-Akt) expression and c-Myc expression. circ_0023984 was remarkably upmodulated in ESCC tumor tissues and cell lines. circ_0023984 overexpression was correlated with advanced clinical stage and lymph node metastasis of ESCC patients. circ_0023984 overexpression remarkably enhanced ESCC cell proliferation, migration, invasion, and cell cycle progression, while knockdown of circ_0023984 showed the opposite effect. circ_0023984 was the molecular sponge of miR-1294. miR-1294 could significantly inhibit ESCC cell proliferation, migration, invasion, and induce cell cycle arrest at G0/G1 phase. circ_0023984 affected ESCC progression through regulating miR-1294 expression. The target genes of miR-1294 were associated with cell cycle arrest and PI3K-Akt signaling pathway. circ_0023984 upregulated the expression of p-Akt and c-Myc by repressing miR-1294. circ_0023984 facilitates the malignant biological behaviors of ESCC cells through inhibiting miR-1294 and activating PI3K/Akt/c-myc pathway.
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Affiliation(s)
- Wenchang Liang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Jianshedong Road No.1, Zhengzhou, 450000, Henan, China.,Department of Oncology, Anyang Tumor Hospital, the Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Henan Medical Key Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, 455000, Henan, China
| | - Cailing Wang
- Department of Oncology, Anyang Tumor Hospital, the Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Henan Medical Key Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, 455000, Henan, China
| | - Junsheng Wang
- Department of Oncology, Anyang Tumor Hospital, the Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Henan Medical Key Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, 455000, Henan, China
| | - Mingzhi Zhang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Jianshedong Road No.1, Zhengzhou, 450000, Henan, China.
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Tang B, Zhang Q, Liu K, Huang Y. Exosomal circRNA FNDC3B promotes the progression of esophageal squamous cell carcinoma by sponging miR-490-5p and regulating thioredoxin reductase 1 expression. Bioengineered 2022; 13:13829-13848. [PMID: 35703190 PMCID: PMC9275986 DOI: 10.1080/21655979.2022.2084484] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Exosomal circular RNAs (circRNAs) have been reported to play critical roles in esophageal squamous cell carcinoma (ESCC). We aimed to investigate the function of exosomal circRNA FNDC3B (circFNDC3B). The RNA levels and protein levels were examined using RT-qPCR and western blot (WB) assays. Colony formation and EdU assays were used to assess cell proliferative ability. Cell migratory and invasive abilities were detected by wound healing and transwell assays. Cell apoptosis was measured by flow cytometry. Glycolysis was measured using commercial kits. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were applied to examine the morphology and size of exosomes. Dual-luciferase reporter, RIP and RNA pull-down assays assessed the interaction of miR-490-5p with circFNDC3B or thioredoxin reductase 1 (TXNRD1). Xenograft tumor model determined the role of exosomal circFNDC3B in vivo. We observed that circFNDC3B was upregulated in ESCC samples and cells, as well as ESCC-derived exosomes. CircFNDC3B could be delivered via exosomes in tumor cells, and the colony formation, proliferation, migration, invasion, glycolysis, and in vivo growth ability of recipient cells were weakened after co-incubation with exosomal circFNDC3B-knockdown donor cells. CircFNDC3B was a miR-490-5p sponge, and miR-490-5p inhibition reversed the role of exosomal circFNDC3B-downregulating in ESCC cells. TXNRD1 was a miR-490-5p target, and TXNRD1 elevation weakened the anti-cancer function of miR-490-5p upregulation in ESCC cells. CircFNDC3B mediated TXNRD1 expression by interacting with miR-490-5p. In conclusion, exosomal circFNDC3B drove ESCC progression via regulating the miR-490-5p/TXNRD1 axis.AbbreviationsEC: esophageal cancer; ESCC: esophageal squamous cell carcinoma; circRNA: circular RNA; WB: western blot; TEM: transmission electron microscopy; NTA: nanoparticle tracking analysis; TXNRD1: thioredoxin reductase 1; IHC: immunohistochemistry; RT-qPCR: reverse transcription-polymerase quantitative chain reaction; GLUT1: glucose transport protein type 1; LDHA: lactate dehydrogenase A.
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Affiliation(s)
- Bo Tang
- Department of Cardio-Thoracic Surgery, Zigong Fourth People's Hospital, Zigong City, China
| | - Qingfeng Zhang
- Department of Cardio-Thoracic Surgery, Zigong Fourth People's Hospital, Zigong City, China
| | - Kui Liu
- Department of Cardio-Thoracic Surgery, Zigong Fourth People's Hospital, Zigong City, China
| | - Yun Huang
- Department of Cardio-Thoracic Surgery, Zigong Fourth People's Hospital, Zigong City, China
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Weidle UH, Sela T, Brinkmann U, Niewoehner J. Circular RNAs With Efficacy in Preclinical In Vitro and In Vivo Models of Esophageal Squamous Cell Carcinoma. Cancer Genomics Proteomics 2022; 19:283-298. [PMID: 35430563 DOI: 10.21873/cgp.20320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer is associated with a dismal prognosis. The armamentarium of approved drugs is focused on chemotherapy with modest therapeutic benefit. Recently, checkpoint inhibitory monoclonal antibody Pembrolizumab was approved. In order to identify new targets and modalities for the treatment of esophagus squamous cell carcinoma (ESCC) we searched the literature for circRNAs involved in the pathogenesis of ESCC. We identified two down-regulated and 17 up-regulated circRNAs as well as a synthetic circRNA with efficacy in preclinical in vivo systems. Down-regulated circRNAs sponge microRNAs directed against tumor suppressor genes. Up-regulated circRNAs sponge microRNAs directed against mRNAs, which encode proteins with pro-tumoral functions. We discuss issues such as reconstitution of down-regulated circRNAs and inhibition of up-regulated circRNAs with short interfering RNA (siRNA)- related entities. Also, we address druggability issues of the identified targets.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
| | - Tatjana Sela
- Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
| | - Ulrich Brinkmann
- Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
| | - Jens Niewoehner
- Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
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Li J, Zhu T, Weng Y, Cheng F, Sun Q, Yang K, Su Z, Ma H. Exosomal circDNER enhances paclitaxel resistance and tumorigenicity of lung cancer via targeting miR-139-5p/ITGB8. Thorac Cancer 2022; 13:1381-1390. [PMID: 35396925 PMCID: PMC9058310 DOI: 10.1111/1759-7714.14402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) are regarded as vital regulatory factors in various cancers. However, the biological functions of circDNER in the paclitaxel (PTX) resistance of lung cancer remain largely unexplored. METHODS Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze circDNER, miR-139-5p, and ITGB8. Cell proliferation was assessed via colony formation and MTT assays. Cell apoptosis was evaluated by flow cytometry. Western blot was performed to assess protein expression. The targeted interaction among circDNER, miR-139-5p, and ITGB8 were validated using dual-luciferase reporter or RNA immunoprecipitation assays. RESULTS Inhibition of circDNER reduced IC50 of PTX, inhibited cell proliferation, invasion and migration, as well as promoted cell apoptosis in PTX-resistant lung cancer cells. Mechanistically, circDNER sponged miR-139-5p to upregulate ITGB8 expression. Overexpression of miR-139-5p reversed the biological functions mediated by circDNER in PTX-resistant lung cancer cells. MiR-139-5p overexpression suppressed PTX resistance and malignant behaviors of PTX-resistant lung cancer cells, with ITGB8 elevation rescued the impacts. Moreover, we demonstrated that circDNER was upregulated in plasma exosomes from lung cancer patients. The plasma exosomes derived from these patients are the key factors enhancing the migration and invasion potential of lung cancer cells. CONCLUSION The circDNER mediated miR-139-5p/ITGB8 axis suppresses lung cancer progression. Our findings suggest that circDNER might act as a potential prognostic biomarker and therapeutic target for lung cancer treatment.
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Affiliation(s)
- Jinyou Li
- Department of Thoracic SurgeryFirst Affiliated Hospital of Soochow UniversitySuzhouChina
- Department of Thoracic SurgeryAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Tao Zhu
- Department of Thoracic SurgeryAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Yuan Weng
- Department of Thoracic SurgeryAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Fengyue Cheng
- Department of Thoracic SurgeryAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Qi Sun
- Department of Thoracic SurgeryAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Kejia Yang
- Department of Thoracic SurgeryAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Zhenyu Su
- Department of Thoracic SurgeryAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Haitao Ma
- Department of Thoracic SurgeryFirst Affiliated Hospital of Soochow UniversitySuzhouChina
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Zheng J, Zhao Z, Ren H, Wang Y, Meng X, Zhang W, Zhang C, Ming L, Lu X. LncRNA HCG11 Facilitates Nasopharyngeal Carcinoma Progression Through Regulating miRNA-490-3p/MAP3K9 Axis. Front Oncol 2022; 12:872033. [PMID: 35463310 PMCID: PMC9021694 DOI: 10.3389/fonc.2022.872033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/04/2022] [Indexed: 11/18/2022] Open
Abstract
Purpose Long noncoding RNAs (LncRNAs) play complex but important roles in the progression of various tumors. This study aimed to elucidate the functional mechanisms of the HLA complex group 11 (HCG11) in nasopharyngeal carcinoma (NPC). Patients and Methods HCG11 levels in NPC specimens were determined by fluorescence in situ hybridization (FISH) and qPCR. Proliferation, apoptosis, and metastasis of NPC cells were determined using CCK8, colony formation, annexin V-PI, and transwell assays. A murine tumor xenograft model was used to investigate the regulatory function of HCG11 in NPC in vivo, and immunohistochemical staining was used to determine the Ki-67 level in tumors. The target relationships between HCG11, microRNA miR-490-3p, and MAPK kinase kinase 9 (MAP3K9) were detected using bioinformatics, qPCR, western blotting, and luciferase reporter assays. Results HCG11 was highly expressed in NPC tissues and was positively associated with tumor stage, lymphatic metastasis, and poor prognosis. Functionally, HCG11 knockdown inhibited proliferation and migration and induced apoptosis of NPC cells. Mechanistically, miR-490-3p is a direct target of HCG11, oncogenic functions of HCG11 in NPC cell proliferation and migration can be partially reversed by the miR-490-3p inhibitor. HCG11 significantly increased mitogen-activated protein kinase MAPK kinase 9 (MAP3K9) levels by inhibiting miR-490-3p. Conclusion HCG11 facilitates NPC progression via MAP3K9 signaling by sponging miRNA-490-3p, which may contribute to new prognostic markers and promising therapeutic targets.
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Affiliation(s)
- Jian Zheng
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhuochen Zhao
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Clinical Laboratory of Henan Province, Zhengzhou, China
| | - Huijun Ren
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Clinical Laboratory of Henan Province, Zhengzhou, China
| | - Yongfeng Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Clinical Laboratory of Henan Province, Zhengzhou, China
| | - Xianchun Meng
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Clinical Laboratory of Henan Province, Zhengzhou, China
| | - Wenjing Zhang
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Cai Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Clinical Laboratory of Henan Province, Zhengzhou, China
| | - Liang Ming
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Clinical Laboratory of Henan Province, Zhengzhou, China
| | - Xiubo Lu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Yang G, Zhang Y, Lin H, Liu J, Huang S, Zhong W, Peng C, Du L. CircRNA circ_0023984 promotes the progression of esophageal squamous cell carcinoma via regulating miR-134-5p/cystatin-s axis. Bioengineered 2022; 13:10578-10593. [PMID: 35440286 PMCID: PMC9161969 DOI: 10.1080/21655979.2022.2063562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Recent studies have shown that circRNAs can act as oncogenic factors or tumor suppressors by sponging microRNAs (miRNAs). The upregulation of circ_0023984 was reported in esophageal squamous cell carcinoma (ESCC). However, its functional role in ESCC remain unclear. In the present study, circ_0023984 expression in ESCC cells and tissues were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB). Subcellular fraction experiment was performed to determine relative nuclear-cytoplasmic localization. The loss-of-function effects of circ_0023984 in ESCC cell lines were investigated by shRNA-mediated knockdown. Functional assays including cell Counting Kit-8 (CCK-8), 5-Ethynyl-2’-deoxyuridine (EDU) incorporation, colony formation and Transwell migration assays were conducted to assess the malignant phenotype. The interaction between the two molecules was analyzed by RNA pull-down, luciferase reporter assay and RNA immunoprecipitation (RIP). The subcutaneous tumor model in nude mice was used to assess the role of circ-0023984 in tumorigenesis. We found that ESCC patients with high circ_0023984 expression was associated with a poor prognosis. The knockdown of circ_0023984 suppressed cell growth, invasion, and migration in ESCC cells. Circ_0023984 interacted with miR-134-5p and inhibited its activity, which promoted the expression of CST4 (Cystatin-S). Circ_0023984 also regulated tumorigenesis in a CST4-dependent manner. Together, our study indicates that the oncogenic role of Circ_0023984 is mediated by miR-134-5p/CST4 Axis in ESCC, which could serve as potential targets for future therapeutic strategies.
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Affiliation(s)
- Ge Yang
- Department of Clinical Laboratory, Affiliated Neijiang Second People's Hospital of Southwest Medical University, Neijiang, P.R, China.,Department of Clinical Laboratory, The First Affiliated Hospital of Southwest Medical University, China Neijiang
| | - Yu Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Southwest Medical University, China Neijiang
| | - Hongni Lin
- Scientific research department, Sichuan Neijiang Health Vocational College, China Neijiang
| | - Jinnbo Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Southwest Medical University, China Neijiang
| | - Shengjie Huang
- Scientific research department, Sichuan Neijiang Health Vocational College, China Neijiang
| | - Wei Zhong
- Nuclear medicine department, Affiliated Neijiang Second People's Hospital of Southwest Medical University, Neijiang, P.R, China
| | - Chao Peng
- Department of intestine surgery, Affiliated Neijiang Second People's Hospital of Southwest Medical University, Neijiang, P.R, China
| | - Lin Du
- Scientific research department, Sichuan Neijiang Health Vocational College, China Neijiang
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Cheng J, Zhang R, Yan M, Li Y. Circular RNA hsa_circ_0000277 promotes tumor progression and DDP resistance in esophageal squamous cell carcinoma. BMC Cancer 2022; 22:238. [PMID: 35241028 PMCID: PMC8895546 DOI: 10.1186/s12885-022-09241-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 01/25/2022] [Indexed: 12/24/2022] Open
Abstract
Background Circular RNAs (circRNAs) are well-known regulators of cancer progression and chemoresistance in various types of cancers. This study was performed to investigate the function of hsa_circ_0000277 in esophageal squamous cell carcinoma (ESCC). Methods RNA levels were analyzed via the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8) assay was applied to determine cell proliferation and half maximal inhibitory concentration (IC50) of cisplatin (DDP). Colony formation ability was evaluated by colony formation assay. Cell cycle and apoptosis were measured using flow cytometry. RNA immunoprecipitation (RIP), pull-down assay and dual-luciferase reporter assays were performed for target interaction analysis. The protein levels were determined through western blot. Xenograft models were established for researching hsa_circ_0000277 function in vivo. Results Hsa_circ_0000277 expression was increased in ESCC cells and tissues, and it had important clinical significance. Downregulation of hsa_circ_0000277 repressed ESCC cell proliferation, colony formation, cell cycle, and DDP resistance. Hsa_circ_0000277 acted as a microRNA-873-5p (miR-873-5p) sponge and Sry-related high-mobility group box 4 (SOX4) was validated as a target of miR-873-5p. Moreover, hsa_circ_0000277/miR-873-5p axis and miR-873-5p/SOX4 axis regulated ESCC cell progression and DDP resistance. Hsa_circ_0000277/miR-873-5p axis activated SOX4/Wnt/β-catenin signaling pathway. Hsa_circ_0000277 facilitated tumorigenesis and DDP resistance by miR-873-5p/SOX4 axis in vivo. Conclusion These findings unraveled that hsa_circ_0000277 promoted ESCC progression and DDP resistance via miR-873-5p/SOX4/Wnt/β-catenin axis, showing a specific molecular mechanism of carcinogenesis and chemoresistance in ESCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09241-9.
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Affiliation(s)
- Jiwei Cheng
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No.127 Dongming Road, Zhengzhou, 450008, Henan Province, China
| | - Ruixiang Zhang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No.127 Dongming Road, Zhengzhou, 450008, Henan Province, China
| | - Ming Yan
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No.127 Dongming Road, Zhengzhou, 450008, Henan Province, China
| | - Yin Li
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No.127 Dongming Road, Zhengzhou, 450008, Henan Province, China.
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Wang H, Zhang X, Qiao L, Wang H. CircRNA circ_0000554 promotes ovarian cancer invasion and proliferation by regulating miR-567. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:19072-19080. [PMID: 34709546 DOI: 10.1007/s11356-021-13710-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 03/25/2021] [Indexed: 06/13/2023]
Abstract
Circular RNAs (circRNAs) indicated potential modulating effects in tumor development. However, the specific role of circ_0000554 in ovarian tumor remains unknown. We found that circ_0000554 was overexpressed in ovarian tumor specimens and cells. Forced expression of circ_0000554 promoted cell growth, invasion, and epithelial to mesenchymal transition (EMT). We illustrated that miR-567 was downregulated in ovarian tumor specimens and cells. circ_0000554 was negatively correlated with miR-567 in ovarian tumor specimens. circ_0000554 sponged miR-567 expression in ovarian tumor. RIP assay showed that elevated expression of miR-567 could be enriched with circ_0000554. Luciferase reporter assay indicated that luciferase intensity was inhibited after treated with miR-567 mimic; however, the luciferase value of mut type was not decreased. Elevated expression of circ_0000554 suppressed miR-567 expression in HO8910 cell. circ_0000554 promoted ovarian tumor cell growth, invasion, and EMT via sponging miR-567. It suggested that circ_0000554 represent a potential therapy target for ovarian tumor.
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Affiliation(s)
- Hui Wang
- Department of Gynaecology and Obstetrics, Shengli Oilfield Central Hospital, Dongying, 57000, Shandong, China
| | - Xuezhong Zhang
- Department of Laboratory Medicine, Zibo Central Hospital, Zibo, 255036, Shandong, China
| | - Lujun Qiao
- Intensive Care Unit, Shengli Oilfield Central Hospital, Dongying, 257000, Shandong, China
| | - Heng Wang
- Intensive Care Unit, Shengli Oilfield Central Hospital, Dongying, 257000, Shandong, China.
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Li T, Li S. Circ_0023984 Facilitates Esophageal Squamous Cell Carcinoma Progression by Regulating miR-433-3p/REV3L Axis. Dig Dis Sci 2022; 67:892-903. [PMID: 33725240 DOI: 10.1007/s10620-021-06916-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/22/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND It has been revealed that circular RNAs (circRNAs) play an important role in regulating the malignant phenotype of tumor cells, thus involving in the progression of malignancies. However, the role of circ_0023984 in esophageal squamous cell carcinoma (ESCC) remains largely unclear. METHODS The quantitative real-time polymerase chain reaction and Western blot assays were used to detect the expression of circ_0023984, microRNA (miR)-443-3p, and protein reversionless 3-like (REV3L). In vitro and in vivo assays were performed using cell counting kit-8, colony formation, transwell, wound healing, flow cytometry, and xenograft assays. The interaction miR-433-3p and circ_0023984 or REV3L was confirmed by dual-luciferase reporter, pull-down or RIP assays. RESULTS Circ_0023984 was highly expressed in ESCC tissues and cells, knockdown of circ_0023984 suppressed cancer cell proliferation, migration, invasion, and promoted cell apoptosis in vitro. Mechanistic analysis confirmed that circ_0023984 functioned as a sponge for miR-433-3p to positively regulate the expression of REV3L that was verified to be a target of miR-433-3p. Circ_0023984 knockdown repressed the tumorigenesis of ESCC cells via targeting miR-433-3p. Additionally, miR-433-3p performed anti-proliferative, anti-migratory, and anti-invasive abilities in ESCC cells, which were reversed by REV3L overexpression. Pre-clinically, silencing of circ_0023984 suppresses the tumorigenesis and growth of xenografts in nude mice. CONCLUSION Circ_0023984 exerted an oncogenic role in ESCC tumorigenesis and aggressiveness through promoting cell growth, migration, and invasion via miR-433-3p/REV3L axis.
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Affiliation(s)
- Ting Li
- Department of Gastroenterology, The NO.2 People's Hospital of Lanzhou City, No. 388 Jingyuan Road, Chengguan District, Lanzhou, 730046, Gansu Province, China
| | - Suping Li
- Department of Gastroenterology, The NO.2 People's Hospital of Lanzhou City, No. 388 Jingyuan Road, Chengguan District, Lanzhou, 730046, Gansu Province, China.
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Yue M, Liu Y, Zuo T, Jiang Y, Pan J, Zhang S, Shen X. Circ_0006948 Contributes to Cell Growth, Migration, Invasion and Epithelial-Mesenchymal Transition in Esophageal Carcinoma. Dig Dis Sci 2022; 67:492-503. [PMID: 33630215 DOI: 10.1007/s10620-021-06894-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 02/03/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Circular RNAs (circRNAs) can act as promoters or inhibitors in cancer progression. Has_circ_0006948 (circ_0006948) was reported to aggravate the malignant behaviors of esophageal carcinoma (EC). AIMS This study focused on investigating the molecular mechanism of circ_0006948 in EC progression. METHODS The quantitative real-time polymerase chain reaction was performed to detect the expression of circ_0006948, microRNA-4262 (miR-4262) and fibronectin type III domain containing 3B (FNDC3B). Cell growth analysis was conducted by Cell Counting Kit-8 and colony formation assays. Cell migration and invasion were assessed by transwell assay. Epithelial-mesenchymal transition (EMT)-associated proteins and FNDC3B protein expression were assayed using western blot. Dual-luciferase reporter and RNA pull-down assays were performed to validate the target combination. Xenograft tumor assay was used for investigating the role of circ_0006948 in vivo. RESULTS Circ_0006948 was upregulated in EC tissues and cells. Downregulating the expression of circ_0006948 or FNDC3B repressed cell growth, migration, invasion and EMT in EC cells. Target analysis indicated that miR-4262 was a target for circ_0006948 and FNDC3B was a downstream gene for miR-4262. Moreover, circ_0006948 could affect the expression of FNDC3B via sponging miR-4262. The effects of si-circ_0006948#1 on EC cells were partly restored by miR-4262 inhibition or FNDC3B overexpression. In addition, circ_0006948 also facilitated EC tumorigenesis in vivo by targeting the miR-4262/FNDC3B axis. CONCLUSION Taken together, circ_0006948 functioned as an oncogenic factor in EC by the miR-4262-mediated FNDC3B expression regulation.
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Affiliation(s)
- Meng Yue
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan, 250013, Shandong Province, China.
| | - Yanxia Liu
- Department of Oncology, Shengli Oil Central Hospital, Dongying City, Shandong Province, China
| | - Taiyang Zuo
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan City, Shandong Province, China
| | - Yakun Jiang
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan, 250013, Shandong Province, China
| | - Jianmei Pan
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan, 250013, Shandong Province, China
| | - Shuhong Zhang
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan, 250013, Shandong Province, China
| | - Xingjie Shen
- Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan, 250013, Shandong Province, China
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Xi SJ, Cai WQ, Wang QQ, Peng XC. Role of circular RNAs in gastrointestinal tumors and drug resistance. World J Clin Cases 2021; 9:10400-10417. [PMID: 35004973 PMCID: PMC8686142 DOI: 10.12998/wjcc.v9.i34.10400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/26/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
The incidence of gastrointestinal cancers has increased significantly over the past decade and gastrointestinal malignancies now rank among the leading causes of mortality globally. Although newer therapeutic strategies such as targeted therapies have greatly improved patient outcomes, their clinical success is limited by drug resistance, treatment failure and recurrence of metastatic disease. Therefore, there is an urgent need for further research identifying accurate and reliable biomarkers for precise treatment strategies. Circular RNAs (circRNAs) exhibit a covalently closed structure, high stability and biological conservation, and their expression is associated with the occurrence and development of gastrointestinal tumors. Moreover, circRNAs may significantly influence drug resistance of gastrointestinal cancers. In this article, we review the role of circRNAs in the occurrence and development of gastrointestinal cancer, their association with drug resistance, and potential application for early diagnosis, treatment and prognosis in gastrointestinal malignancies. Furthermore, we summarize characteristics of circRNA, including mechanism of formation and biological effects via mRNA sponging, chromatin replication, gene regulation, translational modification, signal transduction, and damage repair. Finally, we discuss whether circRNA-related noninvasive testing may be clinically provided in the future. This review provides new insights for the future development of diagnostics and therapeutics based on circRNAs in gastrointestinal tumors.
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Affiliation(s)
- Shi-Jun Xi
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Wen-Qi Cai
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Qin-Qi Wang
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Xiao-Chun Peng
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
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Guo C, Mi J, Li H, Su P, Nie H. Dysregulated circular RNAs as novel biomarkers in esophageal squamous cell carcinoma: a meta-analysis. Cancer Med 2021; 10:7895-7908. [PMID: 34704390 PMCID: PMC8607254 DOI: 10.1002/cam4.3703] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 10/18/2020] [Indexed: 01/10/2023] Open
Abstract
Introduction Circular RNAs (circRNAs) play critical roles in tumorigenesis, but their clinical efficacy in esophageal squamous cell carcinoma (ESCC) still retains controversial. This meta‐analysis aims at evaluating the associations between circRNA expressions and clinicopathologic features as well as the diagnostic and prognostic values of circRNAs in ESCC. Materials & Methods PubMed, EMBASE, and other online databases were systematically searched to collect studies on circRNAs and clinicopathological features, diagnostic, and/or prognostic assessments of ESCC. The quality of included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS‐2) and Newcastle‐Ottawa Scale (NOS) scales. The included studies were quantitatively weighted and merged, and diagnostic indicators, hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated. P values were merged by Fisher᾽s method. Sources of heterogeneity were traced using subgroup, sensitivity, and meta‐regression analyses. Results As a result, 12 studies were included, representing 769 ESCC patients. The meta‐analysis showed that abnormal expressions of circRNAs were associated to TNM stage as well as lymph node and distant metastases in ESCC cases. CircRNA was used to distinguish ESCC patients from healthy controls, and the merged sensitivity, specificity, and the area under the curve (AUC) of ESCC were 0.78 (95% CI: 0.74–0.81), 0.79 (95% CI: 0.75–0.83), and 0.86, respectively. The survival analysis showed that upregulated oncogenic circRNA levels in ESCC tissues was associated with the shorter overall survival (OS) of the patients (univariate analysis: HR = 2.25, 95% CI: 1.71–2.95, p = 0.000, I2 = 0.0%; multivariate analysis: HR = 2.50, 95% CI: 1.61–3.89, p = 0.000, I2 = 0.0%), while the OS of ESCC patients presenting overexpressions of tumor‐suppressive circRNAs was significantly ameliorated (HR = 0.29, 95% CI: 0.20–0.42, p = 0.000, I2 = 0.0%). The subgroup analyses based on circRNA biofunctions, sample size, and reference gene also revealed robust results. Conclusion CircRNAs can be used as promising molecular biomarkers for the early diagnosis and prognosis monitoring of ESCC.
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Affiliation(s)
- Chengcheng Guo
- Department of Pathology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Jianqiang Mi
- Department of Pathology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Haike Li
- Faculty of Basic Medicine, Henan Vocational College of Tuina, Luoyang, China
| | - Panke Su
- Department of Pathology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - He Nie
- Department of Nuclear Medicine, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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Zhen H, Du P, Yi Q, Tang X, Wang T. LINC00958 promotes bladder cancer carcinogenesis by targeting miR-490-3p and AURKA. BMC Cancer 2021; 21:1145. [PMID: 34702201 PMCID: PMC8549181 DOI: 10.1186/s12885-021-08882-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 09/19/2021] [Indexed: 02/01/2023] Open
Abstract
Background Bladder cancer is a prevalent malignancy of the urinary system, in which long non-coding RNAs (lncRNAs) are highly associated. We aimed to elucidate the role of LINC00958 in bladder cancer. Methods LINC00958 expression levels were measured using qRT-PCR. The interaction of LINC00958-miR-490-3p-AURKA was analyzed by luciferase, RIP, and RNA pull-down assays. The biological roles of LINC00958, miR-490-3p, and AURKA in bladder cancer cells were analyzed using CCK8, BrdU, and transwell assays. Results Increased expression of LINC00958 and AURKA was observed in bladder cancer tissues and cell lines. Decreased LINC00958 expression repressed bladder cancer progression and downregulation of miR-490-3p accelerated bladder cancer cell progression. Moreover, LINC00958 sponges miR-490-3p to upregulate AURKA expression, thereby promoting carcinogenesis in bladder cancer cells. Conclusions Our study revealed that LINC00958 facilitated cell proliferation and invasion, and suppressed cell apoptosis by sponging miR-490-3p and upregulating AURKA, thus inspiring a new treatment method for bladder cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08882-6.
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Affiliation(s)
- Hongtao Zhen
- Department of Urology Ward 1, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195 Tongbai Road, Zhongyuan District, Zhengzhou, 450007, Henan, China.
| | - Peng Du
- Department of Urology, Peking University Cancer Hospital, Beijing, 100142, China
| | - Qiang Yi
- Department of Urology Ward 1, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195 Tongbai Road, Zhongyuan District, Zhengzhou, 450007, Henan, China
| | - Xiaolong Tang
- Department of Urology Ward 1, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195 Tongbai Road, Zhongyuan District, Zhengzhou, 450007, Henan, China
| | - Tongqing Wang
- Department of Urology Ward 1, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 195 Tongbai Road, Zhongyuan District, Zhengzhou, 450007, Henan, China
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Hsa_circ_0026628 promotes the development of colorectal cancer by targeting SP1 to activate the Wnt/β-catenin pathway. Cell Death Dis 2021; 12:802. [PMID: 34420031 PMCID: PMC8380248 DOI: 10.1038/s41419-021-03794-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 01/05/2021] [Accepted: 01/13/2021] [Indexed: 12/24/2022]
Abstract
Circular RNAs (circRNAs) have been reported to play crucial roles in the progression of various cancers, including colorectal cancer (CRC). SP1 (Sp1 transcription factor) is a well-recognized oncogene in CRC and is deemed to trigger the Wnt/β-catenin pathway. The present study was designed to investigate the role of circRNAs which shared the same pre-mRNA with SP1 in CRC cells. We identified that hsa_circ_0026628 (circ_0026628), a circular RNA that originated from SP1 pre-mRNA, was upregulated in CRC cells. Sanger sequencing and agarose gel electrophoresis verified the circular characteristic of circ_0026628. Functional assays including CCK-8, colony formation, transwell, immunofluorescence staining, and sphere formation assay revealed the function of circ_0026628. RNA pull-down and mass spectrometry disclosed the proteins interacting with circ_0026628. Mechanistic assays including RIP, RNA pull-down, CoIP, ChIP, and luciferase reporter assays demonstrated the interplays between molecules. The results depicted that circ_0026628 functioned as a contributor to CRC cell proliferation, migration, EMT, and stemness. Mechanistically, circ_0026628 served as the endogenous sponge of miR-346 and FUS to elevate SP1 expression at the post-transcriptional level, thus strengthening the interaction between SP1 and β-catenin to activate the Wnt/β-catenin pathway. In turn, the downstream gene of Wnt/β-catenin signaling, SOX2 (SRY-box transcription factor 2), transcriptionally activated SP1 and therefore boosted circ_0026628 level. On the whole, SOX2-induced circ_0026628 sponged miR-346 and recruited FUS protein to augment SP1, triggering the downstream Wnt/β-catenin pathway to facilitate CRC progression.
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Li Y, Tian D, Chen H, Cai Y, Chen S, Duan S. MicroRNA-490-3p and -490-5p in carcinogenesis: Separate or the same goal? Oncol Lett 2021; 22:678. [PMID: 34345303 PMCID: PMC8323007 DOI: 10.3892/ol.2021.12939] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNA (miR)-490-3p and miR-490-5p, located on chromosome 7q33, are two independent mature products of miR-490 exerting distinct effects on tumor progression. miR-490-3p and miR-490-5p possess antitumor properties. miR-490-3p dysfunction has been associated with malignancies including colorectal cancer, while the abnormal function of miR-490-5p has been more considerably associated with bladder cancer (for example). At present, there are 30 and 11 target genes of miR-490-3p and miR-490-5p, respectively, that have been experimentally verified, of which the cyclin D1 (CCND1) gene is a common target. Through these target genes, miR-490-3p and miR-490-5p are involved in 7 and 3 signaling pathways, respectively, of which only 2 are shared regulatory signaling pathways. The present review introduces two competing endogenous RNA (ceRNA) regulatory networks centered on miR-490-3p and miR-490-5p. These networks may be important promoters of tumor cell proliferation, invasiveness, metastatic potential and apoptosis. Unlike miR-490-5p, miR-490-3p plays a unique role in promoting cancer. However, both are promising molecular markers for early cancer diagnosis and prognosis. In addition, miR-490-3p was also found to be associated with the chemical resistance of cisplatin and paclitaxel. The present review focuses on the abnormal expression of miR-490-3p and miR-490-5p in different tumor types, and their complex ceRNA regulatory networks. The clinical value of miR-490-3p and miR-490-5p in cancer diagnosis, prognosis and treatment is also clarified, and an explanation for the opposing effects of miR-490-3p in tumor research is provided.
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Affiliation(s)
- Yin Li
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, P.R. China
| | - Dongmei Tian
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, P.R. China
| | - Hao Chen
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, P.R. China
| | - Yuanting Cai
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, P.R. China
| | - Sang Chen
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, P.R. China
| | - Shiwei Duan
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, P.R. China.,School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China
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Zhou J, Wang P, Zhang R, Huang X, Dai H, Yuan L, Ruan J. Association of HMGA2 Polymorphisms with Glioma Susceptibility in Chinese Children. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:601-607. [PMID: 34079335 PMCID: PMC8164710 DOI: 10.2147/pgpm.s310780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 05/05/2021] [Indexed: 12/13/2022]
Abstract
Background Glioma is a malignant central nervous system tumor in children, with poor outcomes and prognosis. HMGA2 is a proto-oncogene with increased expression in various malignancies. Methods We explored the association of HMGA2 polymorphisms with glioma susceptibility in Chinese children using a case-control study (191 cases, 248 controls). HMGA2 single nucleotide polymorphisms (rs6581658 A>G; rs8756 A>C; rs968697 T>C) were genotyped using PCR-based TaqMan. Results Increased glioma susceptibility was associated with rs6581658 A>G; AG (adjusted odds ratio (OR) = 1.71, 95% confidence interval (CI) = 1.13–2.58, P = 0.010) or GG (adjusted OR = 3.12, 95% CI = 1.26–7.74, P = 0.014) genotype carriers had significantly raised glioma risk compared with AA genotype carriers. The rs6581658 AG/GG (adjusted OR = 1.85, 95% CI = 1.25–2.73, P = 0.002) and AA/GG (adjusted OR = 2.58, 95% CI = 1.05–6.33, P = 0.038) genotypes were associated with an increased risk of glioma relative to the AA genotype. Subjects with 2–3 risk genotypes had a significantly elevated risk (adjusted OR = 1.93, 95% CI = 1.31–2.84, P = 0.001) relative to those with 0–1 risk genotype. Conclusion HMGA2 rs6581658 A>G is associated with glioma susceptibility in Chinese children.
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Affiliation(s)
- Jingying Zhou
- Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China
| | - Pan Wang
- Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China
| | - Ran Zhang
- Sydney School of Public Health, The University of Sydney, Camperdown, Sydney, NSW, 2006, Australia
| | - Xiaokai Huang
- Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China
| | - Hanqi Dai
- Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China
| | - Li Yuan
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, People's Republic of China
| | - Jichen Ruan
- Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China
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Zhang R, Zhu W, Ma C, Ai K. Silencing of circRNA circ_0001666 Represses EMT in Pancreatic Cancer Through Upregulating miR-1251 and Downregulating SOX4. Front Mol Biosci 2021; 8:684866. [PMID: 34055896 PMCID: PMC8155604 DOI: 10.3389/fmolb.2021.684866] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 04/12/2021] [Indexed: 01/22/2023] Open
Abstract
Background Pancreatic cancer (PC) is an aggressive malignancy and has a poor prognosis. Although emerging research has revealed that circular RNAs (circRNAs) are crucial modulators that control tumor development and metastasis, their functional involvement in PC has not been well characterized. Here, we examined whether and how circRNA circ_0001666 governs epithelial-mesenchymal transition (EMT) in PC. Methods We investigated the effects of circ_0001666 on EMT and PC cell invasion by gain- and loss-of-function assays. We also explored the mechanisms underlying the functions of circ_0001666 in PC cells. Results We found that circ_0001666 is highly expressed in PC tissues and PC cell lines. Patients with high circ_0001666 expression had shorter survival times. In vitro and in vivo experiments have demonstrated that upregulation of circ_0001666 facilitates PC cell proliferation, EMT and invasiveness, whereas knockdown of circ_0001666 exhibits opposite functions. Moreover, circ_0001666 is able to bind to miR-1251, thus increasing the expression of SOX4, which is a direct downstream effector of miR-1251. The oncogenic effects of circ_0001666 on EMT and PC cell invasion were rescued by miR-1251 overexpression. Conclusions These results suggested that circ_0001666 acts as an oncogenic circRNA to promote EMT and invasion of PC cells through sponging miR-1251, and indicated that circ_0001666 could be explored as a potential therapeutic target for PC.
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Affiliation(s)
- Rundong Zhang
- Department of General Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wanli Zhu
- Department of General Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chenchao Ma
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kaixing Ai
- Department of General Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
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CircRNA_2646 functions as a ceRNA to promote progression of esophageal squamous cell carcinoma via inhibiting miR-124/PLP2 signaling pathway. Cell Death Discov 2021; 7:99. [PMID: 33976115 PMCID: PMC8113544 DOI: 10.1038/s41420-021-00461-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/28/2021] [Accepted: 03/23/2021] [Indexed: 11/16/2022] Open
Abstract
MicroRNA-124 (miR-124) has been predicted as a tumor suppressor in esophageal squamous cell carcinoma (ESCC). However, factors contributing to miR-124 reduction remain unclear. Circular RNAs (circRNAs) are a new family of non-coding RNAs with gene regulatory potential via interacting with miRNAs. We predicted three circRNAs, including CircRNA_14359, CircRNA_2646, and CircRNA_129, that could interact with miR-124 by bioinformatics analysis and determined their expressions in ESCC tissues and adjacent normal tissues. We found that CircRNA_2646 was up-regulated in ESCC, negatively correlated with the expression of miR-124 and positively associated with TNM stage and lymph node metastasis of ESCC. Luciferase reporter assay showed that CircRNA_2646 interacted with miR-124 in ESCC Eca109 and TE-1 cells. Moreover, ectopical overexpression of CircRNA_2646 accelerated cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT), but restoration of miR-124 abrogated these functions and promoted Bcl-2-dependent cell apoptosis. Furthermore, it was found that the oncogene Proteolipid Protein 2 (PLP2) was the target gene of miR-124. In Eca109 and TE-1 cells, restoration of miR-124 decreased the level of PLP2 and inhibited PLP2-induced cell proliferation, migration, invasion, and EMT, but enhanced cell apoptosis. The in vivo study confirmed that CircRNA_2646 promoted ESCC development by repressing miR-124 and activating PLP2. Taken together, we identified that CircRNA_2646 functioned as an inhibitor in miR-124 signaling pathway in ESCC for carcinogenesis and could be a promising target for ESCC therapy.
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