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Wang Y, Wang X, Xu J, Zhang D, Cao Y. miR-369-3p regulates the drug resistance of lung cancer cells by targeting PTPN12. Pharmacogenomics 2025:1-6. [PMID: 40366733 DOI: 10.1080/14622416.2025.2504864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 05/08/2025] [Indexed: 05/15/2025] Open
Abstract
OBJECTIVE To explore the impact of low miR-369-3p expression on the resistance of PC-9 cells to osimertinib. METHODS The PC-9/AZD9291 cell line was established with osimertinib. Real-time quantitative PCR was employed to measure the expression levels of miR-369-3p in both PC-9 and PC-9/AZD9291 cells, and Western blotting was utilized to detect PTPN12 protein expression. A dual-luciferase reporter assay was conducted to investigate the target relationship between miR-369-3p and PTPN12. CCK8 assays were performed to evaluate the impact of miR-369-3p inhibition on drug resistance. RESULTS In comparison to PC-9 cells, there was a significant upregulation of miR-369-3p and downregulation of PTPN12 protein in PC-9/AZD9291 cells (p < 0.05). Transfection with the miR-369-3p inhibitor resulted in decreased levels of miR-369-3p and increased expression of PTPN12 protein in PC-9/AZD9291 cells (p < 0.05). Conversely, transfection with miR-369 mimics led to an increase in miR-369-3p levels accompanied by a decrease in PTPN12 protein (p < 0.05). Notably, treatment with the miR-369-3p inhibitor lowered the IC50 value for PC-9/AZD9291 cells; however, following downregulation of PTPN12 using PTPN12-siRNA, sensitivity due to low expression of miR-369-3p was significantly diminished (p < 0.05). CONCLUSION miR-369-3p plays a crucial role in modulating drug resistance in PC-9/AZD9291 cells against osimertinib through regulation of PTPN12.
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Affiliation(s)
- Yan Wang
- Department of Medical Oncology, Tumor Hospital Affiliated to Nantong University & Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - XiaoLi Wang
- Department of Medical Oncology, Tumor Hospital Affiliated to Nantong University & Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - Jun Xu
- Department of Medical Oncology, Tumor Hospital Affiliated to Nantong University & Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - Didi Zhang
- Department of Medical Oncology, Tumor Hospital Affiliated to Nantong University & Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - YongFeng Cao
- Department of Medical Oncology, Tumor Hospital Affiliated to Nantong University & Nantong Tumor Hospital, Nantong, Jiangsu, China
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Bartoszewska E, Misiąg P, Czapla M, Rakoczy K, Tomecka P, Filipski M, Wawrzyniak-Dzierżek E, Choromańska A. The Role of microRNAs in Lung Cancer: Mechanisms, Diagnostics and Therapeutic Potential. Int J Mol Sci 2025; 26:3736. [PMID: 40332376 PMCID: PMC12027727 DOI: 10.3390/ijms26083736] [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: 04/03/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
MicroRNAs (miRNAs) are small RNA molecules that do not have coding functions but play essential roles in various biological processes. In lung cancer, miRNAs affect the processes of tumor initiation, progression, metastasis, and resistance to treatment by regulating gene expression. Tumor-suppressive miRNAs inhibit oncogenic pathways, while oncogenic miRNAs, known as oncomiRs, promote malignant transformation and tumor growth. These dual roles position miRNAs as critical players in lung cancer biology. Studies in recent years have shown the significant potential of miRNAs as both prognostic and diagnostic biomarkers. Circulating miRNAs in plasma or sputum demonstrate specificity and sensitivity in detecting early-stage lung cancer. Liquid biopsy-based miRNA panels distinguish malignant from benign lesions, and specific miRNA expression patterns correlate with disease progression, response to treatment, and overall survival. Therapeutically, miRNAs hold promise for targeted interventions. Strategies such as miRNA replacement therapy using mimics for tumor-suppressive miRNAs and inhibition of oncomiRs with antagomiRs or miRNA sponges have shown preclinical success. Key miRNAs, including the let-7 family, miR-34a, and miR-21, are under investigation for their therapeutic potential. It should be emphasized that delivery difficulties, side effects, and limited stability of therapeutic miRNA molecules remain obstacles to their clinical use. This article examines the roles of miRNAs in lung cancer by indicating their mechanisms of action, diagnostic significance, and therapeutic potential. By addressing current limitations, miRNA-based approaches could revolutionize lung cancer management, offering precise, personalized, and minimally invasive solutions for diagnosis and treatment.
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Affiliation(s)
- Elżbieta Bartoszewska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Piotr Misiąg
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Melania Czapla
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Katarzyna Rakoczy
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Paulina Tomecka
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Michał Filipski
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (P.M.); (M.C.); (K.R.); (P.T.); (M.F.)
- Student Research Group No. K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Elżbieta Wawrzyniak-Dzierżek
- Department and Clinic of Bone Marrow Transplantation, Oncology and Pediatric Hematology, Borowska 213, 50-556 Wroclaw, Poland;
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Niu Y, Fu G, Xia S, Li M, Qiu L, Wang J, Kang K, Gou D. Three Circulating miRNAs Related to Non-Small-Cell Lung Cancer Progression: An Integrative Analysis of Their Biological Roles. BIOLOGY 2025; 14:399. [PMID: 40282264 PMCID: PMC12024873 DOI: 10.3390/biology14040399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025]
Abstract
MicroRNAs (miRNAs) are crucial in physiological and pathological processes and serve as biomarkers for various diseases. We previously validated seven miRNA biomarkers and nine in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In this study, we observed distinct clustering patterns of LUAD or LUSC tissues compared to paired normal tissues based on miRNA expression levels, suggesting the potential involvement of circulating miRNAs in non-small-cell lung cancer (NSCLC) progression. To elucidate their biological function, we identified the most significant differentially expressed miRNAs (DE-miRNAs)-hsa-miR-451a, hsa-miR-139-5p and hsa-miR-126-5p-using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. We then performed protein-protein interaction (PPI) analysis and constructed a miRNA-hub gene regulatory network based on targets predicted by several miRNA-target prediction tools. Additionally, we evaluated the biological functions of these miRNA biomarkers through EdU and wound healing assays in A549 cells. Our study identifies three miRNAs that may contribute to lung cancer progression by modulating cancer-related targets and highlights their potential as biomarkers. Future mechanistic investigations may provide novel insights into NSCLC pathogenesis and open new therapeutic avenues.
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Affiliation(s)
- Yanqin Niu
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518060, China; (Y.N.)
| | - Gaohui Fu
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518060, China; (Y.N.)
| | - Sijian Xia
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518060, China; (Y.N.)
| | - Menglong Li
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518060, China; (Y.N.)
| | - Lin Qiu
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518060, China; (Y.N.)
| | - Jun Wang
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518060, China; (Y.N.)
| | - Kang Kang
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518060, China
| | - Deming Gou
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518060, China; (Y.N.)
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Zamani Sani M, Mirzaei M, Mota A, Mohammadian J, Aboutalebi Vand Beilankouhi E, Rahmati M. MicroRNAs' Significance in Retinoblastoma Diagnosis and Treatment: The Little Heroes. Biochem Genet 2025; 63:1176-1197. [PMID: 39862293 DOI: 10.1007/s10528-024-10976-2] [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: 03/19/2024] [Accepted: 11/09/2024] [Indexed: 01/27/2025]
Abstract
One in 16, 000 live births is affected by the retinal tumor RB (retinoblastoma), which is frequently found in a child's early years. Both of the RB1 alleles that have been locally mutated in the affected retina are present in 60 percent of cases. Retinoblastoma (RB) can be detected using a variety of techniques, including imaging of the brain and orbits, eye examinations under anesthesia (EUAs), and the discovery of cell-free tumor DNA in samples of aqueous humor or plasma. In addition to the conventional surgical, chemotherapy, and radiotherapy approaches to treating retinoblastoma, new approaches have also been developed. Oncogenes, genes of tumor suppressors, and other molecular elements involved in cell growth and division interact complexly during the pathogenesis of retinoblastoma. The development of new therapies depends on comprehending the function of these molecular components. As a small class of non-coding RNAs capable of altering gene expression, microRNAs (miRNA) are understood to represent potential targets for the treatment of cancer. This study aimed to describe the changes in microRNA expression in some types of cancer, with a particular focus on retinoblastoma.
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Affiliation(s)
- Maryam Zamani Sani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Mirzaei
- Department of Ophthalmology, Nikoukari Eye Hospital, Medical School, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mota
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jamal Mohammadian
- School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Rahmati
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Włodarczyk M, Maryńczak K, Burzyński J, Włodarczyk J, Basak J, Fichna J, Majsterek I, Ciesielski P, Spinelli A, Dziki Ł. The role of miRNAs in the pathogenesis, diagnosis, and treatment of colorectal cancer and colitis-associated cancer. Clin Exp Med 2025; 25:86. [PMID: 40091000 PMCID: PMC11911275 DOI: 10.1007/s10238-025-01582-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/01/2025] [Indexed: 03/19/2025]
Abstract
MicroRNAs (miRNAs) are a group of noncoding single-stranded RNA biomolecules that act in posttranscriptional regulation of gene expression. Their role in the development of inflammatory bowel disease (IBD), colitis-associated cancer (CAC), and colorectal cancer (CRC) is currently under investigation. A few miRNAs present promising results in terms of diagnostic or therapeutic use, for example, miR-21 increases in CRC and inflammation, while also being a possible target for cancer therapy; miR-301a increases in inflammation but only in patients with IBD; miR-31 increases in CRC, especially in advanced stages, namely III-IV in TNM scale; miR-200 family plays a role in carcinogenesis of CRC and other tumors; examined as a group, miR-31-5p, miR-223-3p, and let-7f-5p trigger and exacerbate CAC; miR-19a could potentially be used in therapy and prevention of both CRC and CAC. Here, we discuss available studies and outline future directions concerning the validity of using miRNAs in the diagnosis and/or therapy of IBD, CAC, and CRC. Extensive research confirms that miRNAs play an important role in the pathogenesis of CAC and CRC. Since the significantly altered expression of certain miRNAs is an early prognostic marker for the development of these diseases, miRNAs have the potential to serve as diagnostic tools, enabling quick and straightforward disease detection.
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Affiliation(s)
- Marcin Włodarczyk
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland.
| | - Kasper Maryńczak
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Jacek Burzyński
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Jakub Włodarczyk
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
- Department of Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Justyna Basak
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Ireneusz Majsterek
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Przemysław Ciesielski
- Department of General Surgery, Hospital of Our Lady of Perpetual Help in Wołomin, Wołomin, Poland
| | - Antonino Spinelli
- Colon and Rectal Surgery Division, Humanitas Clinical and Research Center, Milan, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Rozzano, Italy
| | - Łukasz Dziki
- Department of General and Oncological Surgery, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
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Poh KC, Ren TM, Ling GL, Goh JSY, Rose S, Wong A, Mehta SS, Goh A, Chong PY, Cheng SW, Wang SSY, Saffari SE, Lim DWT, Chia NY. Development of a miRNA-Based Model for Lung Cancer Detection. Cancers (Basel) 2025; 17:942. [PMID: 40149278 PMCID: PMC11940216 DOI: 10.3390/cancers17060942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/02/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Lung cancer is the leading cause of cancer-related mortality globally, with late-stage diagnoses contributing to poor survival rates. While lung cancer screening with low-dose computed tomography (LDCT) has proven effective in reducing mortality among heavy smokers, its limitations, including high false-positive rates and resource intensiveness, restrict widespread use. Liquid biopsy, particularly using microRNA (miRNA) biomarkers, offers a promising adjunct to current screening strategies. This study aimed to evaluate the predictive power of a panel of serum miRNA biomarkers for lung cancer detection. PATIENTS AND METHODS A case-control study was conducted at two tertiary hospitals, enrolling 82 lung cancer cases and 123 controls. We performed an extensive literature review to shortlist 25 candidate miRNAs, of which 16 showed a significant two-fold increase in expression compared to the controls. Machine learning techniques, including Random Forest, K-Nearest Neighbors, Neural Networks, and Support Vector Machines, were employed to identify the top six miRNAs. We then evaluated predictive models, incorporating these biomarkers with lung nodule characteristics on LDCT. RESULTS A prediction model utilising six miRNA biomarkers (mir-196a, mir-1268, mir-130b, mir-1290, mir-106b and mir-1246) alone achieved area under the curve (AUC) values ranging from 0.78 to 0.86, with sensitivities of 70-78% and specificities of 73-85%. Incorporating lung nodule size significantly improved model performance, yielding AUC values between 0.96 and 0.99, with sensitivities of 92-98% and specificities of 93-98%. CONCLUSIONS A prediction model combining serum miRNA biomarkers and nodule size showed high predictive power for lung cancer. Integration of the prediction model into current lung cancer screening protocols may improve patient outcomes.
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Affiliation(s)
- Kai Chin Poh
- Division of Respiratory Medicine, Sengkang General Hospital, Singapore 544886, Singapore
| | - Toh Ming Ren
- Division of Respiratory Medicine, Sengkang General Hospital, Singapore 544886, Singapore
| | - Goh Liuh Ling
- Molecular Diagnostic Laboratory, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - John S Y Goh
- Professional Officers Division, Singapore Institute of Technology, Singapore 828608, Singapore
| | - Sarrah Rose
- Averywell Limited, Greater Manchester OL8 4QQ, UK
| | - Alexa Wong
- Averywell Limited, Greater Manchester OL8 4QQ, UK
| | | | - Amelia Goh
- Professional Officers Division, Singapore Institute of Technology, Singapore 828608, Singapore
| | - Pei-Yu Chong
- Professional Officers Division, Singapore Institute of Technology, Singapore 828608, Singapore
| | - Sim Wey Cheng
- Molecular Diagnostic Laboratory, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | | | | | | | - Na-Yu Chia
- Averywell Limited, Greater Manchester OL8 4QQ, UK
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Balali MR, Taghizadeh M, Alizadeh M, Karami Y, Karimi F, Khatami SH, Taheri-Anganeh M, Ehtiati S, Movahedpour A, Mahmoudi R, Ghasemi H. MicroRNA biosensors for detection of chronic kidney disease. Clin Chim Acta 2025; 567:120081. [PMID: 39653321 DOI: 10.1016/j.cca.2024.120081] [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: 10/06/2024] [Revised: 12/04/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024]
Abstract
Chronic kidney disease (CKD) is a prevalent health condition characterized by gradual kidney function loss. Early detection is crucial for the effective management and treatment of CKD. A promising biomarker for various diseases, including chronic kidney disease, is microRNAs (miRNAs), which are becoming increasingly important due to their stability and differential expression in various disease-related states, including CKD. Recent developments in microRNA biosensors have made it possible to detect miRNAs associated with CKD in a sensitive and specific manner. This review article discusses the current state of microRNA biosensors for detecting CKD and highlights their potential applications in clinical settings. Various microRNA biosensors, including electrochemical, optical, and nanomaterial-based sensors, are explored for their ability to detect specific miRNAs linked to CKD progression. The advantages and limitations of these biosensors are evaluated, focusing on factors such as sensitivity, specificity, and ease of use. Overall, microRNA biosensors are promising diagnostic tools for early detection of CKD. However, challenges such as standardizing protocols, validating in large cohorts, and translating to clinical practice remain to be addressed. Future research efforts should aim to overcome these limitations to fully realize the potential of microRNA biosensors in improving the diagnosis and management of CKD.
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Affiliation(s)
| | - Mohammad Taghizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Alizadeh
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yousof Karami
- Department of Clinical Science, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
| | | | - Seyyed Hossein Khatami
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Sajad Ehtiati
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Movahedpour
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Reza Mahmoudi
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Hassan Ghasemi
- Research Center for Environmental Contaminants (RCEC), Abadan University of Medical Sciences, Abadan, Iran.
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Fereydouni T, Zargar SJ, Seifi S, Sheikhpour M. Expression Pattern Study of miR-200a and XIAP Gene in the Non-small Cell Lung Cancer Patients’ Blood. IRANIAN BIOMEDICAL JOURNAL 2025; 29:49-56. [PMID: 40223411 PMCID: PMC12040632 DOI: 10.61186/ibj.4354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 12/25/2024] [Indexed: 04/17/2025]
Abstract
Background In non-small cell lung cancer (NSCLC), miR-200a plays a significant role in apoptosis. One of the genes involved in this pathway is XIAP, which has been shown anti-apoptotic activity. Research has indicated a significant association between miR-200a and the XIAP gene in this pathway. The present study investigated the expression profiles of miR-200a and the XIAP gene in NSCLC patients compared to normal individuals, as well as cancer cells compared to normal and apoptosis-inducing conditions. Methods In this study, 40 blood specimens were collected from NSCLC patients and 40 from healthy individuals. After isolating plasma and peripheral blood mononuclear cells from these samples, we analyzed the miR-200a and XIAP gene expression levels using real-time PCR. Subsequently, normal and lung cancer cells were treated with paclitaxel as a model of apoptosis. The antiproliferative effects and induction of apoptosis were then evaluated using the MTT and flow cytometry assays, respectively. Finally, the expression patterns of miR-200a and the XIAP gene were investigated through a real-time PCR method. Results Results indicated that the miR-200a expression level was lower in NSCLC patients than in healthy ones, while the expression level of XIAP gene increased in the NSCLC Patients’ blood. The MTT and flow cytometry results demonstrated a decreased proliferation and increased apoptosis rates in two lung line cells (A549 and MRC5) treated with paclitaxel. XIAP expression level also decreased in A549 cells treated with paclitaxel compared to untreated A549 cells. Conclusion MiR-200a may be associated with the XIAP gene expression and the induction of the apoptosis pathway in NSCLC.
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Affiliation(s)
- Tara Fereydouni
- Department of Biology, Alborz Campus, University of Tehran, Tehran, Iran
| | - Seyed Jalal Zargar
- Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Sharareh Seifi
- Department of Adult Hematology and Oncology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojgan Sheikhpour
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
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Beigi A, Naghib SM, Matini A, Tajabadi M, Mozafari MR. Lipid-Based Nanocarriers for Targeted Gene Delivery in Lung Cancer Therapy: Exploring a Novel Therapeutic Paradigm. Curr Gene Ther 2025; 25:92-112. [PMID: 38778601 DOI: 10.2174/0115665232292768240503050508] [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: 11/14/2023] [Revised: 03/28/2024] [Accepted: 04/03/2024] [Indexed: 05/25/2024]
Abstract
Lung cancer is a significant cause of cancer-related death worldwide. It can be broadly categorised into small-cell lung cancer (SCLC) and Non-small cell lung cancer (NSCLC). Surgical intervention, radiation therapy, and the administration of chemotherapeutic medications are among the current treatment modalities. However, the application of chemotherapy may be limited in more advanced stages of metastasis due to the potential for adverse effects and a lack of cell selectivity. Although small-molecule anticancer treatments have demonstrated effectiveness, they still face several challenges. The challenges at hand in this context comprise insufficient solubility in water, limited bioavailability at specific sites, adverse effects, and the requirement for epidermal growth factor receptor inhibitors that are genetically tailored. Bio-macromolecular drugs, including small interfering RNA (siRNA) and messenger RNA (mRNA), are susceptible to degradation when exposed to the bodily fluids of humans, which can reduce stability and concentration. In this context, nanoscale delivery technologies are utilised. These agents offer encouraging prospects for the preservation and regulation of pharmaceutical substances, in addition to improving the solubility and stability of medications. Nanocarrier-based systems possess the notable advantage of facilitating accurate and sustained drug release, as opposed to traditional systemic methodologies. The primary focus of scientific investigation has been to augment the therapeutic efficacy of nanoparticles composed of lipids. Numerous nanoscale drug delivery techniques have been implemented to treat various respiratory ailments, such as lung cancer. These technologies have exhibited the potential to mitigate the limitations associated with conventional therapy. As an illustration, applying nanocarriers may enhance the solubility of small-molecule anticancer drugs and prevent the degradation of bio-macromolecular drugs. Furthermore, these devices can administer medications in a controlled and extended fashion, thereby augmenting the therapeutic intervention's effectiveness and reducing adverse reactions. However, despite these promising results, challenges remain that must be addressed. Multiple factors necessitate consideration when contemplating the application of nanoparticles in medical interventions. To begin with, the advancement of more efficient delivery methods is imperative. In addition, a comprehensive investigation into the potential toxicity of nanoparticles is required. Finally, additional research is needed to comprehend these treatments' enduring ramifications. Despite these challenges, the field of nanomedicine demonstrates considerable promise in enhancing the therapy of lung cancer and other respiratory diseases.
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Affiliation(s)
- Anahita Beigi
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology, Tehran, Iran
| | - Seyed Morteza Naghib
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology, Tehran, Iran
| | - Amir Matini
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology, Tehran, Iran
| | - Maryam Tajabadi
- School of Metallurgy and Materials Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran, 16844, Iran
| | - Mohammad Reza Mozafari
- Australasian Nanoscience and Nanotechnology Initiative (ANNI), Monash University LPO, Clayton, VIC 3168, Australia
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Azari H, George M, Albracht-Schulte K. Gut Microbiota-microRNA Interactions and Obesity Pathophysiology: A Systematic Review of Integrated Studies. Int J Mol Sci 2024; 25:12836. [PMID: 39684547 DOI: 10.3390/ijms252312836] [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: 10/31/2024] [Revised: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Obesity is the fifth leading cause of death globally and its comorbidities put a high burden on societies and cause disability. In this review, we aim to summarize the interactions and crosstalk between gut microbiota and micro-RNA (miRNA) in obesity. We searched for the relevant literature through PubMed, Web of Science, Scopus, and Science Direct. The study design is registered in the international prospective register of systematic reviews (Prospero). According to the inclusion criteria, eight studies were eligible for assessment (two studies including human subjects and six studies including animal subjects). We report that the interactions of miRNA and gut microbiota in the context of obesity are diverse and in some cases tissue specific. However, the interactions mediate obesity-associated pathways including the inflammatory response, oxidative stress, insulin signaling, gut permeability, and lipogenesis. To mention the most meaningful results, the expression of adipose tissue miRNA-378a-3p/5p was associated with Bifidobacterium and Akkermansia abundance, the expression of hepatic miRNA-34a was related to the Firmicutes phylum, and the expression of miRNA-122-5p and miRNA-375 was associated with the Bacteroides genus. miRNA-microbiota-associated pathological pathways seem to provide an intricate, but promising field for future research directed toward the treatment of obesity and its comorbidities.
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Affiliation(s)
- Hushyar Azari
- Department of Kinesiology and Sport Management and Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
| | - Megan George
- Department of Kinesiology and Sport Management and Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
| | - Kembra Albracht-Schulte
- Department of Kinesiology and Sport Management and Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
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11
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Shen X, Lin Z, Jiang X, Zhu X, Zeng S, Cai S, Liu H. Dumbbell probe initiated multi-rolling circle amplification assisted CRISPR/Cas12a for highly sensitive detection of clinical microRNA. Biosens Bioelectron 2024; 264:116676. [PMID: 39151261 DOI: 10.1016/j.bios.2024.116676] [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: 07/11/2024] [Revised: 08/07/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
A novel miRNA detection technique named Dumbbell probe initiated multi-Rolling Circle Amplification assisted CRISPR/Cas12a (DBmRCA) was developed relying on the ligation-free dumbbell probe and the high-sensitivity CRISPR/Cas12a signal out strategy. This DBmRCA assay streamlines miRNA quantification within a mere 30-min timeframe and with exceptional analytical precision. The efficacy of this method was validated by assessing miRNA levels in clinical samples, revealing distinct expression panel of miR-200a and miR-126 in lung cancer/adjacent/normal tissue specimens. Moreover, a predictive model was established to classify benign and malignant tumor. Due to its time efficiency, enhanced sensitivity, and streamlined workflow, this assay would be a reliable tool for miRNA analysis in clinical settings, offering potential guidance for early diagnosis and treatment of lung cancer.
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Affiliation(s)
- Xudan Shen
- Clinical Research Center, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310020, Zhejiang, China
| | - Ziwei Lin
- Clinical Research Center, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310020, Zhejiang, China
| | - Xianfeng Jiang
- Clinical Research Center, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310020, Zhejiang, China
| | - Xinlan Zhu
- Clinical Research Center, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310020, Zhejiang, China
| | - Su Zeng
- Clinical Research Center, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310020, Zhejiang, China
| | - Sheng Cai
- Clinical Research Center, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310020, Zhejiang, China; Jinhua Institute of Zhejiang University, Jinhua, 321299, Zhejiang, China.
| | - Hui Liu
- Clinical Research Center, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310020, Zhejiang, China.
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12
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Suri C, Swarnkar S, Bhaskar LVKS, Verma HK. Non-Coding RNA as a Biomarker in Lung Cancer. Noncoding RNA 2024; 10:50. [PMID: 39452836 PMCID: PMC11514784 DOI: 10.3390/ncrna10050050] [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: 09/04/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
INTRODUCTION Lung cancer remains one of the most prevalent and deadly cancers globally, with high mortality rates largely due to late-stage diagnosis, aggressive progression, and frequent recurrence. Despite advancements in diagnostic techniques and therapeutic interventions, the overall prognosis for lung cancer patients continues to be dismal. METHOD Emerging research has identified non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, as critical regulators of gene expression, significantly influencing cancer biology. These ncRNAs play pivotal roles in various aspects of lung cancer pathogenesis, including tumor initiation, progression, metastasis, and resistance to therapy. RESULTS We provide a comprehensive analysis of the current understanding of ncRNAs in lung cancer, emphasizing their potential as biomarkers for early diagnosis, prognostication, and the prediction of the therapeutic response. We explore the biological functions of ncRNAs, their involvement in key oncogenic pathways, and the molecular mechanisms by which they modulate gene expression and cellular processes in lung cancer. Furthermore, this review highlights recent advances in ncRNA-based diagnostic tools and therapeutic strategies, such as miRNA mimics and inhibitors, lncRNA-targeted therapies, and circRNA-modulating approaches, offering promising avenues for personalized medicine. CONCLUSION Finally, we discuss the challenges and future directions in ncRNA research, including the need for large-scale validation studies and the development of efficient delivery systems for ncRNA-based therapies. This review underscores the potential of ncRNAs to revolutionize lung cancer management by providing novel diagnostic and therapeutic options that could improve patient outcomes.
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Affiliation(s)
- Chahat Suri
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada;
| | - Shashikant Swarnkar
- Department of Biochemistry, C.C.M. Medical College, Bhilai 490020, Chhattisgarh, India;
| | - LVKS Bhaskar
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495009, Chhattisgarh, India;
| | - Henu Kumar Verma
- Department of Immunopathology, Institute of lungs Health and Immunity, Comprehensive Pnemology Center, Helmholtz Zentrum, Neuherberg, 85764 Munich, Germany
- Lung Health and Immunity, Comprehensive Pneumology Center, Helmholtz Zentrum, Neuherberg, 85764 Munich, Germany
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13
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Chen Y, Zhang L, Wu X, Sun X, Sundah NR, Wong CY, Natalia A, Tam JKC, Lim DWT, Chowbay B, Ang BT, Tang C, Loh TP, Shao H. Magnetic augmentation through multi-gradient coupling enables direct and programmable profiling of circulating biomarkers. Nat Commun 2024; 15:8410. [PMID: 39333499 PMCID: PMC11437193 DOI: 10.1038/s41467-024-52754-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 09/19/2024] [Indexed: 09/29/2024] Open
Abstract
Conventional magnetic biosensing technologies have reduced analytical capacity for magnetic field dimensionality and require extensive sample processing. To address these challenges, we spatially engineer 3D magnetic response gradients for direct and programmable molecular detection in native biofluids. Named magnetic augmentation through triple-gradient coupling for high-performance detection (MATCH), the technology comprises gradient-distributed magnetic nanoparticles encapsulated within responsive hydrogel pillars and suspended above a magnetic sensor array. This configuration enables multi-gradient matching to achieve optimal magnetic activation, response and transduction, respectively. Through focused activation by target biomarkers, the platform preferentially releases sensor-proximal nanoparticles, generating response gradients that complement the sensor's intrinsic detection capability. By implementing an upstream module that recognizes different biomarkers and releases universal activation molecules, the technology achieves programmable detection of various circulating biomarkers in native plasma. It bypasses conventional magnetic labeling, completes in <60 minutes and achieves sensitive detection (down to 10 RNA and 1000 protein copies). We apply the MATCH to measure RNAs and proteins directly in patient plasma, achieving accurate cancer classification.
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Affiliation(s)
- Yuan Chen
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore
| | - Li Zhang
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore
| | - Xingjie Wu
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
| | - Xuecheng Sun
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
| | - Noah R Sundah
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore
| | - Chi Yan Wong
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Auginia Natalia
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore
| | - John K C Tam
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Darren Wan-Teck Lim
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
- Centre for Clinician-Scientist Development, Duke-NUS Medical School, Singapore, Singapore
| | - Balram Chowbay
- Centre for Clinician-Scientist Development, Duke-NUS Medical School, Singapore, Singapore
- Clinical Pharmacology Laboratory, National Cancer Centre Singapore, Singapore, Singapore
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore
| | - Beng Ti Ang
- National Neuroscience Institute, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Carol Tang
- National Neuroscience Institute, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- SG Enable, Innovation, Singapore, Singapore
| | - Tze Ping Loh
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
- Department of Laboratory Medicine, National University Hospital, Singapore, Singapore
| | - Huilin Shao
- Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore.
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore.
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
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14
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Yi X, Chen X, Li Z. miR-200c targeting GLI3 inhibits cell proliferation and promotes apoptosis in non-small cell lung cancer cells. Medicine (Baltimore) 2024; 103:e39658. [PMID: 39312343 PMCID: PMC11419521 DOI: 10.1097/md.0000000000039658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 08/22/2024] [Indexed: 09/25/2024] Open
Abstract
Lung cancer is a common malignant tumor with low cure rate. It has an easy recurrence and metastasis. This study explored whether miR-200c could regulate the biological behavior of non-small cell lung cancer cells through targeting GLI3. Luciferase reporter gene analysis was used to verify the interaction between miR-200c-3p and GLI3. miR-200c-3p and GLI3 were transiently overexpressed into A549 cells. The cell viability rate was detected by cell counting kit-8, cell invasion ability was detected with Transwell, cell apoptosis and cell cycle was determined by flow cytometry, and the expression of GLI3 was detected using quantitative polymerase chain reaction and Western blot, to verify the effect of the interaction between miR-200c-3p and GLI3 on the cell activities. miR-200c-3p overexpression could inhibit cell viability and invasion, promote apoptosis, induce G0/G1 arrest, and inhibit cell division. GLI3 overexpression could reverse the miR-200c-3p inhibition on cell cycle, reduce the number of cells in the G0/G1 phase and increase the number of cells in the S phase. miR-200c-3p overexpression in A549 cells could inhibit cell viability and invasion, and promote apoptosis. miR-200c-3p could target GLI3 to regulate cell cycle and inhibit cell proliferation.
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Affiliation(s)
- Xiangjun Yi
- Department of Oncology, Jiangxi Chest Hospital, Nanchang City, Jiangxi Province, P.R. China
| | - Xuan Chen
- Department of Oncology, Jiangxi Chest Hospital, Nanchang City, Jiangxi Province, P.R. China
| | - Zhenbin Li
- Department of Oncology, Jiangxi Chest Hospital, Nanchang City, Jiangxi Province, P.R. China
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15
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Aliyari M, Hashemy SI, Hashemi SF, Reihani A, Kesharwani P, Hosseini H, Sahebkar A. Targeting the Akt signaling pathway: Exploiting curcumin's anticancer potential. Pathol Res Pract 2024; 261:155479. [PMID: 39068859 DOI: 10.1016/j.prp.2024.155479] [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: 04/28/2024] [Revised: 07/13/2024] [Accepted: 07/19/2024] [Indexed: 07/30/2024]
Abstract
Cancer is recognized as one of the leading causes of death worldwide. In recent years, advancements in early detection and expanding treatment options have contributed to a decrease in mortality rates. However, the emergence of drug-resistant cancers necessitates the exploration of innovative and more effective drugs. The Akt kinases play a central role in various signaling pathways that regulate crucial cellular processes, including cell growth, proliferation, survival, angiogenesis, and glucose metabolism. Due to frequent disruptions of the Akt signaling pathway in numerous human cancers and its broad biological implications, targeting this pathway has become a key focus in combating tumor aggressiveness and a promising avenue for therapeutic intervention. Curcumin, a compound found in turmeric, has been extensively studied for its potential as an anti-cancer agent. It demonstrates inhibitory effects on cancer initiation, progression, and metastasis by influencing various processes involved in tumor growth and development. These effects are achieved through negative regulation of transcription factors, growth factors, cytokines, protein kinases, and other oncogenic molecules. This review aims to explore curcumin's anticancer activity against different types of cancer mediated via the PI3K/Akt signaling pathway, as well as its practical applications in treatment.
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Affiliation(s)
- Mahdieh Aliyari
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Fatemeh Hashemi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirali Reihani
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Fotopoulos I, Nguyen OTD, Nøst TH, Markaki M, Lagani V, Mjelle R, Sandanger TM, Sætrom P, Tsamardinos I, Røe OD. Promising microRNAs in pre-diagnostic serum associated with lung cancer up to eight years before diagnosis: a HUNT study. J Cancer Res Clin Oncol 2024; 150:355. [PMID: 39031255 PMCID: PMC11271336 DOI: 10.1007/s00432-024-05882-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 07/04/2024] [Indexed: 07/22/2024]
Abstract
INTRODUCTION Blood biomarkers for early detection of lung cancer (LC) are in demand. There are few studies of the full microRNome in serum of asymptomatic subjects that later develop LC. Here we searched for novel microRNA biomarkers in blood from non-cancer, ever-smokers populations up to eight years before diagnosis. METHODS Serum samples from 98,737 subjects from two prospective population studies, HUNT2 and HUNT3, were considered initially. Inclusion criteria for cases were: ever-smokers; no known cancer at study entrance; 0-8 years from blood sampling to LC diagnosis. Each future LC case had one control matched to sex, age at study entrance, pack-years, smoking cessation time, and similar HUNT Lung Cancer Model risk score. A total of 240 and 72 serum samples were included in the discovery (HUNT2) and validation (HUNT3) datasets, respectively, and analysed by next-generation sequencing. The validated serum microRNAs were also tested in two pre-diagnostic plasma datasets from the prospective population studies NOWAC (n = 266) and NSHDS (n = 258). A new model adding clinical variables was also developed and validated. RESULTS Fifteen unique microRNAs were discovered and validated in the pre-diagnostic serum datasets when all cases were contrasted against all controls, all with AUC > 0.60. In combination as a 15-microRNAs signature, the AUC reached 0.708 (discovery) and 0.703 (validation). A non-small cell lung cancer signature of six microRNAs showed AUC 0.777 (discovery) and 0.806 (validation). Combined with clinical variables of the HUNT Lung Cancer Model (age, gender, pack-years, daily cough parts of the year, hours of indoor smoke exposure, quit time in years, number of cigarettes daily, body mass index (BMI)) the AUC reached 0.790 (discovery) and 0.833 (validation). These results could not be validated in the plasma samples. CONCLUSION There were a few significantly differential expressed microRNAs in serum up to eight years before diagnosis. These promising microRNAs alone, in concert, or combined with clinical variables have the potential to serve as early diagnostic LC biomarkers. Plasma is not suitable for this analysis. Further validation in larger prospective serum datasets is needed.
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Affiliation(s)
- Ioannis Fotopoulos
- Department of Computer Science, University of Crete, 700 13, Heraklion, Crete, Greece
| | - Olav Toai Duc Nguyen
- Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7030, Trondheim, Norway
- Cancer Clinic, Levanger Hospital, Nord-Trøndelag Health Trust, Kirkegata 2, 7600, Levanger, Norway
| | - Therese Haugdahl Nøst
- Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, P.O. Box 6050 Langnes, 9037, Tromsø, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU-Norwegian University of Science and Technology, Postboks 8905, 7491, Trondheim, Norway
| | - Maria Markaki
- Institute of Applied and Computational Mathematics, FORTH, 700 13, Heraklion, Crete, Greece
| | - Vincenzo Lagani
- Institute of Chemical Biology, Ilia State University, 3/5, Kakuca Cholokashvili Ave, Tbilisi, Georgia
- Biological and Environmental Sciences and Engineering Division (BESE), King Abdullah University of Science and Technology KAUST, Thuwal, Saudi Arabia
- SDAIA-KAUST Center of Excellence in Data Science and Artificial Intelligence, 23952, Thuwal, Saudi Arabia
| | - Robin Mjelle
- Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7030, Trondheim, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU-Norwegian University of Science and Technology, Postboks 8905, 7491, Trondheim, Norway
- Bioinformatics Core Facility, NTNU-Norwegian University of Science and Technology, 7491, Trondheim, Norway
| | - Torkjel Manning Sandanger
- Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, P.O. Box 6050 Langnes, 9037, Tromsø, Norway
| | - Pål Sætrom
- Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7030, Trondheim, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU-Norwegian University of Science and Technology, Postboks 8905, 7491, Trondheim, Norway
- Bioinformatics Core Facility, NTNU-Norwegian University of Science and Technology, 7491, Trondheim, Norway
- Department of Computer Science, Norwegian University of Science and Technology, 7491, Trondheim, Norway
| | - Ioannis Tsamardinos
- Department of Computer Science, University of Crete, 700 13, Heraklion, Crete, Greece
- Institute of Applied and Computational Mathematics, FORTH, 700 13, Heraklion, Crete, Greece
- JADBio Gnosis DA S.A., STEP-C, N. Plastira 100, 700-13, Heraklion, Greece
| | - Oluf Dimitri Røe
- Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7030, Trondheim, Norway.
- Cancer Clinic, Levanger Hospital, Nord-Trøndelag Health Trust, Kirkegata 2, 7600, Levanger, Norway.
- Department of Oncology and Clinical Cancer Research Center, Aalborg University Hospital, 9000, Aalborg, Denmark.
- Department of Clinical Medicine, Aalborg University Hospital, 9000, Aalborg, Denmark.
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17
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Moreira D, Alexandre D, Miranda A, Lourenço P, Baptista PV, Tomaz C, Lu Y, Cruz C. Detecting mir-155-3p through a Molecular Beacon Bead-Based Assay. Molecules 2024; 29:3182. [PMID: 38999134 PMCID: PMC11243622 DOI: 10.3390/molecules29133182] [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: 05/16/2024] [Revised: 06/23/2024] [Accepted: 07/01/2024] [Indexed: 07/14/2024] Open
Abstract
Lung cancer (LC) is recognized as one of the most prevalent and lethal cancers worldwide, underscoring an urgent need for innovative diagnostic and therapeutic approaches. MicroRNAs (miRNAs) have emerged as promising biomarkers for several diseases and their progression, such as LC. However, traditional methods for detecting and quantifying miRNAs, such as PCR, are time-consuming and expensive. Herein, we used a molecular beacon (MB) bead-based assay immobilized in a microfluidic device to detect miR-155-3p, which is frequently overexpressed in LC. The assay relies on the fluorescence enhancement of the MB upon binding to the target miRNA via Watson and Crick complementarity, resulting in a conformational change from a stem-loop to a linear structure, thereby bringing apart the fluorophores at each end. This assay was performed on a microfluidic platform enabling rapid and straightforward target detection. We successfully detected miR-155-3p in a saline solution, obtaining a limit of detection (LOD) of 42 nM. Furthermore, we evaluated the method's performance in more complex biological samples, including A549 cells' total RNA and peripheral blood mononuclear cells (PBMCs) spiked with the target miRNA. We achieved satisfactory recovery rates, especially in A549 cells' total RNA.
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Affiliation(s)
- David Moreira
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Daniela Alexandre
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
- UCIBIO, Department of Life Sciences, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
| | - André Miranda
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Pedro Lourenço
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Pedro V Baptista
- UCIBIO, Department of Life Sciences, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
- i4HB, Associate Laboratory, Institute for Health and Bioeconomy, FCT-NOVA, 2829-516 Caparica, Portugal
| | - Cândida Tomaz
- Departamento de Química, Universidade da Beira Interior, Rua Marquês de Ávila e Bolama, 6201-001 Covilhã, Portugal
| | - Yi Lu
- Department of Chemistry, The University of Texas at Austin, Austin, TX 78712, USA
| | - Carla Cruz
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal
- Departamento de Química, Universidade da Beira Interior, Rua Marquês de Ávila e Bolama, 6201-001 Covilhã, Portugal
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18
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Khameneh SC, Razi S, Lashanizadegan R, Akbari S, Sayaf M, Haghani K, Bakhtiyari S. MicroRNA-mediated metabolic regulation of immune cells in cancer: an updated review. Front Immunol 2024; 15:1424909. [PMID: 39007129 PMCID: PMC11239499 DOI: 10.3389/fimmu.2024.1424909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 06/12/2024] [Indexed: 07/16/2024] Open
Abstract
The study of immunometabolism, which examines how immune cells regulate their metabolism to maintain optimal performance, has become an important area of focus in cancer immunology. Recent advancements in this field have highlighted the intricate connection between metabolism and immune cell function, emphasizing the need for further research. MicroRNAs (miRNAs) have gained attention for their ability to post-transcriptionally regulate gene expression and impact various biological processes, including immune function and cancer progression. While the role of miRNAs in immunometabolism is still being explored, recent studies have demonstrated their significant influence on the metabolic activity of immune cells, such as macrophages, T cells, B cells, and dendritic cells, particularly in cancer contexts. Disrupted immune cell metabolism is a hallmark of cancer progression, and miRNAs have been linked to this process. Understanding the precise impact of miRNAs on immune cell metabolism in cancer is essential for the development of immunotherapeutic approaches. Targeting miRNAs may hold potential for creating groundbreaking cancer immunotherapies to reshape the tumor environment and improve treatment outcomes. In summary, the recognition of miRNAs as key regulators of immune cell metabolism across various cancers offers promising potential for refining cancer immunotherapies. Further investigation into how miRNAs affect immune cell metabolism could identify novel therapeutic targets and lead to the development of innovative cancer immunotherapies.
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Affiliation(s)
| | - Sara Razi
- Vira Ideators of Modern Science, Tehran, Iran
- Vira Pioneers of Modern Science (VIPOMS), Tehran, Iran
| | | | | | - Masoud Sayaf
- Department of Cellular and Molecular Biology, Faculty of Basic Sciences, Azad University Central Tehran Branch, Tehran, Iran
| | - Karimeh Haghani
- Department of Clinical Biochemistry, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Salar Bakhtiyari
- Department of Clinical Biochemistry, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, IL, United States
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19
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Jin H, Liu Y, Lei Y, Li G, Huang L, Zhang Z. Hsa_circ_0004214 involved in the epithelial-mesenchymal transition induced by beryllium sulfate through modulating JAK-STAT signaling pathway. Toxicol Res (Camb) 2024; 13:tfae067. [PMID: 38711927 PMCID: PMC11069455 DOI: 10.1093/toxres/tfae067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 04/04/2024] [Accepted: 04/20/2024] [Indexed: 05/08/2024] Open
Abstract
Background Chronic beryllium disease is characterized by granulomas and pulmonary fibrosis. Recent studies have shown that microRNAs (miRNAs) and circular RNAs (circRNAs) play critical roles in the pathogenesis and development of many diseases. However, the role of miRNAs and circRNAs in pulmonary fibrosis induced by beryllium sulfate (BeSO4) has not been elucidated. Methods Previous studies demonstrated hsa-miR-663b was down-regulated in the 150 μmol/L BeSO4-treated 16HBE cells, while hsa_circ_ 0004214 was up-regulated. Here we found epithelial-mesenchymal transition (EMT) involved in pulmonary fibrosis induced by BeSO4 (4, 8, and 12 mg/kg·BW) in SD rats. Results Elevated expression of hsa-miR-663b blocked the EMT progression of 16HBE cells induced by 150 μmol/L BeSO4. Notably, the overexpression of hsa-miR-663b decreased the expression of leukemia inhibitory factor (LIF), which was predicted as a target gene of hsa-miR-663b by bioinformatics tools. Furthermore, elevated miR-663b inhibited the activation of the downstream Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway induced by BeSO4 in 16HBE cells. Previous study suggested that hsa_circ_0004214 had binding sites for hsa-miR-663b. The results indicated hsa_circ_0004214 alleviated the BeSO4-induced EMT via JAK-STAT pathway in 16HBE cells. Conclusions Collectively, the overexpression of hsa-miR-663b and knockdown of hsa_circ_0004214 attenuated the EMT induced by BeSO4 through the inhibition of JAK-STAT signaling pathway. The aberrant expressed hsa-miR-663b and hsa_circ_0004214 stimulated by BeSO4 may exert an important function in the toxic mechanism of beryllium exposure to 16HBE cells, providing the potential therapeutic targets in chronic beryllium disease.
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Affiliation(s)
- Huiyun Jin
- Department of Preventive Medicine, School of public health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
| | - Yanping Liu
- Department of Preventive Medicine, School of public health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
| | - Yuandi Lei
- Department of Preventive Medicine, School of public health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
| | - Guilan Li
- Department of Preventive Medicine, School of public health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
| | - Lian Huang
- Department of Preventive Medicine, School of public health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
| | - Zhaohui Zhang
- Department of Preventive Medicine, School of public health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, HN 421001, China
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20
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Lv X, Yang L, Xie Y, Momeni MR. Non-coding RNAs and exosomal non-coding RNAs in lung cancer: insights into their functions. Front Cell Dev Biol 2024; 12:1397788. [PMID: 38859962 PMCID: PMC11163066 DOI: 10.3389/fcell.2024.1397788] [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: 03/08/2024] [Accepted: 05/02/2024] [Indexed: 06/12/2024] Open
Abstract
Lung cancer is the second most common form of cancer worldwide Research points to the pivotal role of non-coding RNAs (ncRNAs) in controlling and managing the pathology by controlling essential pathways. ncRNAs have all been identified as being either up- or downregulated among individuals suffering from lung cancer thus hinting that they may play a role in either promoting or suppressing the spread of the disease. Several ncRNAs could be effective non-invasive biomarkers to diagnose or even serve as effective treatment options for those with lung cancer, and several molecules have emerged as potential targets of interest. Given that ncRNAs are contained in exosomes and are implicated in the development and progression of the malady. Herein, we have summarized the role of ncRNAs in lung cancer. Moreover, we highlight the role of exosomal ncRNAs in lung cancer.
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Affiliation(s)
- Xiaolong Lv
- Department of Cardiothoracic Surgery, The People’s Hospital of Changshou, Chongqing, China
| | - Lei Yang
- Department of Cardiothoracic Surgery, The People’s Hospital of Tongliang District, Chongqing, China
| | - Yunbo Xie
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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21
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Hutarew G, Alinger-Scharinger B, Sotlar K, Kraus TFJ. Genome-Wide Methylation Analysis in Two Wild-Type Non-Small Cell Lung Cancer Subgroups with Negative and High PD-L1 Expression. Cancers (Basel) 2024; 16:1841. [PMID: 38791918 PMCID: PMC11119885 DOI: 10.3390/cancers16101841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/25/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
We conducted a pilot study to analyze the differential methylation status of 20 primary acinar adenocarcinomas of the lungs. These adenocarcinomas had to be wild type in mutation analysis and had either high (TPS > 50%; n = 10) or negative (TPS < 1%; n = 10) PD-L1 status to be integrated into our study. To examine the methylation of 866,895 specific sites, we utilized the Illumina Infinium EPIC bead chip array. Both hypermethylation and hypomethylation play significant roles in tumor development, progression, and metastasis. They also impact the formation of the tumor microenvironment, which plays a decisive role in tumor differentiation, epigenetics, dissemination, and immune evasion. The gained methylation patterns were correlated with PD-L1 expression. Our analysis has identified distinct methylation patterns in lung adenocarcinomas with high and negative PD-L1 expression. After analyzing the correlation between the methylation results of genes and promoters with their pathobiology, we found that tumors with high expression of PD-L1 tend to exhibit oncogenic effects through hypermethylation. On the other hand, tumors with negative PD-L1 expression show loss of their suppressor functions through hypomethylation. The suppressor functions of hypermethylated genes and promoters are ineffective compared to simultaneously activated dominant oncogenic mechanisms. The tumor microenvironment supports tumor growth in both groups.
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Affiliation(s)
- Georg Hutarew
- Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Müllner Hauptstr. 48, A-5020 Salzburg, Austria; (B.A.-S.); (K.S.); (T.F.J.K.)
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22
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Cao D, Wu Z, Yang R, Yao L, Huang J, Ding Y, Ruzi A, Pan Z, Pan Y, Li D, Gu W, Zhang J. miR-769-3p inhibits cellular proliferation of KSHV-infected SH-SY5Y cells through targeting mTOR. J Cancer 2024; 15:3338-3349. [PMID: 38817860 PMCID: PMC11134426 DOI: 10.7150/jca.93595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 02/27/2024] [Indexed: 06/01/2024] Open
Abstract
The infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the most common causes of death in AIDS patients. Our studies have found that KSHV can infect SH-SY5Y cells (named SK-RG) in vivo and mTOR was up-regulated, which results in remarkable enhancement of cell proliferation, migration. But the regulatory role of mTOR in KSHV infected neurons has not yet been fully elucidated. Here, we find that miR-769-3p is decreased in SK-RG cells, which can exert anti-KSHV effect through negatively regulating the expression of mTOR. The knockdown of mTOR or overexpress of miR-769-3p decreased the proliferation, migration ability and cell cycle related protein of SK-RG cells, and the expression of KSHV related genes. In contrast, activating mTOR function by 3BDO treatment weakened the cellular behaviors of miR-769-3p overexpressing cells. Meanwhile, overexpressed miR-769-3p and rapamycin showed a shared inhibition trend in the effects on cell proliferation and motility. Our data indicated that miR-769-3p can inhibit cell proliferation and migration by down regulating mTOR in KSHV infected SH-SY5Y cells, and can be a candidate molecule for anti-KSHV therapy.
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Affiliation(s)
- Dongdong Cao
- School of medicine, Shihezi University/Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education,832002, Xinjiang, China
| | - Zhaofu Wu
- School of medicine, Shihezi University/Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education,832002, Xinjiang, China
- The Affiliated Hospital of Hubei Provincial Government/Hubei Rehabilitation Hospital, 430064, Hubei, China
| | - Rui Yang
- School of medicine, Shihezi University/Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education,832002, Xinjiang, China
| | - Lixia Yao
- School of medicine, Shihezi University/Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education,832002, Xinjiang, China
| | - Jinhong Huang
- School of medicine, Shihezi University/Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education,832002, Xinjiang, China
| | - Yufei Ding
- Department of Pathology, Yili Friendship Hospital, 835099, Xinjiang, China
| | - Aynisahan Ruzi
- Department of Pathology, Bazhou Hospital, 841000, Xinjiang, China
| | - Zemin Pan
- School of medicine, Shihezi University/Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education,832002, Xinjiang, China
| | - Yuanming Pan
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 9 Beiguan Street, Tongzhou District, Beijing 101149, China
| | - Dongmei Li
- School of medicine, Shihezi University/Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education,832002, Xinjiang, China
| | - Wenyi Gu
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), St Lucia, Brisbane QLD 4072, Australia
| | - Jinli Zhang
- School of medicine, Shihezi University/Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education,832002, Xinjiang, China
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Chen X, Huang C, Zhang J, Hu Q, Wang D, You Q, Guo Y, Chen H, Xu J, Hu M. Mini crRNA-mediated CRISPR/Cas12a system (MCM-CRISPR/Cas12a) and its application in RNA detection. Talanta 2024; 268:125350. [PMID: 37922816 DOI: 10.1016/j.talanta.2023.125350] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/21/2023] [Accepted: 10/25/2023] [Indexed: 11/07/2023]
Abstract
Some non-coding RNAs are abnormally expressed during the occurrence and development of diseases, so it is necessary to develop analytical methods that can specifically and sensitively detect them. In typical CRISPR/Cas12a system, a complete crRNA that can recognize single-stranded or double-stranded DNA is necessary to activate its trans-cleavage activity, which limits its direct application in RNA detection. Here, we prospectively find that slicing the facilitated crRNA in the typical CRISPR/Cas12a system at a fitted site did not affect its trans-cleavage activity, and a mini crRNA-mediated CRISPR/Cas12a system (MCM-CRISPR/Cas12a) was proposed based on this. This system can detect non-coding RNA to pM-level (10 pM for miRNA-21). To expand the application of this system, we combined it with HCR and CHA to establish a detection platform for non-coding RNA. The results show that the proposed method can specifically detect RNA to fM-level (2.5 fM for miRNA-21, 8.98 fM for miR-128-3p, and 81.6 fM for lncRNA PACER). The spiked recovery rates of miRNA-21, miR-128-3p, and lncRNA PACER in normal human serum were in range from 104.7 to 109.4 %, indicating the proposed method owns good applicability. In general, this MCM-CRISPR/Cas12a system further breaks the limitations of the typical CRISPR/Cas12a system that cannot be directly used for non-coding RNA detection. Besides, its combination with HCR and CHA achieves highly sensitive detection of non-coding RNA.
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Affiliation(s)
- Xiaolong Chen
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China.
| | - Chaowang Huang
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Jing Zhang
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Qiao Hu
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Dan Wang
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Qianyi You
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Yawen Guo
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Huaping Chen
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Jing Xu
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Mingdong Hu
- Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China; Department of Health Management, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China.
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24
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Fatima F, Chourasiya NK, Mishra M, Kori S, Pathak S, Das R, Kashaw V, Iyer AK, Kashaw SK. Curcumin and its Derivatives Targeting Multiple Signaling Pathways to Elicit Anticancer Activity: A Comprehensive Perspective. Curr Med Chem 2024; 31:3668-3714. [PMID: 37221681 DOI: 10.2174/0929867330666230522144312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/23/2023] [Accepted: 04/07/2023] [Indexed: 05/25/2023]
Abstract
The uncontrolled growth and spread of aberrant cells characterize the group of disorders known as cancer. According to GLOBOCAN 2022 analysis of cancer patients in either developed countries or developing countries the main concern cancers are breast cancer, lung cancer, and liver cancer which may rise eventually. Natural substances with dietary origins have gained interest for their low toxicity, anti-inflammatory, and antioxidant effects. The evaluation of dietary natural products as chemopreventive and therapeutic agents, the identification, characterization, and synthesis of their active components, as well as the enhancement of their delivery and bioavailability, have all received significant attention. Thus, the treatment strategy for concerning cancers must be significantly evaluated and may include the use of phytochemicals in daily lifestyle. In the present perspective, we discussed one of the potent phytochemicals, that has been used over the past few decades known as curcumin as a panacea drug of the "Cure-all" therapy concept. In our review firstly we included exhausted data from in vivo and in vitro studies on breast cancer, lung cancer, and liver cancer which act through various cancer-targeting pathways at the molecular level. Now, the second is the active constituent of turmeric known as curcumin and its derivatives are enlisted with their targeted protein in the molecular docking studies, which help the researchers design and synthesize new curcumin derivatives with respective implicated molecular and cellular activity. However, curcumin and its substituted derivatives still need to be investigated with unknown targeting mechanism studies in depth.
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Affiliation(s)
- Firdous Fatima
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Nikhil Kumar Chourasiya
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Mitali Mishra
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Sandhya Pathak
- Department of Chemistry, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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25
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Shang M, Ma M, Su G, Xiao L. Application value of miRNA-182 as a biomarker for cancer diagnosis: a systematic review with meta-analysis. Biomark Med 2023; 17:907-918. [PMID: 38205594 DOI: 10.2217/bmm-2023-0176] [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] [Indexed: 01/12/2024] Open
Abstract
Aim: This study aims to establish the potential reliability and validity of miRNA-182 as a diagnostic tool in oncology, and hence to contribute to the decision-making process in clinical settings. Materials & methods: To further evaluate the role of miRNA-182 as a cancer biomarker, we conducted a search of the PubMed, Cochrane Library, Wanfang and China National Knowledge Infrastructure databases of existing literature. Conclusion: These results suggest that miRNA-182 could function as a potential molecular marker for cancer detection and diagnosis. The effect of miRNA-182 on tumor development should be further studied to confirm these results and add to the current understanding of its role in cancer.
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Affiliation(s)
- Mengyu Shang
- School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Mengdan Ma
- Shantou University Medical College, Shantou, 515041, China
| | - Ganglin Su
- Shantou University Medical College, Shantou, 515041, China
| | - Liang Xiao
- Department of Surgery and Oncology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518035, China
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26
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Le MT, Nguyen HT, Nguyen XH, Do XH, Mai BT, Ngoc Nguyen HT, Trang Than UT, Nguyen TH. Regulation and therapeutic potentials of microRNAs to non-small cell lung cancer. Heliyon 2023; 9:e22080. [PMID: 38058618 PMCID: PMC10696070 DOI: 10.1016/j.heliyon.2023.e22080] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 12/08/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80%-85% of total cases and leading to millions of deaths worldwide. Drug resistance is the primary cause of treatment failure in NSCLC, which urges scientists to develop advanced approaches for NSCLC treatment. Among novel approaches, the miRNA-based method has emerged as a potential approach as it allows researchers to modulate target gene expression. Subsequently, cell behaviors are altered, which leads to the death and the depletion of cancer cells. It has been reported that miRNAs possess the capacity to regulate multiple genes that are involved in various signaling pathways, including the phosphoinositide 3-kinase, receptor tyrosine kinase/rat sarcoma virus/mitogen-activated protein kinase, wingless/integrated, retinoblastoma, p53, transforming growth factor β, and nuclear factor-kappa B pathways. Dysregulation of these signaling pathways in NSCLC results in abnormal cell proliferation, tissue invasion, and drug resistance while inhibiting apoptosis. Thus, understanding the roles of miRNAs in regulating these signaling pathways may enable the development of novel NSCLC treatment therapies. However, a comprehensive review of potential miRNAs in NSCLC treatment has been lacking. Therefore, this review aims to fill the gap by summarizing the up-to-date information on miRNAs regarding their targets, impact on cancer-associated pathways, and prospective outcomes in treating NSCLC. We also discuss current technologies for delivering miRNAs to the target cells, including virus-based, non-viral, and emerging extracellular vesicle-based delivery systems. This knowledge will support future studies to develop an innovative miRNA-based therapy and select a suitable carrier to treat NSCLC effectively.
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Affiliation(s)
- Mai Thi Le
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
- Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, 100000, Viet Nam
| | - Huyen-Thu Nguyen
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
| | - Xuan-Hung Nguyen
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
- College of Health Sciences, Vin University, Hanoi, 100000, Viet Nam
- Vinmec-VinUni Institute of Immunology, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
| | - Xuan-Hai Do
- Department of Gastroenterology, 108 Military Central Hospital, Hanoi, Viet Nam
| | - Binh Thanh Mai
- Department of Practical and Experimental Surgery, Vietnam Military Medical University, 160 Phung Hung Street, Phuc La, Ha Dong, Hanoi, Viet Nam
| | - Ha Thi Ngoc Nguyen
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
| | - Uyen Thi Trang Than
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
- Vinmec-VinUni Institute of Immunology, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
| | - Thanh-Hong Nguyen
- Vinmec Hi-tech Center, Vinmec Healthcare System, Hanoi, 100000, Viet Nam
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Martinez-Espinosa I, Serrato JA, Ortiz-Quintero B. The Role of Exosome-Derived microRNA on Lung Cancer Metastasis Progression. Biomolecules 2023; 13:1574. [PMID: 38002256 PMCID: PMC10669807 DOI: 10.3390/biom13111574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/16/2023] [Accepted: 10/19/2023] [Indexed: 11/26/2023] Open
Abstract
The high mortality from lung cancer is mainly attributed to the presence of metastases at the time of diagnosis. Despite being the leading cause of lung cancer death, the underlying molecular mechanisms driving metastasis progression are still not fully understood. Recent studies suggest that tumor cell exosomes play a significant role in tumor progression through intercellular communication between tumor cells, the microenvironment, and distant organs. Furthermore, evidence shows that exosomes release biologically active components to distant sites and organs, which direct metastasis by preparing metastatic pre-niche and stimulating tumorigenesis. As a result, identifying the active components of exosome cargo has become a critical area of research in recent years. Among these components are microRNAs, which are associated with tumor progression and metastasis in lung cancer. Although research into exosome-derived microRNA (exosomal miRNAs) is still in its early stages, it holds promise as a potential target for lung cancer therapy. Understanding how exosomal microRNAs promote metastasis will provide evidence for developing new targeted treatments. This review summarizes current research on exosomal miRNAs' role in metastasis progression mechanisms, focusing on lung cancer.
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Affiliation(s)
| | | | - Blanca Ortiz-Quintero
- Department of Molecular Biomedicine and Translational Research, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City CP 14080, Mexico; (I.M.-E.); (J.A.S.)
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28
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Carmona R, López-Sánchez C, Garcia-Martinez V, Garcia-López V, Muñoz-Chápuli R, Lozano-Velasco E, Franco D. Novel Insights into the Molecular Mechanisms Governing Embryonic Epicardium Formation. J Cardiovasc Dev Dis 2023; 10:440. [PMID: 37998498 PMCID: PMC10672416 DOI: 10.3390/jcdd10110440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 10/20/2023] [Accepted: 10/22/2023] [Indexed: 11/25/2023] Open
Abstract
The embryonic epicardium originates from the proepicardium, an extracardiac primordium constituted by a cluster of mesothelial cells. In early embryos, the embryonic epicardium is characterized by a squamous cell epithelium resting on the myocardium surface. Subsequently, it invades the subepicardial space and thereafter the embryonic myocardium by means of an epithelial-mesenchymal transition. Within the myocardium, epicardial-derived cells present multilineage potential, later differentiating into smooth muscle cells and contributing both to coronary vasculature and cardiac fibroblasts in the mature heart. Over the last decades, we have progressively increased our understanding of those cellular and molecular mechanisms driving proepicardial/embryonic epicardium formation. This study provides a state-of-the-art review of the transcriptional and emerging post-transcriptional mechanisms involved in the formation and differentiation of the embryonic epicardium.
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Affiliation(s)
- Rita Carmona
- Department of Human Anatomy, Legal Medicine and History of Science, Faculty of Medicine, University of Málaga, 29071 Málaga, Spain;
| | - Carmen López-Sánchez
- Department of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Badajoz, Spain; (C.L.-S.); (V.G.-M.)
| | - Virginio Garcia-Martinez
- Department of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Badajoz, Spain; (C.L.-S.); (V.G.-M.)
| | - Virginio Garcia-López
- Department of Medical and Surgical Therapeutics, Pharmacology Area, Faculty of Medicine and Health Sciences, University of Extremadura, 06006 Badajoz, Spain;
| | - Ramón Muñoz-Chápuli
- Department of Animal Biology, Faculty of Science, University of Málaga, 29071 Málaga, Spain;
| | - Estefanía Lozano-Velasco
- Cardiovascular Research Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain;
| | - Diego Franco
- Cardiovascular Research Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain;
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29
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Asghariazar V, Kadkhodayi M, Sarailoo M, Jolfayi AG, Baradaran B. MicroRNA-143 as a potential tumor suppressor in cancer: An insight into molecular targets and signaling pathways. Pathol Res Pract 2023; 250:154792. [PMID: 37689002 DOI: 10.1016/j.prp.2023.154792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 08/25/2023] [Accepted: 09/02/2023] [Indexed: 09/11/2023]
Abstract
MicroRNAs (MiRNAs), which are highly conserved and small noncoding RNAs, negatively regulate gene expression and influence signaling pathways involved in essential biological activities, including cell proliferation, differentiation, apoptosis, and cell invasion. MiRNAs have received much attention in the past decade due to their significant roles in cancer development. In particular, microRNA-143 (miR-143) is recognized as a tumor suppressor and is downregulated in most cancers. However, it seems that miR-143 is upregulated in rare cases, such as prostate cancer stem cells, and acts as an oncogene. The present review will outline the current studies illustrating the impact of miR-143 expression levels on cancer progression and discuss its target genes and their relevant signaling pathways to discover a potential therapeutic way for cancer.
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Affiliation(s)
- Vahid Asghariazar
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Deputy of Research and Technology, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Mahtab Kadkhodayi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Animal Biology, Faculty of Natural Sciences, The University of Tabriz, Tabriz, Iran
| | - Mehdi Sarailoo
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Amir Ghaffari Jolfayi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wu R, Zhong Q, Liu H, Liu S. MicroRNA-577/EIF5A2 axis suppressed the proliferation of DDP-resistant nasopharyngeal carcinoma cells by blocking TGF-β signaling pathway. Chem Biol Drug Des 2023; 102:815-827. [PMID: 37500510 DOI: 10.1111/cbdd.14293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/18/2023] [Accepted: 06/30/2023] [Indexed: 07/29/2023]
Abstract
Diaminodichoroplatinum (DDP) resistance of tumor cells is the culprit of nasopharyngeal carcinoma (NPC) treatment failure. MicroRNA-577 is lowly expressed in NPC tissues, but relevant mechanism is poorly studied. Therefore, this study investigated the role of microRNA-577 in NPC cells with DDP resistance and its mechanism. DDP-resistant NPC cells were established by treatment with DDP at increased concentrations (2, 4, 6, 8, or 10 μg/mL). MicroRNA-577 and EIF5A2 mRNA expressions were detected by qRT-PCR. Cell biological behaviors were assessed via cell function experiments. Expressions of epithelial mesenchymal transformation (EMT)-related proteins were quantified by western blot. The targeting relationship between eukaryotic translation initiation factor 5A2 (EIF5A2) and microRNA-577 was verified through dual-luciferase reporter assay. The tumor volume and weight were measured after subcutaneous tumorigenesis in mice. As observed from the results, microRNA-577 expression was reduced in NPC cells and DDP-resistant NPC cells. Up-regulated microRNA-577 suppressed the malignant behaviors and EMT of DDP-resistant NPC cells, and facilitated cell apoptosis. MicroRNA-577 targeted EIF5A2, and overexpressed EIF5A2 reversed the above effects of up-regulated microRNA-577 on DDP-resistant NPC cells. Besides, EIF5A2 positively regulated TGF-β signaling pathway, and TGF-β treatment offset the promoting effects of EIF5A2 silencing on apoptosis of DDP-resistant NPC cells. Up-regulated microRNA-577 suppressed the proliferation of DDP-resistant NPC cells, and down-regulated the levels of EIF5A2 and TGF-β as well as EMT in vivo. Collectively, microRNA-577/EIF5A2 axis hinders the EMT progression through the blockage of TGF-β signaling pathway, so as to inhibit the proliferation of DDP-resistant NPC.
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Affiliation(s)
- Renrui Wu
- Department of Oncology, Ganzhou City People's Hospital, Ganzhou, China
| | - Qiong Zhong
- Department of Oncology, Ganzhou City People's Hospital, Ganzhou, China
| | - Huafeng Liu
- Department of Oncology, Ganzhou City People's Hospital, Ganzhou, China
| | - Shubin Liu
- Department of Oncology, Ganzhou City People's Hospital, Ganzhou, China
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Gohlke L, Alahdab A, Oberhofer A, Worf K, Holdenrieder S, Michaelis M, Cinatl J, Ritter CA. Loss of Key EMT-Regulating miRNAs Highlight the Role of ZEB1 in EGFR Tyrosine Kinase Inhibitor-Resistant NSCLC. Int J Mol Sci 2023; 24:14742. [PMID: 37834189 PMCID: PMC10573279 DOI: 10.3390/ijms241914742] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Despite recent advances in the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance to targeted therapy remains a major obstacle. Epithelial-mesenchymal transition (EMT) has been identified as a key resistance mechanism in NSCLC. Here, we investigated the mechanistic role of key EMT-regulating small non-coding microRNAs (miRNAs) in sublines of the NSCLC cell line HCC4006 adapted to afatinib, erlotinib, gefitinib, or osimertinib. The most differentially expressed miRNAs derived from extracellular vesicles were associated with EMT, and their predicted target ZEB1 was significantly overexpressed in all resistant cell lines. Transfection of a miR-205-5p mimic partially reversed EMT by inhibiting ZEB1, restoring CDH1 expression, and inhibiting migration in erlotinib-resistant cells. Gene expression of EMT-markers, transcription factors, and miRNAs were correlated during stepwise osimertinib adaptation of HCC4006 cells. Temporally relieving cells of osimertinib reversed transition trends, suggesting that the implementation of treatment pauses could provide prolonged benefits for patients. Our results provide new insights into the contribution of miRNAs to drug-resistant NSCLC harboring EGFR-activating mutations and highlight their role as potential biomarkers and therapeutic targets.
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Affiliation(s)
- Linus Gohlke
- Institute of Pharmacy, Clinical Pharmacy, University Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany;
| | - Ahmad Alahdab
- Institute of Pharmacy, Clinical Pharmacy, University Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany;
| | - Angela Oberhofer
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany; (A.O.); (K.W.); (S.H.)
| | - Karolina Worf
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany; (A.O.); (K.W.); (S.H.)
| | - Stefan Holdenrieder
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany; (A.O.); (K.W.); (S.H.)
| | - Martin Michaelis
- School of Biosciences, Division of Natural Sciences, University of Kent, Canterbury, Kent CT2 7NJ, UK;
| | - Jindrich Cinatl
- Institute of Medical Virology, University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany;
| | - Christoph A Ritter
- Institute of Pharmacy, Clinical Pharmacy, University Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany;
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Pace A, Scirocchi F, Napoletano C, Zizzari IG, Po A, Megiorni F, Asquino A, Pontecorvi P, Rahimi H, Marchese C, Ferretti E, Nuti M, Rughetti A. Targeting FGFRs by pemigatinib induces G1 phase cell cycle arrest, cellular stress and upregulation of tumor suppressor microRNAs. J Transl Med 2023; 21:626. [PMID: 37715207 PMCID: PMC10504800 DOI: 10.1186/s12967-023-04450-7] [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: 05/25/2023] [Accepted: 08/18/2023] [Indexed: 09/17/2023] Open
Abstract
BACKGROUND Fibroblast growth factor receptor (FGFR) gene family alterations are found in several cancers, indicating their importance as potential therapeutic targets. The FGFR-tyrosine kinase inhibitor (TKI) pemigatinib has been introduced in the treatment of advanced cholangiocarcinoma and more recently for relapsed or refractory myeloid/lymphoid neoplasms with FGFR2 and FGFR1 rearrangements, respectively. Several clinical trials are currently investigating the possible combination of pemigatinib with immunotherapy. In this study, we analyzed the biological and molecular effects of pemigatinib on different cancer cell models (lung, bladder, and gastric), which are currently objective of clinical trial investigations. METHODS NCI-H1581 lung, KATO III gastric and RT-112 bladder cancer cell lines were evaluated for FGFR expression by qRT-PCR and Western blot. Cell lines were treated with Pem and then characterized for cell proliferation, apoptosis, production of intracellular reactive oxygen species (ROS), and induction of senescence. The expression of microRNAs with tumor suppressor functions was analyzed by qRT-PCR, while modulation of the proteins coded by their target genes was evaluated by Western blot and mRNA. Descriptive statistics was used to analyze the various data and student's t test to compare the analysis of two groups. RESULTS Pemigatinib exposure triggered distinct signaling pathways and reduced the proliferative ability of all cancer cells, inducing G1 phase cell cycle arrest and strong intracellular stress resulting in ROS production, senescence and apoptosis. Pemigatinib treatment also caused the upregulation of microRNAs (miR-133b, miR-139, miR-186, miR-195) with tumor suppressor functions, along with the downregulation of validated protein targets with oncogenic roles (c-Myc, c-MET, CDK6, EGFR). CONCLUSIONS These results contribute to clarifying the biological effects and molecular mechanisms mediated by the anti-FGFR TKI pemigatinib in distinct tumor settings and support its exploitation for combined therapies.
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Affiliation(s)
- Angelica Pace
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Fabio Scirocchi
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Chiara Napoletano
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
| | | | - Agnese Po
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Francesca Megiorni
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Angela Asquino
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Paola Pontecorvi
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Hassan Rahimi
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Elisabetta Ferretti
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Marianna Nuti
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Aurelia Rughetti
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
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Torabi M, Khafaei M, Jahanbin B, Sadeghi M. Assessment of the relationship between miR-499C/T (rs3746444) polymorphism and lung carcinoma in Iranian population; a case-control study. Afr Health Sci 2023; 23:301-307. [PMID: 38357128 PMCID: PMC10862644 DOI: 10.4314/ahs.v23i3.36] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024] Open
Abstract
Introduction Lung carcinoma is characterized by uncontrollable division of respiratory system cells with detrimental and lethal consequences on human health. Critical roles of microRNAs (miR) are scientifically approved in biological and pathological pathways, such as the role of miR-499 (rs3746444) in lung carcinomas. Thus, in this case-control investigation, we aimed to assess the probable relationship between miR-499C/T variant and the occurrence of lung carcinoma in Iranian population for the first time. Methods Genotype of miR-499 polymorphism was described by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) assay in patients and healthy individuals. Following definite diagnosis of lung carcinoma, the blood samples were collected, and the DNA extraction was performed by Salting-Out method. Finally, data were analysed by SPSS (v. 20) and the significant level was considered p-value<0.05. Results Statistically, the frequency of combined genotypes of CC+CT were 83.33% and 35% and TT+CT were 100% and 92% in case and control individuals, respectively. Also, individuals with genotypes of TC (OR: 3.08, CI95%: 3.03-3.17, p<0.0001), TC+CC (OR: 0.10, CI95%: 0.05-0.23, p<0.0001), CC (OR: 0, CI95%: 0.00-0.60, p=0.0214), and TC (OR: 0.07, CI95%: 0.030.15, p<0.0001) represented statistically significant (p<0.05) differences lung carcinoma than those with TT, TT, TT+TC, and TT+CC genotypes, respectively. The frequency of miR-499C (78.5%) and miR-499T (21.5%) alleles were also statistically significantly (p<0.05) difference associated with lung carcinoma in patients than controls. Conclusion In this study, a possible relationship among miR-499C/T polymorphism and lung carcinoma was detected in Iranian population. Since this study was conducted for the first time, thus other supplementary assessments are needed for definite conclusion.
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Affiliation(s)
- Mehdi Torabi
- Human Genetics Research Center, Baqiyatallah Medical Science University, Tehran, Iran
| | - Mostafa Khafaei
- Human Genetics Research Center, Baqiyatallah Medical Science University, Tehran, Iran
| | - Behnaz Jahanbin
- Cancer Institute, Pathology Department, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Sadeghi
- Human Genetics Research Center, Baqiyatallah Medical Science University, Tehran, Iran
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Frydrychowicz M, Kuszel Ł, Dworacki G, Budna-Tukan J. MicroRNA in lung cancer-a novel potential way for early diagnosis and therapy. J Appl Genet 2023; 64:459-477. [PMID: 36821071 PMCID: PMC10457410 DOI: 10.1007/s13353-023-00750-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/31/2023] [Accepted: 02/07/2023] [Indexed: 02/24/2023]
Abstract
Lung cancer is the most common cause of cancer-related deaths in the world. One of the reasons of poor prognosis and high mortality of lung cancer patients is the diagnosis of the disease in its advanced stage. Despite innovative diagnostic methods and multiple completed and ongoing clinical trials aiming at therapy improvement, no significant increase in patients' long-term survival has been noted over last decades. Patients would certainly benefit from early detection of lung cancer. Therefore, it is crucial to find new biomarkers that can help predict outcomes and tumor responses in order to maximize therapy effectiveness and avoid over- or under-treating patients with lung cancer. Nowadays, scientists' attention is mainly dedicated to so-called liquid biopsy, which is fully non-invasive and easily available method based on simple blood draw. Among common liquid biopsy elements, circulating tumor nucleic acids are worth mentioning. Epigenetic biomarkers, particularly miRNA expression, have several distinct features that make them promising prognostic markers. In this review, we described miRNA's involvement in tumorigenesis and present it as a predictor of cancer development and progression, potential indicator of treatment efficacy, and most importantly promising therapeutic target.
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Affiliation(s)
- Magdalena Frydrychowicz
- Department of Clinical Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Łukasz Kuszel
- Department of Medical Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Grzegorz Dworacki
- Department of Clinical Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Joanna Budna-Tukan
- Department of Histology and Embryology, Poznan University of Medical Sciences, 61-781 Poznan, Poland
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Seyhan AA. Circulating microRNAs as Potential Biomarkers in Pancreatic Cancer-Advances and Challenges. Int J Mol Sci 2023; 24:13340. [PMID: 37686149 PMCID: PMC10488102 DOI: 10.3390/ijms241713340] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
There is an urgent unmet need for robust and reliable biomarkers for early diagnosis, prognosis, and prediction of response to specific treatments of many aggressive and deadly cancers, such as pancreatic cancer, and liquid biopsy-based miRNA profiling has the potential for this. MiRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many cancers, functioning as either oncomes or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling of dysregulated miRNAs in pancreatic cancer has been shown to correlate with disease diagnosis, indicate optimal treatment options and predict response to a specific therapy. Specific miRNA signatures can track the stages of pancreatic cancer and hold potential as diagnostic, prognostic, and predictive markers, as well as therapeutics such as miRNA mimics and miRNA inhibitors (antagomirs). Furthermore, identified specific miRNAs and genes they regulate in pancreatic cancer along with downstream pathways can be used as potential therapeutic targets. However, a limited understanding and validation of the specific roles of miRNAs, lack of tissue specificity, methodological, technical, or analytical reproducibility, harmonization of miRNA isolation and quantification methods, the use of standard operating procedures, and the availability of automated and standardized assays to improve reproducibility between independent studies limit bench-to-bedside translation of the miRNA biomarkers for clinical applications. Here I review recent findings on miRNAs in pancreatic cancer pathogenesis and their potential as diagnostic, prognostic, and predictive markers.
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Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
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Wang X, Wang X, Jiang T, Zhang Z, Xie N, Yang G. MiR-22-3p suppresses NSCLC cell migration and EMT via targeting RAC1 expression. Funct Integr Genomics 2023; 23:281. [PMID: 37620594 PMCID: PMC10449966 DOI: 10.1007/s10142-023-01211-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/04/2023] [Accepted: 08/14/2023] [Indexed: 08/26/2023]
Abstract
Previous studies have demonstrated the tumor-suppressive function of microRNA-22-3p (miR-22-3p) in several cancers, whereas the significance of miR-22-3p in non-small cell lung cancer (NSCLC) remains unclear. In this study, we explored the biological function and molecular mechanism of miR-22-3p in NSCLC cells. First, we assessed the expression of miR-22-3p in NSCLC tissues and cells based on RT-qPCR and TCGA database. Compared with normal lung tissues and cells, miR-22-3p expression was dramatically decreased in lung cancer tissues and cells. miR-22-3p expression was also correlated with lymph node metastasis and tumor size, but not TNM stages. We further explored the in vitro function of miR-22-3p on the migration and epithelial-mesenchymal transition (EMT) of NSCLC cells. The results showed that overexpression of miR-22-3p suppressed the migration and EMT of NSCLC cells, whereas silencing miR-22-3p showed the opposite effect. Luciferase assay demonstrated that RAS-related C3 botulinum toxin substrate 1 (RAC1) was the target gene for miR-22-3p. Mechanistically, we demonstrated that miR-22-3p suppressed the cell migration and EMT via downregulation of RAC1 because the inhibitory effect of miR-22-3p on cell migration and EMT of NSCLC cells was reversed by RAC1 overexpression. Based on these novel data, the miR-22-3p/RAC1 axis may be an alternative target in the therapeutic intervention of NSCLC.
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Affiliation(s)
- Xuejiao Wang
- Department of Thoracic Surgery, The Second Affiliated Hospital of the Air Force Medical University, Baqiao District, Xinsi Road 569, Xi'an, Shaanxi, China
| | - Xiaobin Wang
- Department of Thoracic Surgery, The Second Affiliated Hospital of the Air Force Medical University, Baqiao District, Xinsi Road 569, Xi'an, Shaanxi, China
| | - Tao Jiang
- Department of Thoracic Surgery, The Second Affiliated Hospital of the Air Force Medical University, Baqiao District, Xinsi Road 569, Xi'an, Shaanxi, China
| | - Zhipei Zhang
- Department of Thoracic Surgery, The Second Affiliated Hospital of the Air Force Medical University, Baqiao District, Xinsi Road 569, Xi'an, Shaanxi, China
| | - Nianlin Xie
- Department of Thoracic Surgery, The Second Affiliated Hospital of the Air Force Medical University, Baqiao District, Xinsi Road 569, Xi'an, Shaanxi, China.
| | - Guang Yang
- Department of Thoracic Surgery, The Second Affiliated Hospital of the Air Force Medical University, Baqiao District, Xinsi Road 569, Xi'an, Shaanxi, China.
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Bache M, Kadler F, Struck O, Medenwald D, Ostheimer C, Güttler A, Keßler J, Kappler M, Riemann A, Thews O, Seliger B, Vordermark D. Correlation between Circulating miR-16, miR-29a, miR-144 and miR-150, and the Radiotherapy Response and Survival of Non-Small-Cell Lung Cancer Patients. Int J Mol Sci 2023; 24:12835. [PMID: 37629015 PMCID: PMC10454434 DOI: 10.3390/ijms241612835] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/10/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Despite the success of current therapy concepts, patients with advanced non-small-cell lung cancer (NSCLC) still have a very poor prognosis. Therefore, biological markers are urgently needed, which allow the assessment of prognosis, or prediction of the success of therapy or resistance in this disease. Circulating microRNAs (miRs) have potential as biomarkers for the prognosis and prediction of response to therapy in cancer patients. Based on recent evidence that circulating miR-16, miR-29a, miR-144 and miR-150 can be regulated by ionizing radiation, the concentration of these four miRs was assessed in the plasma of NSCLC patients at different time points of radiotherapy by digital droplet PCR (ddPCR). Furthermore, their impact on patients' prognosis was evaluated. The mean plasma levels of miR-16, miR-29a, miR-144 and miR-150 significantly differed intra- and inter-individually, and during therapy in NSCLC patients, but showed a strong positive correlation. The individual plasma levels of miR-16, miR-29a and miR-144 had prognostic value in NSCLC patients during or at the end of radiotherapy in Cox's regression models. NSCLC patients with low levels of these three miRs at the end of radiotherapy had the worst prognosis. However, miR-150 plasma levels and treatment-dependent changes were not predictive. In conclusion, circulating miR-16, miR-29a and miR-144, but not miR-150, have a prognostic value in NSCLC patients undergoing radiotherapy.
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Affiliation(s)
- Matthias Bache
- Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; (F.K.); (O.S.); (D.M.); (A.G.); (J.K.); (D.V.)
| | - Frauke Kadler
- Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; (F.K.); (O.S.); (D.M.); (A.G.); (J.K.); (D.V.)
| | - Olivia Struck
- Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; (F.K.); (O.S.); (D.M.); (A.G.); (J.K.); (D.V.)
- Department of Radiology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany
| | - Daniel Medenwald
- Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; (F.K.); (O.S.); (D.M.); (A.G.); (J.K.); (D.V.)
| | - Christian Ostheimer
- Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; (F.K.); (O.S.); (D.M.); (A.G.); (J.K.); (D.V.)
| | - Antje Güttler
- Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; (F.K.); (O.S.); (D.M.); (A.G.); (J.K.); (D.V.)
| | - Jacqueline Keßler
- Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; (F.K.); (O.S.); (D.M.); (A.G.); (J.K.); (D.V.)
| | - Matthias Kappler
- Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany;
| | - Anne Riemann
- Julius Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 6, 06112 Halle, Germany; (A.R.); (O.T.)
| | - Oliver Thews
- Julius Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 6, 06112 Halle, Germany; (A.R.); (O.T.)
| | - Barbara Seliger
- Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Str. 16, 06112 Halle, Germany;
- Institute for Translational Immunology, Brandenburg Medical School “Theodor Fontane”, 14770 Brandenburg, Germany
- Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
| | - Dirk Vordermark
- Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; (F.K.); (O.S.); (D.M.); (A.G.); (J.K.); (D.V.)
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Ke S, Chen S, Jiang Y, Gong H, Yu J, Li X, Chen Y, Li X, Wang Q, Liu Y. Bibliometric and visualized analysis of applying tumor markers in lung cancer diagnosis from 2000 to 2022. CANCER INNOVATION 2023; 2:265-282. [PMID: 38089746 PMCID: PMC10686150 DOI: 10.1002/cai2.74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 03/15/2023] [Accepted: 04/04/2023] [Indexed: 10/15/2024]
Abstract
Background Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Tumor marker (TM) detection can indicate the existence and growth of a tumor and has therefore been used extensively for diagnosing LC. Here, we conducted a bibliometric analysis to examine TM-related publications for LC diagnosis to illustrate the current state and future trends of this field, as well as to identify additional promising TMs with high sensitivity. Methods Publications regarding TMs in LC diagnosis were downloaded from the Web of Science Core Collection. CiteSpace was applied to perform a bibliometric analysis of journals, cocitation authors, keywords, and references related to this field. VOSviewer was used to generate concise diagrams about countries, institutions, authors, and keywords. Changes in the TM research frontier were analyzed through citation burst detection. Results A total of 990 studies were analyzed in this work. The collaboration network analysis revealed that the People's Republic of China, Yonsei University, and Molina R were the most productive country, institution, and scholar, respectively. Additionally, Molina R was the author with the most citations. The National Natural Science Foundation of China was the largest funding source. "Carcinoembryonic antigen (CEA) as tumor marker in lung cancer" was the top reference with the most citations, Lung Cancer was the core journal, and "serum tumor marker" experienced a citation burst over the past 5 years. Conclusion This bibliometric analysis of TMs in LC diagnosis presents the current trends and frontiers in this field. We summarized the research status of this field and the methods to improve the diagnostic efficacy of traditional serum TMs, as well as provided new directions and ideas for improving the LC clinical detection rate. Priority should be given to the transformation of computer-assisted diagnostic technology for clinical applications. In addition, circulating tumor cells, exosomes, and microRNAs were the current most cutting-edge TMs.
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Affiliation(s)
- Shi‐Peng Ke
- The Second Clinical Medical SchoolNanchang UniversityNanchangChina
| | - Si‐Mei Chen
- Department of Blood TransfusionThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang UniversityJiangxi Province Key Laboratory MedicineNanchangChina
| | - Yi Jiang
- The Ophthalmology & Optometry SchoolNanchang UniversityNanchangChina
| | | | - Jia‐Li Yu
- The Second Clinical Medical SchoolNanchang UniversityNanchangChina
| | - Xu Li
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang UniversityJiangxi Province Key Laboratory MedicineNanchangChina
- School of Public HealthNanchang UniversityNanchangChina
| | - Yin‐Yi Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang UniversityJiangxi Province Key Laboratory MedicineNanchangChina
- School of Public HealthNanchang UniversityNanchangChina
| | - Xiao‐Hang Li
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang UniversityJiangxi Province Key Laboratory MedicineNanchangChina
- School of Public HealthNanchang UniversityNanchangChina
| | - Qun‐Xia Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang UniversityJiangxi Province Key Laboratory MedicineNanchangChina
- School of Public HealthNanchang UniversityNanchangChina
| | - Yan‐Zhao Liu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang UniversityJiangxi Province Key Laboratory MedicineNanchangChina
- School of Public HealthNanchang UniversityNanchangChina
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39
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Xia X, Pi W, Chen M, Wang W, Cai D, Wang X, Lan Y, Yang H. Emerging roles of PHLPP phosphatases in lung cancer. Front Oncol 2023; 13:1216131. [PMID: 37576883 PMCID: PMC10414793 DOI: 10.3389/fonc.2023.1216131] [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: 05/03/2023] [Accepted: 07/12/2023] [Indexed: 08/15/2023] Open
Abstract
Pleckstrin homologous domain leucine-rich repeating protein phosphatases (PHLPPs) were originally identified as protein kinase B (Akt) kinase hydrophobic motif specific phosphatases to maintain the cellular homeostasis. With the continuous expansion of PHLPPs research, imbalanced-PHLPPs were mainly found as a tumor suppressor gene of a variety of solid tumors. In this review, we simply described the history and structures of PHLPPs and summarized the recent achievements in emerging roles of PHLPPs in lung cancer by 1) the signaling pathways affected by PHLPPs including Phosphoinositide 3-kinase (PI3K)/AKT, RAS/RAF/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and Protein kinase C (PKC) signaling cascades. 2) function of PHLPPs regulatory factor USP46 and miR-190/miR-215, 3) the potential roles of PHLPPs in disease prognosis, Epidermal growth factor receptors (EGFR)- tyrosine kinase inhibitor (TKI) resistance and DNA damage, 4) and the possible function of PHLPPs in radiotherapy, ferroptosis and inflammation response. Therefore, PHLPPs can be considered as either biomarker or prognostic marker for lung cancer treatment.
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Affiliation(s)
| | | | | | | | | | | | | | - Haihua Yang
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Taizhou Hospital Affiliated to Wenzhou Medical University, Taizhou, Zhejiang, China
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40
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Tomioka Y, Suetsugu T, Seki N, Tanigawa K, Hagihara Y, Shinmura M, Asai S, Kikkawa N, Inoue H, Mizuno K. The Molecular Pathogenesis of Tumor-Suppressive miR-486-5p and miR-486-3p Target Genes: GINS4 Facilitates Aggressiveness in Lung Adenocarcinoma. Cells 2023; 12:1885. [PMID: 37508549 PMCID: PMC10378275 DOI: 10.3390/cells12141885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/14/2023] [Accepted: 07/16/2023] [Indexed: 07/30/2023] Open
Abstract
The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre-miR-486 (miR-486-5p and miR-486-3p) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre-miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes (MKI67, GINS4, RRM2, HELLS, MELK, TIMELESS, and SAPCD2) predicted a poorer prognosis of LUAD patients (p < 0.05). We focused on GINS4, a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre-miR-486, and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD.
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Affiliation(s)
- Yuya Tomioka
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Takayuki Suetsugu
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Kengo Tanigawa
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Yoko Hagihara
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Masahiro Shinmura
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Shunichi Asai
- Head and Neck Surgery, Chiba Cancer Center, Nitona, Chiba 260-8717, Japan
| | - Naoko Kikkawa
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
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Park EG, Lee DH, Kim WR, Lee YJ, Bae WH, Kim JM, Shin HJ, Ha H, Yi JM, Cho SG, Choi YH, Leem SH, Cha HJ, Kim SW, Kim HS. Human Endogenous Retrovirus-H-Derived miR-4454 Inhibits the Expression of DNAJB4 and SASH1 in Non-Muscle-Invasive Bladder Cancer. Genes (Basel) 2023; 14:1410. [PMID: 37510314 PMCID: PMC10379226 DOI: 10.3390/genes14071410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/04/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
Although most human endogenous retroviruses (HERVs) have been silenced and lost their ability to translocate because of accumulated mutations during evolution, they still play important roles in human biology. Several studies have demonstrated that HERVs play pathological roles in numerous human diseases, especially cancer. A few studies have revealed that long non-coding RNAs that are transcribed from HERV sequences affect cancer progression. However, there is no study on microRNAs derived from HERVs related to cancer. In this study, we identified 29 microRNAs (miRNAs) derived from HERV sequences in the human genome. In particular, we discovered that miR-4454, which is HERV-H-derived miRNA, was upregulated in non-muscle-invasive bladder cancer (NMIBC) cells. To figure out the effects of upregulated miR-4454 in NMIBC, genes whose expression was downregulated in NMIBC, as well as tumor suppressor genes, were selected as putative target genes of miR-4454. The dual-luciferase assay was used to determine the negative relationship between miR-4454 and its target genes, DNAJB4 and SASH1, and they were confirmed to be promising target genes of miR-4454. Taken together, this study suggests that the upregulation of miR-4454 derived from HERV-H in NMIBC reduces the expression of the tumor suppressor genes, DNAJB4 and SASH1, to promote NMIBC progression.
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Affiliation(s)
- Eun Gyung Park
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (D.H.L.); (W.R.K.); (Y.J.L.); (W.H.B.); (J.-m.K.); (H.J.S.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Du Hyeong Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (D.H.L.); (W.R.K.); (Y.J.L.); (W.H.B.); (J.-m.K.); (H.J.S.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Woo Ryung Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (D.H.L.); (W.R.K.); (Y.J.L.); (W.H.B.); (J.-m.K.); (H.J.S.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Yun Ju Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (D.H.L.); (W.R.K.); (Y.J.L.); (W.H.B.); (J.-m.K.); (H.J.S.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Woo Hyeon Bae
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (D.H.L.); (W.R.K.); (Y.J.L.); (W.H.B.); (J.-m.K.); (H.J.S.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Jung-min Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (D.H.L.); (W.R.K.); (Y.J.L.); (W.H.B.); (J.-m.K.); (H.J.S.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Hae Jin Shin
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (E.G.P.); (D.H.L.); (W.R.K.); (Y.J.L.); (W.H.B.); (J.-m.K.); (H.J.S.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Hongseok Ha
- Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea;
| | - Joo Mi Yi
- Department of Microbiology and Immunology, Inje University College of Medicine, Busan 47392, Republic of Korea;
| | - Ssang Goo Cho
- Department of Stem Cell & Regenerative Biotechnology, Institute of Advanced Regenerative Science, Konkuk University, Seoul 05029, Republic of Korea;
| | - Yung Hyun Choi
- Department of Biochemistry, College of Korean Medicine, Dong-Eui University, Busan 47227, Republic of Korea;
| | - Sun Hee Leem
- Department of Biological Science, Dong-A University, Busan 49315, Republic of Korea;
| | - Hee Jae Cha
- Department of Parasitology and Genetics, College of Medicine, Kosin University, Busan 49104, Republic of Korea;
| | - Sang Woo Kim
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea;
| | - Heui Soo Kim
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea;
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Baran K, Kordiak J, Jabłoński S, Brzeziańska-Lasota E. Panel of miR-150 and linc00673, regulators of CCR6/CCL20 may serve as non-invasive diagnostic marker of non-small cell lung cancer. Sci Rep 2023; 13:9642. [PMID: 37316552 DOI: 10.1038/s41598-023-36485-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 06/05/2023] [Indexed: 06/16/2023] Open
Abstract
The C-C motif ligand 20 (CCL20) is a chemokine that specifically binds to the chemokine receptor 6 (CCR6) and the CCL20/CCR6 axis has been implicated in the non-small lung cancer (NSCLC) development and progression. Its expression is regulated by mutual interactions of non-coding RNAs (ncRNAs). This goals of presented study was to evaluate the expression level of CCR6/CCL20 mRNA in NSCLC tissue comparative to selected ncRNAs: miR-150, linc00673. The expression level of the studied ncRNAs was also assessed in serum extracellular vesicles (EVs). Thirty patients (n = 30) were enrolled as the study cohort. Total RNA was isolated from tumor tissue, adjacent macroscopically unchanged tissue and serum EVs. The expression level of studied genes and ncRNAs were estimated based on the qPCR method. Higher expression level of CCL20 mRNA but lower expression level of CCR6 mRNA were observed in tumor in comparison to control tissue. Relative to the smoking status, higher CCL20 (p < 0.05) and CCR6 mRNA (p > 0.05) expression levels were observed in current smokers than in never smokers. In serum EVs the expression level of miR-150 has a negative correlation with AJCC tumor staging, whereas the expression level of linc00673 positively correlated (p > 0.05). The lower expression level of miR-150 and higher expression level of linc00673 in serum EVs were observed in NSCLC patients with lymph nodes metastases (p > 0.05). Regarding the histopathological type, significantly lower expression level of miR-150 and higher expression level of linc00673 were observed in the serum EVs of patients with AC compared to patient with SCC. Our findings revealed that smoking significantly changed the expression level of CCL20 mRNA in NSCLC tissue. Changes in expression levels of miR-150 and linc00673 in the serum EVs of NSCLC patients in relation to presence of lymph node metastases and the stage of cancer development may serve as a non-invasive molecular biomarkers of tumor progression. Furthermore, expression levels of miR-150 and linc00673 may serve as non-intrusive diagnostic biomarkers differentiating adenocarcinoma from squamous cell carcinoma.
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Affiliation(s)
- Kamila Baran
- Department of Biomedicine and Genetics, Chair of Biology and Medical Microbiology, Medical University of Lodz, Lodz, Poland.
| | - Jacek Kordiak
- Department of Thoracic, General and Oncological Surgery, Medical University of Lodz, Lodz, Poland
| | - Sławomir Jabłoński
- Department of Thoracic, General and Oncological Surgery, Medical University of Lodz, Lodz, Poland
| | - Ewa Brzeziańska-Lasota
- Department of Biomedicine and Genetics, Chair of Biology and Medical Microbiology, Medical University of Lodz, Lodz, Poland
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Li M, Liu T, Cheng W, Jin H, Wang X. A test of miR-128-3p and miR-33a-5p in serum exosome as biomarkers for auxiliary diagnosis of non-small cell lung cancer. J Thorac Dis 2023; 15:2616-2626. [PMID: 37324093 PMCID: PMC10267929 DOI: 10.21037/jtd-23-398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 05/10/2023] [Indexed: 06/17/2023]
Abstract
Background Lung cancer is the malignant tumor with the highest incidence and mortality rate in the world today, and non-small cell lung cancer (NSCLC) is its most common type. However, there is still a paucity of specific tumor markers for lung cancer screening. Herein, we detected and compared the levels of miR-128-3p and miR-33a-5p in serum exosomes of NSCLC patients and healthy volunteers, with the aim of identifying suitable exosomal microRNAs (miRNAs) as tumor biomarkers, and explored their value in the auxiliary diagnosis of NSCLC. Methods All participants were recruited from September 1, 2022 to December 30, 2022, and met the inclusion criteria. The case group included 20 patients with lung nodules who were highly suspected of having lung cancer (two cases were excluded). A total of 18 healthy volunteers (control group) were also enrolled. Blood samples were collected in both the case group before surgery and in the control group. Quantitative real-time polymerase chain reaction method was used to detect the expression of miR-128-3p and miR-33a-5p in serum exosomes. The main indicators of statistical analysis included the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Results Compared with the healthy control group, the NSCLC case group had significantly lower expression levels of serum exosome miR-128-3p and miR-33a-5p (P<0.01, P<0.001), and there was a significant positive correlation between the two exosome miRNAs (r=0.848, P<0.01). The AUC values of miR-128-3p alone and miR-33a-5p alone in distinguishing case group and control group were 0.789 [95% confidence interval (CI): 0.637-0.940; sensitivity: 61.1%; specificity: 94.4%; P=0.003] and 0.821 (95% CI: 0.668-0.974; sensitivity: 77.8%; specificity: 83.3%; and P=0.001), respectively. The combination of miR-128-3p and miR-33a-5p had an AUC of 0.855 (95% CI: 0.719-0.991; P<0.001) for distinguishing case group and control group, which was greater than the AUC values of miR-128-3p alone and miR-33a-5p alone (cut-off value: 0.034; sensitivity: 83.3%; and specificity: 88.9%). However, there was no significant difference in the AUC among these three groups (P>0.05). Conclusions Serum exosome miR-128-3p and miR-33a-5p showed good performance in NSCLC screening and may be used as new biomarkers for large-scale NSCLC screening.
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Affiliation(s)
- Mengxing Li
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Tao Liu
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Wen Cheng
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hai Jin
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xiaowei Wang
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
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Bortoletto AS, Parchem RJ. KRAS Hijacks the miRNA Regulatory Pathway in Cancer. Cancer Res 2023; 83:1563-1572. [PMID: 36946612 PMCID: PMC10183808 DOI: 10.1158/0008-5472.can-23-0296] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/01/2023] [Accepted: 03/20/2023] [Indexed: 03/23/2023]
Abstract
Extensive studies have focused on the misregulation of individual miRNAs in cancer. More recently, mutations in the miRNA biogenesis and processing machinery have been implicated in several malignancies. Such mutations can lead to global miRNA misregulation, which may promote many of the well-known hallmarks of cancer. Interestingly, recent evidence also suggests that oncogenic Kristen rat sarcoma viral oncogene homolog (KRAS) mutations act in part by modulating the activity of members of the miRNA regulatory pathway. Here, we highlight the vital role mutations in the miRNA core machinery play in promoting malignant transformation. Furthermore, we discuss how mutant KRAS can simultaneously impact multiple steps of miRNA processing and function to promote tumorigenesis. Although the ability of KRAS to hijack the miRNA regulatory pathway adds a layer of complexity to its oncogenic nature, it also provides a potential therapeutic avenue that has yet to be exploited in the clinic. Moreover, concurrent targeting of mutant KRAS and members of the miRNA core machinery represents a potential strategy for treating cancer.
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Affiliation(s)
- Angelina S. Bortoletto
- Center for Cell and Gene Therapy, Stem Cell and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Department of Neuroscience, Translational Biology and Molecular Medicine Program, Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas
| | - Ronald J. Parchem
- Center for Cell and Gene Therapy, Stem Cell and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Department of Neuroscience, Translational Biology and Molecular Medicine Program, Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas
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Zheng P, Jiang J, Li L, Wei L, Li J, Jin L. Circ_SATB2 knockdown inhibits the tumorigenesis of non-small cell lung cancer via miR-760/KIF2A axis. Histol Histopathol 2023; 38:431-441. [PMID: 36196919 DOI: 10.14670/hh-18-530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2023]
Abstract
PURPOSE This study was aimed at exploring the function and underlying mechanism of circ_SATB2 in non-small cell lung cancer (NSCLC). METHODS The levels of circ_SATB2, microRNA-760 (miR-760) and Kinesin family member 2a (KIF2A) were determined using quantitative real-time polymerase chain reaction or western blot assay. The proliferation was detected using MTT and colony formation assays. Cell cycle and apoptosis were evaluated by flow cytometry. Transwell assay for migration and invasion and western blot for metastasis-associated proteins were conducted. Dual-luciferase reporter assay was used to analyze the interaction between miR-760 and circ_SATB2 or KIF2A. The effect of circ_SATB2 on NSCLC tumor growth in vivo was studied by xenograft mice model. RESULTS Circ_SATB2 was upregulated in NSCLC tissues and cells. Circ_SATB2 knockdown caused inhibitory effects on NSCLC cell proliferation and metastasis but accelerated apoptosis. Circ_SATB2 served as a sponge of miR-760 to act in the development of NSCLC. Moreover, miR-760 could target KIF2A, and KIF2A expression was positively regulated by circ_SATB2. Furthermore, KIF2A overexpression neutralized miR-760-mediated inhibition effects on NSCLC cell progression. Besides, circ_SATB2 enhanced NSCLC tumorigenesis by targeting miR-760/KIF2A axis in vivo. CONCLUSION Circ_SATB2 was highly expressed and participated in the progression of NSCLC through the modulation of the miR-760/KIF2A axis, suggesting that circ_SATB2 might be a potential biomarker for the diagnosis of NSCLC.
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Affiliation(s)
- Pengchao Zheng
- Cardio-Thoracic Surgery, Jing Men NO.2 People's Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen, Hubei, China
| | - Jianhua Jiang
- Cardio-Thoracic Surgery, Jing Men NO.2 People's Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen, Hubei, China
| | - Lei Li
- Cardio-Thoracic Surgery, Jing Men NO.2 People's Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen, Hubei, China
| | - Liang Wei
- Cardio-Thoracic Surgery, Jing Men NO.2 People's Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen, Hubei, China
| | - Jie Li
- Cardio-Thoracic Surgery, Jing Men NO.2 People's Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen, Hubei, China
| | - Ling Jin
- Cardio-Thoracic Surgery, Jing Men NO.2 People's Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen, Hubei, China.
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Yang Y, Liu H, Chen Y, Xiao N, Zheng Z, Liu H, Wan J. Liquid biopsy on the horizon in immunotherapy of non-small cell lung cancer: current status, challenges, and perspectives. Cell Death Dis 2023; 14:230. [PMID: 37002211 PMCID: PMC10066332 DOI: 10.1038/s41419-023-05757-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/14/2023] [Accepted: 03/17/2023] [Indexed: 04/03/2023]
Abstract
Non-small cell lung cancer (NSCLC) is one of the most threatening malignancies to human health and life. In most cases, patients with NSCLC are already at an advanced stage when they are diagnosed. In recent years, lung cancer has made great progress in precision therapy, but the efficacy of immunotherapy is unstable, and its response rate varies from patient to patient. Several biomarkers have been proposed to predict the outcomes of immunotherapy, such as programmed cell death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). Nevertheless, the detection assays are invasive and demanding on tumor tissue. To effectively predict the outcomes of immunotherapy, novel biomarkers are needed to improve the performance of conventional biomarkers. Liquid biopsy is to capture and detect circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and exosomes in body fluids, such as blood, saliva, urine, pleural fluid and cerebrospinal fluid as samples from patients, so as to make analysis and diagnosis of cancer and other diseases. The application of liquid biopsy provides a new possible solution, as it has several advantages such as non-invasive, real-time dynamic monitoring, and overcoming tumor heterogeneity. Liquid biopsy has shown predictive value in immunotherapy, significantly improving the precision treatment of lung cancer patients. Herein, we review the application of liquid biopsy in predicting the outcomes of immunotherapy in NSCLC patients, and discuss the challenges and future directions in this field.
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Affiliation(s)
- Ying Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hongyang Liu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Youming Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Nan Xiao
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaoyang Zheng
- Department of Clinical Laboratory, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Hongchun Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Junhu Wan
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Ghidotti P, Petraroia I, Fortunato O, Pontis F. Immunomodulatory role of EV-derived non-coding RNA in lung cancer. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2023; 4:59-71. [PMID: 39698297 PMCID: PMC11648522 DOI: 10.20517/evcna.2022.42] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/17/2023] [Accepted: 03/09/2023] [Indexed: 12/20/2024]
Abstract
Lung cancer is the deadliest cancer worldwide, primarily because of its metastatic spread. Extracellular vesicles (EVs) are small lipid-bilayer particles released by almost all types of cells. EVs play fundamental roles in cell-cell communication and cell-environment interactions by carrying proteins, nucleic acids such as DNA and RNA (mRNAs, lncRNAs, and miRNAs), and other bioactive molecules that are able to influence the behaviour of recipient cells. EVs have been described as key players in the modulation of tumour progression and the anticancer immune response. In this review, we highlight current knowledge on the role of non-coding RNAs in the modulation of the immune response, focusing on lung cancer. Since EVs are fundamental cell-to-cell mediators, we discuss the current knowledge on the immunomodulatory properties of tumour-derived EVs and, in particular, their ncRNA cargo during the different phases of lung cancer development and progression.
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Affiliation(s)
| | | | - Orazio Fortunato
- Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy
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Lai X, Zhong J, Zhang B, Zhu T, Liao R. Exosomal Non-Coding RNAs: Novel Regulators of Macrophage-Linked Intercellular Communication in Lung Cancer and Inflammatory Lung Diseases. Biomolecules 2023; 13:536. [PMID: 36979471 PMCID: PMC10046066 DOI: 10.3390/biom13030536] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/08/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023] Open
Abstract
Macrophages are innate immune cells and often classified as M1 macrophages (pro-inflammatory states) and M2 macrophages (anti-inflammatory states). Exosomes are cell-derived nanovesicles that range in diameter from 30 to 150 nm. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), are abundant in exosomes and exosomal ncRNAs influence immune responses. Exosomal ncRNAs control macrophage-linked intercellular communication via their targets or signaling pathways, which can play positive or negative roles in lung cancer and inflammatory lung disorders, including acute lung injury (ALI), asthma, and pulmonary fibrosis. In lung cancer, exosomal ncRNAs mediated intercellular communication between lung tumor cells and tumor-associated macrophages (TAMs), coordinating cancer proliferation, migration, invasion, metastasis, immune evasion, and therapy resistance. In inflammatory lung illnesses, exosomal ncRNAs mediate macrophage activation and inflammation to promote or inhibit lung damage. Furthermore, we also discussed the possible applications of exosomal ncRNA-based therapies for lung disorders.
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Affiliation(s)
- Xingning Lai
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China
- Research Unit for Perioperative Stress Assessment and Clinical Decision, Chinese Academy of Medical Sciences (2018RU012), West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Zhong
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China
- Research Unit for Perioperative Stress Assessment and Clinical Decision, Chinese Academy of Medical Sciences (2018RU012), West China Hospital, Sichuan University, Chengdu 610041, China
| | - Boyi Zhang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China
- Research Unit for Perioperative Stress Assessment and Clinical Decision, Chinese Academy of Medical Sciences (2018RU012), West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Zhu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China
- Research Unit for Perioperative Stress Assessment and Clinical Decision, Chinese Academy of Medical Sciences (2018RU012), West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ren Liao
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China
- Research Unit for Perioperative Stress Assessment and Clinical Decision, Chinese Academy of Medical Sciences (2018RU012), West China Hospital, Sichuan University, Chengdu 610041, China
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49
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Fischer S, Spath N, Hamed M. Data-Driven Radiogenomic Approach for Deciphering Molecular Mechanisms Underlying Imaging Phenotypes in Lung Adenocarcinoma: A Pilot Study. Int J Mol Sci 2023; 24:4947. [PMID: 36902378 PMCID: PMC10003564 DOI: 10.3390/ijms24054947] [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: 12/23/2022] [Revised: 02/13/2023] [Accepted: 02/23/2023] [Indexed: 03/08/2023] Open
Abstract
The heterogeneity of lung tumor nodules is reflected in their phenotypic characteristics in radiological images. The radiogenomics field employs quantitative image features combined with transcriptome expression levels to understand tumor heterogeneity molecularly. Due to the different data acquisition techniques for imaging traits and genomic data, establishing meaningful connections poses a challenge. We analyzed 86 image features describing tumor characteristics (such as shape and texture) with the underlying transcriptome and post-transcriptome profiles of 22 lung cancer patients (median age 67.5 years, from 42 to 80 years) to unravel the molecular mechanisms behind tumor phenotypes. As a result, we were able to construct a radiogenomic association map (RAM) linking tumor morphology, shape, texture, and size with gene and miRNA signatures, as well as biological correlates of GO terms and pathways. These indicated possible dependencies between gene and miRNA expression and the evaluated image phenotypes. In particular, the gene ontology processes "regulation of signaling" and "cellular response to organic substance" were shown to be reflected in CT image phenotypes, exhibiting a distinct radiomic signature. Moreover, the gene regulatory networks involving the TFs TAL1, EZH2, and TGFBR2 could reflect how the texture of lung tumors is potentially formed. The combined visualization of transcriptomic and image features suggests that radiogenomic approaches could identify potential image biomarkers for underlying genetic variation, allowing a broader view of the heterogeneity of the tumors. Finally, the proposed methodology could also be adapted to other cancer types to expand our knowledge of the mechanistic interpretability of tumor phenotypes.
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Affiliation(s)
- Sarah Fischer
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Ernst-Heydemannstr. 8, 18057 Rostock, Germany
- Department of Systems Biology and Bioinformatics, University of Rostock, Ulmenstr. 69, 18057 Rostock, Germany
| | - Nicolas Spath
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Ernst-Heydemannstr. 8, 18057 Rostock, Germany
- Department of Medicine II, Hematology and Oncology, University Hospital Schleswig-Holstein, Arnold-Hellerstr. 3, 24105 Kiel, Germany
| | - Mohamed Hamed
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Ernst-Heydemannstr. 8, 18057 Rostock, Germany
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50
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Niu H, Wang D, Wen T, Liu H, Jie J, Song L, Li D. Anwuligan inhibits the progression of non-small cell lung cancer via let-7c-3p/PI3K/AKT/mTOR axis. Cancer Med 2023; 12:5908-5925. [PMID: 36412203 PMCID: PMC10028152 DOI: 10.1002/cam4.5382] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 09/25/2022] [Accepted: 10/11/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Anwuligan (ANW) isolated from nutmeg, also known as myristyl lignan, has attracted attention due to its therapeutic potential in diseases. However, its effect on lung cancer is still unclear. METHODS In this study, the cytotoxicity of ANW on non-small cell lung cancer (NSCLC) cells was detected using a Cell Counting Kit-8 (CCK-8) assay. In vitro, clone formation, wound healing, and Transwell assays were used to investigate the migratory and invasive abilities of NSCLC cells after ANW treatment. The expression levels of the associated proteins were detected using Western blotting. A luciferase assay was used to validate the binding of let-7c-3p to the 3'-untranslated region (UTR) of PIK3CA. In vivo, an A549 cell xenograft mouse model was used to verify the effect of ANW on tumor growth. RESULTS The results showed that ANW treatment (20 or 50 μM) had obvious cytotoxicity against A549 and H460 cells, suppressing cell proliferation and migration in vitro. In vivo, the growth of the implanted tumor was inhibited by ANW in a nude mouse model. The growth of NSCLC cells was also inhibited by let-7c-3p overexpression in vitro and in vivo. The inhibitory effect of ANW on the proliferation and metastasis of NSCLC cells was weakened by the downregulation of let-7c-3p, whereas it was enhanced by the overexpression of let-7c-3p; PIK3CA was the main target of let-7c-3p. CONCLUSIONS In summary, ANW inhibits the growth and metastasis of NSCLC cells in vivo and in vitro by upregulating the expression of let-7c-3p, which can regulate the PI3K/AKT/mTOR signaling pathway. PIK3CA is the main target of let-7c-3p.
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Affiliation(s)
- Huikun Niu
- Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Dexiang Wang
- Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingting Wen
- Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Han Liu
- Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Jing Jie
- Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Lei Song
- Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Dan Li
- Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
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