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Saadh MJ, Allela OQB, Kareem RA, Baldaniya L, Ballal S, Vashishth R, Parmar M, Sameer HN, Hamad AK, Athab ZH, Adil M. Prognostic gene expression profile of colorectal cancer. Gene 2025; 955:149433. [PMID: 40122415 DOI: 10.1016/j.gene.2025.149433] [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: 12/20/2024] [Revised: 02/26/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Colorectal cancer is a major global health burden, with significant heterogeneity in clinical outcomes among patients. Identifying robust prognostic gene expression signatures can help stratify patients, guide treatment decisions, and improve clinical management. This review provides an overview of current prognostic gene expression profiles in colorectal cancer research. We have synthesized evidence from numerous published studies investigating the association between tumor gene expression patterns and patient survival outcomes. The reviewed literature reveals several promising gene signatures that have demonstrated the ability to predict disease-free survival and overall survival in CRC patients, independent of standard clinicopathological risk factors. These genes are crucial in fundamental biological processes, including cell cycle control, epithelial-mesenchymal transition, and immune regulation. The implementation of prognostic gene expression tests in clinical practice holds great potential for enabling more personalized management strategies for colorectal cancer.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | | | - Lalji Baldaniya
- Marwadi University Research Center, Department of Pharmacy, Faculty of Health Sciences, Marwadi University, Rajkot 360003 Gujarat, India.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India.
| | - Raghav Vashishth
- Department of Surgery, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India.
| | - Manisha Parmar
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India.
| | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar 64001, Iraq.
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq.
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Wu L, Zhu X, Pan S, Chen Y, Luo C, Zhao Y, Xing J, Shi K, Zhang S, Li J, Chai J, Ling X, Qiu J, Wang Y, Shen Z, Jie W, Guo J. Diabetes Advances Cardiomyocyte Senescence Through Interfering Rnd3 Expression and Function. Aging Cell 2025:e70031. [PMID: 40025898 DOI: 10.1111/acel.70031] [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: 08/10/2024] [Revised: 01/27/2025] [Accepted: 02/17/2025] [Indexed: 03/04/2025] Open
Abstract
Rnd3 is a small Rho-GTPase that has been implicated in various cardiovascular diseases. Yet, its role in diabetes-induced cardiomyocyte senescence remains unknown. Here we tested the role of Rnd3 in cardiomyocyte senescence and diabetic cardiomyopathy (DCM). The expression of Rnd3 was found to be reduced in peripheral blood mononuclear cells from diabetic patients and correlated negatively with age but positively with cardiac function. In 96-week-old Sprague Dawley (SD) rats, cardiac function was impaired, accompanied by an increased number of SA-β-gal-positive cells and elevated levels of the senescence-associated secretory phenotype (SASP) related factors, compared to those of 12-week-old rats. Diabetes and high glucose (HG, 35 mmol/L D-glucose) suppressed Rnd3 expression in cardiomyocytes and induced cardiomyocyte senescence. The deficiency of Rnd3 exacerbated cardiomyocyte senescence in vitro and in vivo. MicroRNA sequencing in AC16 cells identified a conserved miR-103a-3p (present in humans and rats) as a key HG-upregulated microRNA that bound to the Rnd3 3'-UTR. In cultured cardiomyocytes, miR-103a-3p inhibitors antagonized HG-induced cardiomyocyte senescence dependent on Rnd3 expression. Treatment with AAV9 vectors carrying miR-103a-3p sponges and Rnd3-overexpressing plasmids alleviated cardiomyocyte senescence and restored cardiac function in diabetic SD rats. HG stimulation increased STAT3 (Tyr705) phosphorylation and promoted its nuclear translocation in H9C2 cells, an effect exacerbated by Rnd3 knockout. Mechanistically, Rnd3 interacted with p-STAT3 in the cytoplasm, facilitating proteasome-mediated ubiquitination and p-STAT3 degradation. The STAT3 inhibitor S3I-201 blocked HG-induced STAT3 activation and mitigated cardiomyocyte senescence. These findings suggest that diabetes induces cardiomyocyte senescence via the miR-103a-3p/Rnd3/STAT3 signaling pathway, highlighting a potential therapeutic target for DCM.
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Affiliation(s)
- Linxu Wu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
- Public Research Center of Hainan Medical University, Haikou, China
| | - Xinglin Zhu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Shanshan Pan
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Yan Chen
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Cai Luo
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Yangyang Zhao
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Jingci Xing
- Department of Pathology and Pathophysiology, School of Basic Medicine Sciences, Guangdong Medical University, Zhanjiang, China
| | - Kaijia Shi
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Shuya Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Jiaqi Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Jinxuan Chai
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Xuebin Ling
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jianmin Qiu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
| | - Yan Wang
- Public Research Center of Hainan Medical University, Haikou, China
| | - Zhihua Shen
- Department of Pathology and Pathophysiology, School of Basic Medicine Sciences, Guangdong Medical University, Zhanjiang, China
| | - Wei Jie
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Junli Guo
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research, School of Public Health, Hainan Medical University, Haikou, China
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, China
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Kumar RMR. Exosomal microRNAs: impact on cancer detection, treatment, and monitoring. Clin Transl Oncol 2025; 27:83-94. [PMID: 38971914 DOI: 10.1007/s12094-024-03590-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 06/30/2024] [Indexed: 07/08/2024]
Abstract
Exosomes, measuring between 30 and 150 nm in diameter, are small vesicles enclosed by a lipid bilayer membrane. They are released by various cells in the body and carry a diverse payload of molecules, including proteins, lipids, mRNA, and different RNA species such as long non-coding RNA, circular RNA, and microRNA (miRNA). With lengths of approximately 19-22 nucleotides, miRNAs constitute the predominant cargo in exosomes and serve as crucial regulators of protein biosynthesis. In cancer detection, exosomal miRNAs show promise as non-invasive biomarkers due to their stability and presence in various bodily fluids, aiding in early detection and precise diagnosis with specific miRNA signatures linked to different cancer types. Moreover, exosomal miRNAs influence treatment outcomes by affecting cellular processes like cell growth, cell death, and drug resistance, thereby impacting response to therapy. Additionally, they serve as indicators of disease progression and treatment response, providing insights that can guide treatment decisions and improve patient care. Through longitudinal studies, changes in exosomal miRNA profiles have been observed to correlate with disease progression, metastasis, and response to therapy, highlighting their potential for real-time monitoring of tumor dynamics and treatment efficacy. Understanding the intricate roles of exosomal miRNAs in cancer biology offers opportunities for developing innovative diagnostic tools and therapeutic strategies tailored to individual patients, ultimately advancing precision medicine approaches and improving outcomes for cancer patients. This review aims to provide an understanding of the role of exosomal miRNAs in cancer detection, treatment, and monitoring, shedding light on their potential for revolutionising oncology practices and patient care.
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Affiliation(s)
- Ram Mohan Ram Kumar
- Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India.
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Yadav R, Khatkar R, Yap KCH, Kang CYH, Lyu J, Singh RK, Mandal S, Mohanta A, Lam HY, Okina E, Kumar RR, Uttam V, Sharma U, Jain M, Prakash H, Tuli HS, Kumar AP, Jain A. The miRNA and PD-1/PD-L1 signaling axis: an arsenal of immunotherapeutic targets against lung cancer. Cell Death Discov 2024; 10:414. [PMID: 39343796 PMCID: PMC11439964 DOI: 10.1038/s41420-024-02182-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 08/21/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024] Open
Abstract
Lung cancer is a severe challenge to the health care system with intrinsic resistance to first and second-line chemo/radiotherapies. In view of the sterile environment of lung cancer, several immunotherapeutic drugs including nivolumab, pembrolizumab, atezolizumab, and durvalumab are currently being used in clinics globally with the intention of releasing exhausted T-cells back against refractory tumor cells. Immunotherapies have a limited response rate and may cause immune-related adverse events (irAEs) in some patients. Hence, a deeper understanding of regulating immune checkpoint interactions could significantly enhance lung cancer treatments. In this review, we explore the role of miRNAs in modulating immunogenic responses against tumors. We discuss various aspects of how manipulating these checkpoints can bias the immune system's response against lung cancer. Specifically, we examine how altering the miRNA profile can impact the activity of various immune checkpoint inhibitors, focusing on the PD-1/PD-L1 pathway within the complex landscape of lung cancer. We believe that a clear understanding of the host's miRNA profile can influence the efficacy of checkpoint inhibitors and significantly contribute to existing immunotherapies for lung cancer patients. Additionally, we discuss ongoing clinical trials involving immunotherapeutic drugs, both as standalone treatments and in combination with other therapies, intending to advance the development of immunotherapy for lung cancer.
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Affiliation(s)
- Ritu Yadav
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Rinku Khatkar
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Kenneth C-H Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chloe Yun-Hui Kang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Juncheng Lyu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rahul Kumar Singh
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Surojit Mandal
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Adrija Mohanta
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rajiv Ranjan Kumar
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Vivek Uttam
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Uttam Sharma
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Manju Jain
- Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
| | | | | | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Aklank Jain
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India.
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Lv M, Li X, Zheng C, Tian W, Yang H, Yin Z, Zhou B. Exosomal miR-130b-3p suppresses metastasis of non-small cell lung cancer cells by targeting DEPDC1 via TGF-β signaling pathway. Int J Biol Macromol 2024; 275:133594. [PMID: 38960258 DOI: 10.1016/j.ijbiomac.2024.133594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/25/2024] [Accepted: 06/29/2024] [Indexed: 07/05/2024]
Abstract
Exosomal miRNAs have vital functions in mediating intercellular communication as well as tumor occurrence and development. Thus, our research was aimed at exploring the regulatory mechanisms of exosomal miR-130b-3p/DEP domain containing 1 (DEPDC1)/transforming growth factor-β (TGF-β) signaling pathway in non-small cell lung cancer (NSCLC). Here we indicated that exosomal miR-130b-3p expression decreased in the serum of NSCLC patients, and it was of significant diagnostic value. Moreover, elevated miR-130b-3p levels suppressed the proliferation and migration of NSCLC cells, and enhanced their apoptosis. Conversely, miR-130b-3p down-regulation led to an opposite effect. As the upstream of DEPDC1, miR-130b-3p directly bound to 3'UTR in DEPDC1 to regulate its expression. DEPDC1 levels affected the proliferation, migration, and apoptosis of NSCLC cells via TGF-β signaling pathway. Exosomal miR-130b-3p was highly expressed in BEAS-2B cells, besides, BEAS-2B cells transferred exosomal miR-130b-3p to NSCLC cells. Finally, exosomal miR-130b-3p suppressed NSCLC cell growth and migration, promoted their apoptosis via TGF-β signaling pathway by decreasing DEPDC1 expression, and suppressed epithelial-mesenchymal transition (EMT) in NSCLC cells. In conclusion, exosomal miR-130b-3p has the potential to be a predictive biomarker for NSCLC, thereby stimulating the exploration of diagnostic and therapeutic approaches targeting NSCLC.
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Affiliation(s)
- Meiwen Lv
- Department of Clinical Epidemiology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
| | - Chang Zheng
- Department of Clinical Epidemiology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Wen Tian
- Department of Clinical Epidemiology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - He Yang
- Department of Clinical Epidemiology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Zhihua Yin
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
| | - Baosen Zhou
- Department of Clinical Epidemiology, The First Hospital of China Medical University, Shenyang 110001, China.
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He G, Liu J, Yu Y, Wei S, Peng X, Yang L, Li H. Revisiting the advances and challenges in the clinical applications of extracellular vesicles in cancer. Cancer Lett 2024; 593:216960. [PMID: 38762194 DOI: 10.1016/j.canlet.2024.216960] [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: 03/14/2024] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/20/2024]
Abstract
Extracellular vesicles (EVs) have been the subject of an exponentially growing number of studies covering their biogenesis mechanisms, isolation and analysis techniques, physiological and pathological roles, and clinical applications, such as biomarker and therapeutic uses. Nevertheless, the heterogeneity of EVs both challenges our understanding of them and presents new opportunities for their potential application. Recently, the EV field experienced a wide range of advances. However, the challenges also remain huge. This review focuses on the recent progress and difficulties encountered in the practical use of EVs in clinical settings. In addition, we also explored the concept of EV heterogeneity to acquire a more thorough understanding of EVs and their involvement in cancer, specifically focusing on the fundamental nature of EVs.
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Affiliation(s)
- Guangpeng He
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China; Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China; Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Yifan Yu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China; Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Shibo Wei
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China; Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China; Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China; Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China; Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
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Liu C, Yin T, Zhang M, Li Z, Xu B, Lv H, Wang P, Wang J, Hao J, Zhang L. Function of miR-21-5p derived from ADSCs-exos on the neuroinflammation after cerebral ischemia. J Stroke Cerebrovasc Dis 2024; 33:107779. [PMID: 38768666 DOI: 10.1016/j.jstrokecerebrovasdis.2024.107779] [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: 10/12/2023] [Revised: 02/13/2024] [Accepted: 05/16/2024] [Indexed: 05/22/2024] Open
Abstract
INTRODUCTION Cerebral ischemia (CI) induces a profound neuroinflammatory response, but the underlying molecular mechanism remains unclear. Exosomes from adipose-derived stem cells (ADSC-exos) have been found to play a crucial role in cell communication by transferring molecules including microRNAs (miRNAs), which have been shown to modulate the inflammatory response after CI and are viable molecular targets for altering brain function. The current study aimed to explore the contribution of ADSC-exosomal miR-21-5p to the neuroinflammation after CI. METHODS The differentially expressed miR-21-5p in CI was screened based on literature search. The target mRNAs of miR-21-5p were predicted using online databases and verified by luciferase reporter assay. Then, BV2 cells were treated with hemin to simulate the inflammatory response after CI, and its animal model was induced using the MCAO method. Ischemia was evaluated in rats using 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining. ADSCs-exos were further isolated and identified by western blot analysis and transmission electron microscope. RESULTS MiR-21-5p was significantly down-regulated in CI and alleviated neuropathic damage after CI by the PIK3R1/PI3K/AKT signaling axis. And miR-21-5p derived from ADSCs-exos alleviated neuroinflammation after CI via promoting microglial M2 polarization. CONCLUSION We demonstrated that ADSC-exosomal miR-21-5p mitigated post-CI inflammatory response through the PIK3R1/PI3K/AKT signaling axis and could offer neuroprotection after CI through promoting polarization of M2 microglia.
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Affiliation(s)
- Chao Liu
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Tengkun Yin
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Meng Zhang
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Zhongchen Li
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Bin Xu
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Hang Lv
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Peijian Wang
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Jiyue Wang
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Jiheng Hao
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China
| | - Liyong Zhang
- Department of Neurosurgery, Liaocheng Brain Hospital, No. 45 Huashan Road, Dongchangfu District, Liaocheng, Shandong 252000, China.
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Xu T, Huangfu B, He X, Huang K. Exosomes as mediators of signal transmitters in biotoxins toxicity: a comprehensive review. Cell Biol Toxicol 2024; 40:27. [PMID: 38693223 PMCID: PMC11062979 DOI: 10.1007/s10565-024-09867-4] [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: 01/14/2024] [Accepted: 04/23/2024] [Indexed: 05/03/2024]
Abstract
Small membranes known as exosomes surround them and are released by several cell types both in vitro and in vivo. These membranes are packed with a variety of biomolecules, including proteins, lipids, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and non-coding RNA (ncRNA). As a source of biological nanomaterials, exosomes play a role in information and substance transmission between cells and have been identified as a general method of facilitating communication during interactions between the body, target organs, and toxins.. In order to understand the changes and mechanism of the composition and level of exosomes after biotoxin infection, this review focuses on current findings on the exosomes and highlights their novel uses in the toxicity mechanism. Exosomes are mainly used as a delivery carrier or mediated by receptors, and play an immune role after the toxin enters the body. This review expounds on the importance of exosomes in the toxicological mechanism of biotoxins and provides new insights for further diagnosis of toxic biomarkers, detoxification, and treatment development.
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Affiliation(s)
- Tongxiao Xu
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering; China Agricultural University, Beijing, 100083, China
| | - Bingxin Huangfu
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering; China Agricultural University, Beijing, 100083, China
| | - Xiaoyun He
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering; China Agricultural University, Beijing, 100083, China.
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Beijing, 100083, China.
| | - Kunlun Huang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering; China Agricultural University, Beijing, 100083, China.
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Beijing, 100083, China.
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Hui K, Dong C, Hu C, Li J, Yan D, Jiang X. VEGFR affects miR-3200-3p-mediated regulatory T cell senescence in tumour-derived exosomes in non-small cell lung cancer. Funct Integr Genomics 2024; 24:31. [PMID: 38363405 DOI: 10.1007/s10142-024-01305-2] [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: 10/17/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/17/2024]
Abstract
Numerous studies have demonstrated that regulatory T (Treg) cells play an important role in the tumour microenvironment (TME). The aim of this study was to investigate whether VEGFR2 affects the expression of miR-3200-3p in exosomes secreted by tumour cells, thereby influencing Treg senescence in the TME. The results showed that VEGFR2 expression level was the highest in Calu-1 cells, and after transfection with si-VEGFR2, the exosomes secreted from Calu-1 cells were extracted and characterised with no significant difference from the exosomes of the untransfected group, but the expression of miR-3200-3p in the exosomes of the transfected si-VEGFR2 group was elevated. The Cell Counting Kit-8 (CCK-8) and flow cytometry (FCM) results suggested that exosomes highly expressing miR-3200-3p could inhibit Treg cell viability and promote apoptosis levels when treated with Treg cells. Detection of the senescence-associated proteins p16 INK4A and MMP3 by western blot (WB) revealed that exosomes highly expressing miR-3200-3p were able to elevate their protein expression levels. Tumour xenograft experiments demonstrated that exosomes with high miR-3200-3p expression promoted Treg cell senescence and inhibited subcutaneous tumour growth in nude mice. Dual-luciferase reporter assays and RNA pull-down assays showed that miR-3200-3p could be linked with DDB1. Overexpression of DDB1 reverses changes in DCAF1/GSTP1/ROS protein expression caused by exosomes with high miR-3200-3p expression. In conclusion, inhibition of VEGFR2 expression in tumour cells promotes the expression of miR-3200-3p in exosomes secreted by tumour cells. miR-3200-3p enters the TME through exosomes and acts on DDB1 in Treg cells to promote senescence of Treg cells to inhibit tumour progression.
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Affiliation(s)
- Kaiyuan Hui
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, No. 6 Zhenhua East Road, Lianyungang, 222061, Jiangsu, China
| | - Changhong Dong
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, No. 6 Zhenhua East Road, Lianyungang, 222061, Jiangsu, China
| | - Chenxi Hu
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, No. 6 Zhenhua East Road, Lianyungang, 222061, Jiangsu, China
| | - Jiawen Li
- Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, China
| | - Dongyue Yan
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, No. 6 Zhenhua East Road, Lianyungang, 222061, Jiangsu, China
| | - Xiaodong Jiang
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, No. 6 Zhenhua East Road, Lianyungang, 222061, Jiangsu, China.
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An SX, Yu ZJ, Fu C, Wei MJ, Shen LH. Biological factors driving colorectal cancer metastasis. World J Gastrointest Oncol 2024; 16:259-272. [PMID: 38425391 PMCID: PMC10900157 DOI: 10.4251/wjgo.v16.i2.259] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 12/23/2023] [Accepted: 01/08/2024] [Indexed: 02/02/2024] Open
Abstract
Approximately 20% of colorectal cancer (CRC) patients present with metastasis at diagnosis. Among Stage I-III CRC patients who undergo surgical resection, 18% typically suffer from distal metastasis within the first three years following initial treatment. The median survival duration after the diagnosis of metastatic CRC (mCRC) is only 9 mo. mCRC is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue, allowing cancer cells to spread from primary to distant organs; however, increasing evidence suggests that the mCRC process can begin early in tumor development. CRC patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological alterations. Different genomic and nongenomic events can induce subclone diversity, which leads to cancer and metastasis. Throughout the course of mCRC, metastatic cascades are associated with invasive cancer cell migration through the circulatory system, extravasation, distal seeding, dormancy, and reactivation, with each step requiring specific molecular functions. However, cancer cells presenting neoantigens can be recognized and eliminated by the immune system. In this review, we explain the biological factors that drive CRC metastasis, namely, genomic instability, epigenetic instability, the metastatic cascade, the cancer-immunity cycle, and external lifestyle factors. Despite remarkable progress in CRC research, the role of molecular classification in therapeutic intervention remains unclear. This review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.
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Affiliation(s)
- Shuai-Xing An
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Antitumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang 110122, Liaoning Province, China
- BD Department, Greenpine Pharma Group Co., Ltd, Tianjin 300020, China
| | - Zhao-Jin Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Antitumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang 110122, Liaoning Province, China
| | - Chen Fu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Antitumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang 110122, Liaoning Province, China
| | - Min-Jie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Antitumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang 110122, Liaoning Province, China
| | - Long-Hai Shen
- Center of Oncology, Genertec Liaoyou Gem Flower Hospital, PanJin 124010, Liaoning Province, China
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Zhang J, Pan Y, Jin L, Yang H, Cao P. Exosomal-miR-522-3p derived from cancer-associated fibroblasts accelerates tumor metastasis and angiogenesis via repression bone morphogenetic protein 5 in colorectal cancer. J Gastroenterol Hepatol 2024; 39:107-120. [PMID: 37984826 DOI: 10.1111/jgh.16345] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 05/26/2023] [Accepted: 08/21/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is a gastrointestinal tract malignancy. Exosomes secreted by cancer-associated fibroblasts (CAFs) are reported to participate in tumor progression by delivering noncoding RNA or small proteins. However, the function of exosomal miR-522-3p in CRC remains unclear. METHODS CAFs were derived from tumor tissues, and exosomes were identified by western blot or TEM/NTA and originated from CAFs/NFs. The viability, invasion, and migration of HUVECs and CRC cells was examined using MTT, Transwell, and wound healing assays, respectively. The molecular interactions were validated using dual luciferase reporter assay and RIP. Xenograft and lung metastasis mouse models were generated to assess tumor growth and metastasis. RESULTS Exosomes extracted from CAFs/NFs showed high expression of CD63, CD81, and TSG101. CAF-derived exosomes significantly increased the viability, angiogenesis, invasion, and migration of HUVECs and CRC cells, thereby aggravating tumor growth, invasion, and angiogenesis in vivo. miR-522-3p was upregulated in CAF-derived exosomes and CRC tissues. Depletion of miR-522-3p reversed the effect of exosomes derived from CAFs in migration, angiogenesis, and invasion of HUVECs and CRC cells. Furthermore, bone morphogenetic protein 5 (BMP5) was identified as a target gene of miR-522-3p, and upregulation of BMP5 reversed the promoting effect of miR-522-3p mimics or CAF-derived exosomes on cell invasion, migration, and angiogenesis of HUVECs and CRC cells. CONCLUSION Exosomal miR-522-3p from CAFs promoted the growth and metastasis of CRC through downregulating BMP5, which might provide new strategies for the treatment of CRC.
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Affiliation(s)
- Jun Zhang
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Yuliang Pan
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Long Jin
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Huiyun Yang
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Peiguo Cao
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
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Cui Z, Amevor FK, Zhao X, Mou C, Pang J, Peng X, Liu A, Lan X, Liu L. Potential therapeutic effects of milk-derived exosomes on intestinal diseases. J Nanobiotechnology 2023; 21:496. [PMID: 38115131 PMCID: PMC10731872 DOI: 10.1186/s12951-023-02176-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/25/2023] [Indexed: 12/21/2023] Open
Abstract
Exosomes are extracellular vesicles with the diameter of 30 ~ 150 nm, and are widely involved in intercellular communication, disease diagnosis and drug delivery carriers for targeted disease therapy. Therapeutic application of exosomes as drug carriers is limited due to the lack of sources and methods for obtaining adequate exosomes. Milk contains abundant exosomes, several studies have shown that milk-derived exosomes play crucial roles in preventing and treating intestinal diseases. In this review, we summarized the biogenesis, secretion and structure, current novel methods used for the extraction and identification of exosomes, as well as discussed the role of milk-derived exosomes in treating intestinal diseases, such as inflammatory bowel disease, necrotizing enterocolitis, colorectal cancer, and intestinal ischemia and reperfusion injury by regulating intestinal immune homeostasis, restoring gut microbiota composition and improving intestinal structure and integrity, alleviating conditions such as oxidative stress, cell apoptosis and inflammation, and reducing mitochondrial reactive oxygen species (ROS) and lysosome accumulation in both humans and animals. In addition, we discussed future prospects for the standardization of milk exosome production platform to obtain higher concentration and purity, and complete exosomes derived from milk. Several in vivo clinical studies are needed to establish milk-derived exosomes as an effective and efficient drug delivery system, and promote its application in the treatment of various diseases in both humans and animals.
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Affiliation(s)
- Zhifu Cui
- College of Animal Science and Technology, Southwest University, Chongqing, P. R. China
| | - Felix Kwame Amevor
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Sichuan, P. R. China
| | - Xingtao Zhao
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan, P. R. China
| | - Chunyan Mou
- College of Animal Science and Technology, Southwest University, Chongqing, P. R. China
| | - Jiaman Pang
- College of Animal Science and Technology, Southwest University, Chongqing, P. R. China
| | - Xie Peng
- College of Animal Science and Technology, Southwest University, Chongqing, P. R. China
| | - Anfang Liu
- College of Animal Science and Technology, Southwest University, Chongqing, P. R. China
| | - Xi Lan
- College of Animal Science and Technology, Southwest University, Chongqing, P. R. China.
| | - Lingbin Liu
- College of Animal Science and Technology, Southwest University, Chongqing, P. R. China.
- College of Animal Science and Technology, Chongqing Key Laboratory of Forage & Herbivore, Chongqing Engineering Research Center for Herbivores Resource Protection and Utilization, Southwest University, Beibei, Chongqing, 400715, P. R. China.
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13
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You D, Wang Y, Xu J, Yang R, Wang W, Wang X, Cao X, Li Y, Yu L, Wang W, Shi Y, Zhang C, Yang H, He Y, Bian L. MiR-3529-3p from PDGF-BB-induced cancer-associated fibroblast-derived exosomes promotes the malignancy of oral squamous cell carcinoma. Discov Oncol 2023; 14:166. [PMID: 37668846 PMCID: PMC10480386 DOI: 10.1007/s12672-023-00753-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 07/11/2023] [Indexed: 09/06/2023] Open
Abstract
AIMS This study aims to explore the role of exosomes from cancer-associated fibroblasts (CAFs) induced by PDGF-BB in promoting the malignancy of oral squamous cell carcinoma (OSCC) and provide new insight into the mechanism of OSCC progression and its treatment. MAIN METHODS Exosomes were extracted from human oral mucosa fibroblasts (hOMFs) and CAFs. Differentially expressed miRNAs of exosomes between hOMFs and CAFs were analysed using high-throughput sequencing and self-programmed R software. Cal-27, a human tongue squamous carcinoma cell line, was treated with exosomes. Differentially expressed miRNAs between clinical cancer tissues and adjacent tissues and between hOMF and CAF exosomes were verified by qRT‒PCR. The effect of miR-3529-3p on Cal-27 cells was clarified by overexpressing or knocking down miR-3529-3p in Cal-27 cells. Sample expression and differentially expressed miRNA expression were compared between cancer and paracarcinoma tissues. KEY FINDINGS We found that exosomes from CAFs (CAF-Exos) were internalized by tongue squamous carcinoma cells and promoted their proliferation, migration, invasion, and antiapoptotic effects. MiR-3529-3p was a significant differentially expressed miRNA between CAF-Exos and exosomes from hOMFs (hOMF-Exos). The overexpression of miR-3529-3p promoted proliferation, migration, and invasion and inhibited apoptosis of Cal-27 cells. SIGNIFICANCE This study explores the role of PDGF-BB-induced CAFs in promoting malignancy in OSCC. This study will provide new insight into the mechanism of OSCC progression and its treatment.
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Affiliation(s)
- Dingyun You
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
- The Yunnan Key Laboratory of Stomatological, Kunming Medical University, Kunming, 650106 Yunnan China
| | - Yanghao Wang
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032 Yunnan China
| | - Jianguo Xu
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
- The Yunnan Key Laboratory of Stomatological, Kunming Medical University, Kunming, 650106 Yunnan China
| | - Rongqiang Yang
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
- The Yunnan Key Laboratory of Stomatological, Kunming Medical University, Kunming, 650106 Yunnan China
| | - Weizhou Wang
- Department of Orthopaedics, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032 Yunnan China
| | - Xiaofang Wang
- Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650032 Yunnan China
| | - Xue Cao
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, 650500 Yunnan China
| | - Yiting Li
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
- The Yunnan Key Laboratory of Stomatological, Kunming Medical University, Kunming, 650106 Yunnan China
| | - Lifu Yu
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
| | - Weihong Wang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
| | - Yanan Shi
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
| | - Changbin Zhang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
| | - Hefeng Yang
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
- The Yunnan Key Laboratory of Stomatological, Kunming Medical University, Kunming, 650106 Yunnan China
| | - Yongwen He
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, 650106 Yunnan China
- The Yunnan Key Laboratory of Stomatological, Kunming Medical University, Kunming, 650106 Yunnan China
- Department of Dental Research, Qujing Medical College, Qujing, 655011 Yunnan China
| | - Li Bian
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032 Yunnan China
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Wu Q, Li L, Jia Y, Xu T, Zhou X. Advances in studies of circulating microRNAs: origination, transportation, and distal target regulation. J Cell Commun Signal 2023; 17:445-455. [PMID: 36357651 PMCID: PMC9648873 DOI: 10.1007/s12079-022-00705-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 10/07/2022] [Indexed: 11/12/2022] Open
Abstract
In the past few years, numerous advances emerged in terms of circulating microRNA(miRNA) regulating gene expression by circulating blood to the distal tissues and cells. This article reviewed and summarized the process of circulating miRNAs entering the circulating system to exert gene regulation, especially exogenous miRNAs (such as plant miRNAs), from the perspective of the circulating miRNAs source (cell secretion or gastrointestinal absorption), the transport form and pharmacokinetics in circulating blood, and the evidence of distal regulation to gene expression, thereby providing a basis for their in-depth research and even application prospects.
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Affiliation(s)
- Qingni Wu
- Evidence Based Medicine Research Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China
| | - Longxue Li
- Laboratory Animal Science and Technology Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China
- Key Laboratory of Animal Model of TCM Syndromes of Depression, Jiangxi Administration of traditional Chinese Medicine, 330004, Nanchang, China
| | - Yao Jia
- Evidence Based Medicine Research Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China
| | - Tielong Xu
- Evidence Based Medicine Research Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China.
| | - Xu Zhou
- Evidence Based Medicine Research Center, Jiangxi University of Chinese Medicine, 330004, Nanchang, China.
- Key Laboratory of Drug-Targeting and Drug Delivery System of Sichuan Province, 610000, Chengdu, China.
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15
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Chen C, Yang C, Tian X, Liang Y, Wang S, Wang X, Shou Y, Li H, Xiao Q, Shu J, Sun M, Chen K. Downregulation of miR-100-5p in cancer-associated fibroblast-derived exosomes facilitates lymphangiogenesis in esophageal squamous cell carcinoma. Cancer Med 2023. [PMID: 37184125 DOI: 10.1002/cam4.6078] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 04/27/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC), an aggressive gastrointestinal tumor, often has high early lymphatic metastatic potential. Cancer-associated fibroblasts (CAFs) are primary components in tumor microenvironment (TME), and the impact of CAFs and its derived exosomes on lymphangiogenesis remains elusive. MATERIALS AND METHODS CAFs and the microlymphatic vessel density (MLVD) in ESCC was examined. Exosomes were extracted from primary normal fibroblast (NFs) and CAFs. Subsequently, tumor-associated lymphatic endothelial cells (TLECs) were treated with these exosomes, and the effect on their biological behavior was examined. miR-100-5p was selected as the target miRNA, and its effect on TLECs was examined. The target of miR-100-5p was predicted and confirmed. Subsequently, IGF1R, PI3K, AKT, and p-AKT expression in TLECs and tumors treated with exosomes and miR-100-5p were examined. RESULTS A large number of CAFs and microlymphatic vessels were present in ESCC, leading to a poor prognosis. CAF-derived exosomes promoted proliferation, migration, invasion, and tube formation in TLECs. Further, they also enhanced lymphangiogenesis in ESCC xenografts. miR-100-5p levels were significantly lower in CAF-derived exosomes than in NF-derived exosomes. miR-100-5p inhibited proliferation, migration, invasion, and tube formation in TLECs. Further, miR-100-5p inhibited lymphangiogenesis in ESCC xenografts. Mechanistic studies revealed that this inhibition was mediated by the miR-100-5p-induced inhibition of IGF1R/PI3K/AKT axis. CONCLUSION Taken together, our study demonstrates that CAF-derived exosomes with decreased miR-100-5p levels exhibit pro-lymphangiogenesis capacity, suggesting a possibility of targeting IGF1R/PI3K/AKT axis as a strategy to inhibit lymphatic metastasis in ESCC.
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Affiliation(s)
- Chao Chen
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chenbo Yang
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiangyu Tian
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Osteology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yinghao Liang
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Shuaiyuan Wang
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoqian Wang
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuwei Shou
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hui Li
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
| | - Qiankun Xiao
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
| | - Jiao Shu
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Miaomiao Sun
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Kuisheng Chen
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Tumor Pathology, Zhengzhou University, Zhengzhou, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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16
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Yang Q, Wang B, Zheng Q, Li H, Meng X, Zhou F, Zhang L. A Review of Gut Microbiota-Derived Metabolites in Tumor Progression and Cancer Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207366. [PMID: 36951547 PMCID: PMC10214247 DOI: 10.1002/advs.202207366] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/15/2023] [Indexed: 05/27/2023]
Abstract
Gut microbiota-derived metabolites are key hubs connecting the gut microbiome and cancer progression, primarily by remodeling the tumor microenvironment and regulating key signaling pathways in cancer cells and multiple immune cells. The use of microbial metabolites in radiotherapy and chemotherapy mitigates the severe side effects from treatment and improves the efficacy of treatment. Immunotherapy combined with microbial metabolites effectively activates the immune system to kill tumors and overcomes drug resistance. Consequently, various novel strategies have been developed to modulate microbial metabolites. Manipulation of genes involved in microbial metabolism using synthetic biology approaches directly affects levels of microbial metabolites, while fecal microbial transplantation and phage strategies affect levels of microbial metabolites by altering the composition of the microbiome. However, some microbial metabolites harbor paradoxical functions depending on the context (e.g., type of cancer). Furthermore, the metabolic effects of microorganisms on certain anticancer drugs such as irinotecan and gemcitabine, render the drugs ineffective or exacerbate their adverse effects. Therefore, a personalized and comprehensive consideration of the patient's condition is required when employing microbial metabolites to treat cancer. The purpose of this review is to summarize the correlation between gut microbiota-derived metabolites and cancer, and to provide fresh ideas for future scientific research.
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Affiliation(s)
- Qiqing Yang
- General SurgeryCancer CenterDepartment of Breast SurgeryZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)Hangzhou310058China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Bin Wang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Qinghui Zheng
- General SurgeryCancer CenterDepartment of Breast SurgeryZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)Hangzhou310058China
| | - Heyu Li
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Xuli Meng
- General SurgeryCancer CenterDepartment of Breast SurgeryZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)Hangzhou310058China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
- International Biomed‐X Research CenterSecond Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhou310058China
- Center for Infection & Immunity of International Institutes of Medicine The Fourth Affiliated HospitalZhejiang University School of MedicineYiwu322000China
- Cancer CenterZhejiang UniversityHangzhou310058China
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Zhang Z, He C, Bao C, Li Z, Jin W, Li C, Chen Y. MiRNA Profiling and Its Potential Roles in Rapid Growth of Velvet Antler in Gansu Red Deer ( Cervus elaphus kansuensis). Genes (Basel) 2023; 14:424. [PMID: 36833351 PMCID: PMC9957509 DOI: 10.3390/genes14020424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
A significant variety of cell growth factors are involved in the regulation of antler growth, and the fast proliferation and differentiation of various tissue cells occur during the yearly regeneration of deer antlers. The unique development process of velvet antlers has potential application value in many fields of biomedical research. Among them, the nature of cartilage tissue and the rapid growth and development process make deer antler a model for studying cartilage tissue development or rapid repair of damage. However, the molecular mechanisms underlying the rapid growth of antlers are still not well studied. MicroRNAs are ubiquitous in animals and have a wide range of biological functions. In this study, we used high-throughput sequencing technology to analyze the miRNA expression patterns of antler growth centers at three distinct growth phases, 30, 60, and 90 days following the abscission of the antler base, in order to determine the regulatory function of miRNA on the rapid growth of antlers. Then, we identified the miRNAs that were differentially expressed at various growth stages and annotated the functions of their target genes. The results showed that 4319, 4640, and 4520 miRNAs were found in antler growth centers during the three growth periods. To further identify the essential miRNAs that could regulate fast antler development, five differentially expressed miRNAs (DEMs) were screened, and the functions of their target genes were annotated. The results of KEGG pathway annotation revealed that the target genes of the five DEMs were significantly annotated to the "Wnt signaling pathway", "PI3K-Akt signaling pathway", "MAPK signaling pathway", and "TGF-β signaling pathway", which were associated with the rapid growth of velvet antlers. Therefore, the five chosen miRNAs, particularly ppy-miR-1, mmu-miR-200b-3p, and novel miR-94, may play crucial roles in rapid antler growth in summer.
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Affiliation(s)
- Zhenxiang Zhang
- Qinghai Provincial Key Laboratory of Adaptive Management on Alpine Grassland, Academy of Animal Science and Veterinary Medicine, Qinghai University, Xining 810016, China
- College of Eco–Environmental Engineering, Qinghai University, Xining 810016, China
| | - Caixia He
- College of Eco–Environmental Engineering, Qinghai University, Xining 810016, China
| | - Changhong Bao
- College of Eco–Environmental Engineering, Qinghai University, Xining 810016, China
| | - Zhaonan Li
- College of Eco–Environmental Engineering, Qinghai University, Xining 810016, China
| | - Wenjie Jin
- College of Eco–Environmental Engineering, Qinghai University, Xining 810016, China
| | - Changzhong Li
- College of Eco–Environmental Engineering, Qinghai University, Xining 810016, China
| | - Yanxia Chen
- College of Eco–Environmental Engineering, Qinghai University, Xining 810016, China
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Yuan H, Chen B, Chai R, Gong W, Wan Z, Zheng B, Hu X, Guo Y, Gao S, Dai Q, Yu P, Tu S. Loss of exosomal micro-RNA-200b-3p from hypoxia cancer-associated fibroblasts reduces sensitivity to 5-flourouracil in colorectal cancer through targeting high-mobility group box 3. Front Oncol 2022; 12:920131. [PMID: 36276139 PMCID: PMC9581251 DOI: 10.3389/fonc.2022.920131] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 09/09/2022] [Indexed: 11/24/2022] Open
Abstract
Hypoxia-mediated tumor progression is a major problem in colorectal cancer (CRC). MicroRNA (miR)-200b-3p can attenuate tumorigenesis in CRC, while exosomal miRNAs derived from cancer-associated fibroblasts (CAFs) can promote cancer progression. Nevertheless, the function of exosomal miR-200b-3p derived from CAFs in CRC remains unclear. In this study, CAFs and normal fibroblasts (NFs) were isolated from CRC and adjacent normal tissues. Next, exosomes were isolated from the supernatants of CAFs cultured under normoxia and hypoxia. Cell viability was tested using the cell counting kit-8 assay, and flow cytometry was used to assess cell apoptosis. Cell invasion and migration were evaluated using the transwell assay. Dual-luciferase was used to investigate the relationship between miR-200b-3p and high-mobility group box 3 (HMBG3). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the miR-200b-3p and HMBG3 level. Our results found that the miR-200b-3p level was sharply reduced in CRC tissues compared to adjacent normal tissues. Additionally, the miR-200b-3p level was reduced in exosomes derived from hypoxic CAFs compared to exosomes derived from CAFs under normoxia. Exosomes derived from hypoxic CAFs weakened the sensitivity of CRC cells to 5-fluorouracil (5-FU) compared to hypoxic CAFs-derived exosomes. However, hypoxic CAFs-derived exosomes with upregulated miR-200b-3p increased the sensitivity of CRC cells to 5-fluorouracil (5-FU) compared to hypoxic CAFs-derived exosomes. In addition, HMBG3 was identified as the downstream target of miR-200b-3p in CRC cells, and its overexpression partially reversed the anti-tumor effect of the miR-200b-3p agomir on CRC via the mediation of the β-catenin/c-Myc axis. Furthermore, compared to exosomes derived from normoxia CAFs, exosomes derived from hypoxic CAFs weakened the therapeutic effects of 5-FU on CRC in vivo via the upregulation of HMGB3 levels. Collectively, the loss of exosomal miR-200b-3p in hypoxia CAFs reduced the sensitivity to 5-FU in CRC by targeting HMGB3. Thus, our research outlines a novel method for the treatment of CRC.
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Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
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Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
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20
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Cui G, Wang C, Liu J, Shon K, Gu R, Chang C, Ren L, Wei F, Sun Z. Development of an exosome-related and immune microenvironment prognostic signature in colon adenocarcinoma. Front Genet 2022; 13:995644. [PMID: 36176299 PMCID: PMC9513147 DOI: 10.3389/fgene.2022.995644] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The correlation between exosomes and the tumor immune microenvironment has been proved to affect tumorigenesis and progression of colon adenocarcinoma (COAD). However, it remained unclear whether exosomes had an impact on the prognostic indications of COAD patients.Methods: Expression of exosome-related genes (ERGs) and clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The ERGs associated with prognosis were identified and exosome-related prognostic signature was constructed. Patients in two risk groups were classified according to the risk score calculation formula: Risk score = 1.0132 * CCKBR + 0.2416 * HOXC6 + 0.7618 * POU4F1. The expression of three ERGs was investigated by qRT-PCR. After that, we developed a nomogram predicting the likelihood of survival and verified its predictive efficiency. The differences of tumor immune microenvironment, immune cell infiltration, immune checkpoint and sensitivity to drugs in two risk groups were analyzed.Results: A prognostic signature was established based on the three ERGs (CCKBR, HOXC6, and POU4F1) and patients with different risk group were distinguished. Survival analysis revealed the negative associated of risk score and prognosis, ROC curve analyses showed the accuracy of this signature. Three ERGs expression was investigated by qRT-PCR in three colorectal cancer cell lines. Moreover, risk score was positively correlated with tumor mutational burden (TMB), immune activities, microsatellite instability level, the expression of immune checkpoint genes. Meanwhile, the expression level of three ERGs and the risk score were markedly related with the sensitive response to chemotherapy.Conclusion: The novel signature composed of three ERGs with precise predictive capabilities can be used to predict prognosis and provide a promising therapeutic target for improving the efficacy of immunotherapy.
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Affiliation(s)
- Guoliang Cui
- Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Can Wang
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kinyu Shon
- Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- *Correspondence: Fei Wei, ; Zhiguang Sun,
| | - Renjun Gu
- School of Traditional Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Cheng Chang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Lang Ren
- Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Fei Wei
- Department of Physiology, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- *Correspondence: Fei Wei, ; Zhiguang Sun,
| | - Zhiguang Sun
- Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- *Correspondence: Fei Wei, ; Zhiguang Sun,
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21
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The Exosome Journey: From Biogenesis to Regulation and Function in Cancers. JOURNAL OF ONCOLOGY 2022; 2022:9356807. [PMID: 35898929 PMCID: PMC9313905 DOI: 10.1155/2022/9356807] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/01/2022] [Accepted: 06/20/2022] [Indexed: 12/26/2022]
Abstract
Exosomes are a type of small endosomal-derived vesicles ranging from 30 to 150 nm, which can serve as functional mediators in cell-to-cell communication and various physiological and pathological processes. In recent years, exosomes have emerged as crucial mediators of intracellular communication among tumor cells, immune cells, and stromal cells, which can shuttle bioactive molecules, such as proteins, lipids, RNA, and DNA. Exosomes exhibit the high bioavailability, biological stability, targeting specificity, low toxicity, and immune characteristics, suggesting their potentials in the diagnosis and treatment of cancers. They can be applied as an effective tool in the diagnostics, therapeutics, and drug delivery in cancers. This review summarizes the regulation and functions of exosomes in various cancers to augment our understanding of exosomes, which paves the way for parallel advancements in the therapeutic approach of cancers. In this review, we also discuss the challenges and prospects for clinical application of exosome-based diagnostics and therapeutics for cancers.
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22
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Mitchell MI, Ma J, Carter CL, Loudig O. Circulating Exosome Cargoes Contain Functionally Diverse Cancer Biomarkers: From Biogenesis and Function to Purification and Potential Translational Utility. Cancers (Basel) 2022; 14:3350. [PMID: 35884411 PMCID: PMC9318395 DOI: 10.3390/cancers14143350] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/01/2022] [Accepted: 07/07/2022] [Indexed: 12/12/2022] Open
Abstract
Although diagnostic and therapeutic treatments of cancer have tremendously improved over the past two decades, the indolent nature of its symptoms has made early detection challenging. Thus, inter-disciplinary (genomic, transcriptomic, proteomic, and lipidomic) research efforts have been focused on the non-invasive identification of unique "silver bullet" cancer biomarkers for the design of ultra-sensitive molecular diagnostic assays. Circulating tumor biomarkers, such as CTCs and ctDNAs, which are released by tumors in the circulation, have already demonstrated their clinical utility for the non-invasive detection of certain solid tumors. Considering that exosomes are actively produced by all cells, including tumor cells, and can be found in the circulation, they have been extensively assessed for their potential as a source of circulating cell-specific biomarkers. Exosomes are particularly appealing because they represent a stable and encapsulated reservoir of active biological compounds that may be useful for the non-invasive detection of cancer. T biogenesis of these extracellular vesicles is profoundly altered during carcinogenesis, but because they harbor unique or uniquely combined surface proteins, cancer biomarker studies have been focused on their purification from biofluids, for the analysis of their RNA, DNA, protein, and lipid cargoes. In this review, we evaluate the biogenesis of normal and cancer exosomes, provide extensive information on the state of the art, the current purification methods, and the technologies employed for genomic, transcriptomic, proteomic, and lipidomic evaluation of their cargoes. Our thorough examination of the literature highlights the current limitations and promising future of exosomes as a liquid biopsy for the identification of circulating tumor biomarkers.
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Affiliation(s)
- Megan I Mitchell
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Junfeng Ma
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
| | - Claire L Carter
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Olivier Loudig
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
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23
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Lou C, Shi J, Xu Q. Exosomal miR-626 promotes the malignant behavior of oral cancer cells by targeting NFIB. Mol Biol Rep 2022; 49:4829-4840. [PMID: 35711020 DOI: 10.1007/s11033-022-07336-x] [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: 10/13/2021] [Revised: 03/02/2022] [Accepted: 03/04/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Tumor-derived exosomes, as emerging regulators of intercellular communication, are important for tumorigenesis and development in multiple tumors. The purpose of this study was to investigate whether exosomal miR-626 exists. More importantly, if exosomal miR-626 exists, the mechanism by which it is transferred into neighboring cancer cells and contributes to tumor progression needs to be clarified. METHODS AND RESULTS The expression of miRNA and mRNA are analyzed by RT-qPCR. Proliferation, colony formation, wound healing, cell cycle are carried out to assess the function of exosomal miR-626. Furthermore, a xenograft experiment is utilized to conform the cancer-promoting role of exosomal miR-626 in oral cancer. Here, we showed that miR-626 is upregulated in oral cancer-derived exosomes and can be transferred between oral cancer cells. Exosomal miR-626 promotes cancer cell proliferation, colony formation, migration and G0/G1-to-S phase transition. Nuclear factor I/B (NFIB), a tumor suppressor gene in various cancers, was predicted to be a potential target of miR-626 by using three algorithms. Luciferase reporter assay data revealed that miR-626 can directly bind to the 3'-UTR of NFIB and subsequently suppress its expression and downstream signaling. Restoration of NFIB expression rescued the malignant phenotype induced by exosomal miR-626. In addition, exosomal miR-626 administration facilitated cancer growth in a xenograft tumor model, accompanied by downregulation of NFIB expression. CONCLUSIONS Our data demonstrate that exosomal miR-626 can facilitate the development of oral cancer by inhibiting the expression of its target NFIB. Exosomal miR-626 might be a therapeutic target for oral cancer.
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Affiliation(s)
- Chao Lou
- Department of Oral and Maxillofacial-Head Neck Oncology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road 639, 200011, Shanghai, China
| | - Jianbo Shi
- Department of Oral and Maxillofacial-Head Neck Oncology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road 639, 200011, Shanghai, China.
| | - Qin Xu
- Department of Oral and Maxillofacial-Head Neck Oncology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road 639, 200011, Shanghai, China.
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24
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Dai L, Chen X, Zhang H, Zeng H, Yin Z, Ye Z, Wei Y. RND3 Transcriptionally Regulated by FOXM1 Inhibits the Migration and Inflammation of Synovial Fibroblasts in Rheumatoid Arthritis Through the Rho/ROCK Pathway. J Interferon Cytokine Res 2022; 42:279-289. [PMID: 35699481 DOI: 10.1089/jir.2021.0228] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic immune disease. Rho family GTPase 3 (RND3) has been reported to play an important role in inflammatory diseases. In this study, the expression of RND3 in RA was analyzed by gene chips. After RND3 was overexpressed, cell counting kit-8 assay was to detect the viability of fibroblast-like synovial cells (RA-FLSs). Transwell assays were to appraise the migratory and invasive capacities of RA-FLSs. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were to estimate inflammatory response. In addition, MMP3 and MMP9 levels were also tested by ELISA analysis. After forkhead box M1 (FOXM1) was overexpressed, RND3 expression was detected by Western blot. The transcriptional relationship between FOXM1 and RND3 was predicted by HumanTFDB and JASPAR databases. Luciferase reporter and chromatin immunoprecipitation assays verified the binding ability of FOXM1 and RND3. The role of FOXM1/RND3 axis in RA was detected again by functional experiments. Western blot detected the expression of Rho/ROCK pathway-related proteins. RND3 expression was downregulated in RA. Overexpression of RND3 reduced the proliferation, migration, invasion, and inflammation of RA-FLSs. RND3 was inhibited by FOXM1 transcription, and upregulated FOXM1 reduced the inhibitory effect of RND3 overexpression on cell growth and inflammation, which might be associated with the Rho/ROCK pathway. RND3 transcriptionally regulated by FOXM1 inhibited the migration and inflammation of RA-FLSs in RA through the Rho/ROCK pathway.
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Affiliation(s)
- Liping Dai
- Department of Rheumatology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Xinpeng Chen
- Department of Rheumatology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Huichang Zhang
- Department of Rheumatology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Huiqiong Zeng
- Department of Rheumatology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Zhihua Yin
- Department of Rheumatology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Zhizhong Ye
- Department of Rheumatology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Yazhi Wei
- Department of Rheumatology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
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25
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Rodrigues-Junior DM, Tsirigoti C, Lim SK, Heldin CH, Moustakas A. Extracellular Vesicles and Transforming Growth Factor β Signaling in Cancer. Front Cell Dev Biol 2022; 10:849938. [PMID: 35493080 PMCID: PMC9043557 DOI: 10.3389/fcell.2022.849938] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Complexity in mechanisms that drive cancer development and progression is exemplified by the transforming growth factor β (TGF-β) signaling pathway, which suppresses early-stage hyperplasia, yet assists aggressive tumors to achieve metastasis. Of note, several molecules, including mRNAs, non-coding RNAs, and proteins known to be associated with the TGF-β pathway have been reported as constituents in the cargo of extracellular vesicles (EVs). EVs are secreted vesicles delimited by a lipid bilayer and play critical functions in intercellular communication, including regulation of the tumor microenvironment and cancer development. Thus, this review aims at summarizing the impact of EVs on TGF-β signaling by focusing on mechanisms by which EV cargo can influence tumorigenesis, metastatic spread, immune evasion and response to anti-cancer treatment. Moreover, we emphasize the potential of TGF-β-related molecules present in circulating EVs as useful biomarkers of prognosis, diagnosis, and prediction of response to treatment in cancer patients.
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Affiliation(s)
| | - Chrysoula Tsirigoti
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology (A*-STAR), Singapore, Singapore
| | - Carl-Henrik Heldin
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- *Correspondence: Aristidis Moustakas,
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26
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Exosomal LINC01213 Plays a Role in the Transition of Androgen-Dependent Prostate Cancer Cells into Androgen-Independent Manners. JOURNAL OF ONCOLOGY 2022; 2022:8058770. [PMID: 35310913 PMCID: PMC8930242 DOI: 10.1155/2022/8058770] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/17/2022] [Indexed: 11/23/2022]
Abstract
Background Castration-resistant prostate cancer (CRPC), one of the prostate cancers, is a medical conundrum around the world. Some studies have demonstrated that many long noncoding RNAs in exosomes are very important in many types of cancer, including prostate cancer. However, until now, the function of exosomes in the occurrence and development of CRPC has not been reported. Methods In vitro, cell coculture was used in LNCap cells and PC-3 cells, while the isolation and purification of exosomes and the subsequent treatment assays were used in functional studies. In vitro assays were performed to detect the transformation of ADPC cells (androgen-dependent prostate cancer) into AIPC cells (androgen-independent prostate cancer). Subsequently, a lncRNA-sequencing assay was performed to detect different lncRNA expression profiles in ADPC cells cocultured with or without AIPC exosomes. The role of LINC01213 was analysed by a TCGA database after silencing the expression of LINC01213. CCK-8, qRT-PCR, and Western blotting studies were performed to analyse the possible mechanism by which exosomes participate in prostate cancer progression. Results In the coculture system, ADPC cells acquired androgen deprivation tolerance through exosome-mediated intercellular communication. Exosomes secreted by AIPC cells can promote the transformation of ADPC cells into androgen-independent cells in vitro and in vivo. lncRNA sequencing showed that LINC01213 was upregulated in exosomes derived from AIPC cell lines. The rescue experiments were preformed, and the results revealed that most of the functions of LINC01213 were performed by Wnt/β-catenin. Conclusions All the findings showed that exosomes play a key role in CRPC progression by upregulating LINC01213 and activating Wnt/β-catenin signalling.
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27
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Wang X, Cui Z, Zeng B, Qiong Z, Long Z. Human mesenchymal stem cell derived exosomes inhibit the survival of human melanoma cells through modulating miR-138-5p/SOX4 pathway. Cancer Biomark 2022; 34:533-543. [PMID: 35275523 DOI: 10.3233/cbm-210409] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Melanoma, a skin cancer derived from malignant melanocytes, is characterized by high aggressiveness and mortality. However, its exact etiology is unknown. Recently, the roles of exosomes and exosomal microRNAs (miRNAs) in the progression and therapy of various disorders, including melanoma, have gained attention. We investigated the impact of miR-138-5p from exosomes released by human mesenchymal stem cells (HMSCs) on the pathogenesis of melanoma. We isolated exosomes from HMSCs (HMSC-exos) by ultracentrifugation and verified them by specific biomarkers and transmission electron microscopy. We used CCK8, flow cytometry, quantitative real-time PCR (qRT-PCR), and Western blots to investigate cell proliferation, apoptosis, and mRNA and protein levels, respectively. Additionally, we used luciferase assays to examine the relationship between miR-138-5p and SOX4. Administration of HMSC-exos dramatically repressed the growth of melanoma cells. Elevated miR-138-5p levels in HMSC-exos were linked to increased cell apoptosis, and miR-138-5p downregulation had the opposite effects on cells. SOX4 was targeted by miR-138-5p through direct binding to the SOX4 3'UTR. In melanoma tissues, miR-138-5p was downregulated, and SOX4 was upregulated and was negatively correlated. MiR-138-5p plays a crucial role in melanoma progression. The negative regulation of SOX4 transcription mediates the function of miR-138-5p. These findings provide a novel concept of melanoma pathogenesis and identify a valuable target (miR-138-5p/SOX4 axis) in treating this disease.
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Affiliation(s)
- Xinhua Wang
- Department of Dermatology, Shigatse People's Hospital, Shigatse, The Tibet Autonomous Region, China.,Department of Dermatology, Shigatse People's Hospital, Shigatse, The Tibet Autonomous Region, China
| | - Zhengfeng Cui
- Department of Medical and Political Science, Shigatse People's Hospital, Shigatse, The Tibet Autonomous Region, China.,Department of Dermatology, Shigatse People's Hospital, Shigatse, The Tibet Autonomous Region, China
| | - Basangdan Zeng
- Department of Medical and Political Science, Shigatse People's Hospital, Shigatse, The Tibet Autonomous Region, China
| | - Zhaxi Qiong
- Department of Medical and Political Science, Shigatse People's Hospital, Shigatse, The Tibet Autonomous Region, China
| | - Ziwen Long
- Department of Gastric Cancer Sugery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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28
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Jiang P, Ma X, Han S, Ma L, Ai J, Wu L, Zhang Y, Xiao H, Tian M, Tao WA, Zhang S, Chai R. Characterization of the microRNA transcriptomes and proteomics of cochlear tissue-derived small extracellular vesicles from mice of different ages after birth. Cell Mol Life Sci 2022; 79:154. [PMID: 35218422 PMCID: PMC11072265 DOI: 10.1007/s00018-022-04164-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 12/30/2021] [Accepted: 01/23/2022] [Indexed: 12/22/2022]
Abstract
The cochlea is an important sensory organ for both balance and sound perception, and the formation of the cochlea is a complex developmental process. The development of the mouse cochlea begins on embryonic day (E)9 and continues until postnatal day (P)21 when the hearing system is considered mature. Small extracellular vesicles (sEVs), with a diameter ranging from 30 to 200 nm, have been considered a significant medium for information communication in both physiological and pathological processes. However, there are no studies exploring the role of sEVs in the development of the cochlea. Here, we isolated tissue-derived sEVs from the cochleae of FVB mice at P3, P7, P14, and P21 by ultracentrifugation. These sEVs were first characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Next, we used small RNA-seq and mass spectrometry to characterize the microRNA transcriptomes and proteomes of cochlear sEVs from mice at different ages. Many microRNAs and proteins were discovered to be related to inner ear development, anatomical structure development, and auditory nervous system development. These results all suggest that sEVs exist in the cochlea and are likely to be essential for the normal development of the auditory system. Our findings provide many sEV microRNA and protein targets for future studies of the roles of cochlear sEVs.
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Affiliation(s)
- Pei Jiang
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Xiangyu Ma
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Shanying Han
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Leyao Ma
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Jingru Ai
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Leilei Wu
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Yuan Zhang
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Hairong Xiao
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Mengyao Tian
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - W Andy Tao
- Department of Chemistry, Department of Biochemistry, Purdue University, West Lafayette, Indiana, 47907, USA.
- Center for Cancer Research, Purdue University, West Lafayette, Indiana, 47907, USA.
| | - Shasha Zhang
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
| | - Renjie Chai
- State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
- Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China.
- Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, 100069, China.
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Jahan S, Mukherjee S, Ali S, Bhardwaj U, Choudhary RK, Balakrishnan S, Naseem A, Mir SA, Banawas S, Alaidarous M, Alyenbaawi H, Iqbal D, Siddiqui AJ. Pioneer Role of Extracellular Vesicles as Modulators of Cancer Initiation in Progression, Drug Therapy, and Vaccine Prospects. Cells 2022; 11:490. [PMID: 35159299 PMCID: PMC8833976 DOI: 10.3390/cells11030490] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs' role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools.
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Affiliation(s)
- Sadaf Jahan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Shouvik Mukherjee
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Shaheen Ali
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Urvashi Bhardwaj
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Ranjay Kumar Choudhary
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Santhanaraj Balakrishnan
- Medical Equipment Technology, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Asma Naseem
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Shabir Ahmad Mir
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Saeed Banawas
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
- Department of Biomedical Sciences, Oregon State University, Corvallis, OR 97331, USA
| | - Mohammed Alaidarous
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Hadeel Alyenbaawi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Danish Iqbal
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Arif Jamal Siddiqui
- Department of Biology, College of Science, University of Hail, Hail 81451, Saudi Arabia
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He G, Peng X, Wei S, Yang S, Li X, Huang M, Tang S, Jin H, Liu J, Zhang S, Zheng H, Fan Q, Liu J, Yang L, Li H. Exosomes in the hypoxic TME: from release, uptake and biofunctions to clinical applications. Mol Cancer 2022; 21:19. [PMID: 35039054 PMCID: PMC8762953 DOI: 10.1186/s12943-021-01440-5] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 10/02/2021] [Indexed: 02/06/2023] Open
Abstract
Hypoxia is a remarkable trait of the tumor microenvironment (TME). When facing selective pressure, tumor cells show various adaptive characteristics, such as changes in the expression of cancer hallmarks (increased proliferation, suppressed apoptosis, immune evasion, and so on) and more frequent cell communication. Because of the adaptation of cancer cells to hypoxia, exploring the association between cell communication mediators and hypoxia has become increasingly important. Exosomes are important information carriers in cell-to-cell communication. Abundant evidence has proven that hypoxia effects in the TME are mediated by exosomes, with the occasional formation of feedback loops. In this review, we equally focus on the biogenesis and heterogeneity of cancer-derived exosomes and their functions under hypoxia and describe the known and potential mechanism ascribed to exosomes and hypoxia. Notably, we call attention to the size change of hypoxic cancer cell-derived exosomes, a characteristic long neglected, and propose some possible effects of this size change. Finally, jointly considering recent developments in the understanding of exosomes and tumors, we describe noteworthy problems in this field that urgently need to be solved for better research and clinical application.
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Affiliation(s)
- Guangpeng He
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shibo Wei
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shuo Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Mingyao Huang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shilei Tang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Hongyuan Jin
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Sheng Zhang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Hongyu Zheng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Qing Fan
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Jingang Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
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Dang Y, Zhang S, Wang Y, Zhao G, Chen C, Jiang W. State-of-the-Art: Exosomes in Colorectal Cancer. Curr Cancer Drug Targets 2021; 22:2-17. [PMID: 34758717 DOI: 10.2174/1568009621666211110094442] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/06/2021] [Accepted: 09/09/2021] [Indexed: 11/22/2022]
Abstract
Colorectal cancer (CRC) has a high prevalence and mortality rate, globally. To date, the progression mechanisms of CRC are still elusive. Exosomes (~100 nm in diameter) correspond to a subset of extracellular vesicles formed by an array of cancerous cells and stromal cells. These particular nanovesicles carry and transmit bioactive molecules, like proteins, lipids, and genetic materials, which mediate the crosstalk between cancer cells and the microenvironment. Accumulating evidence has shown the decisive functions of exosomes in the development, metastasis, and therapy resistance of CRC. Furthermore, some recent studies have also revealed the abilities of exosomes to function as either biomarkers or therapeutic targets for CRC. This review focuses on the specific mechanisms of exosomes in regulating CRC progression, and summarizes the potential clinical applications of exosomes in the diagnosis and therapy of CRC.
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Affiliation(s)
- Yan Dang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Yongjun Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Guiping Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Chuyan Chen
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
| | - Wei Jiang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing. China
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Zhang Y, Li W, Li H, Zhou M, Zhang J, Fu Y, Zhang C, Sun X. Circ_USP36 Silencing Attenuates Oxidized Low-Density Lipoprotein-Induced Dysfunction in Endothelial Cells in Atherosclerosis Through Mediating miR-197-3p/ROBO1 Axis. J Cardiovasc Pharmacol 2021; 78:e761-e772. [PMID: 34369900 DOI: 10.1097/fjc.0000000000001124] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/15/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Circular RNAs (circRNAs) are reported to play pivotal regulatory roles in atherosclerosis progression. In the present study, we explored the biological role of circRNA ubiquitin-specific peptidase 36 (circ_USP36; hsa_circ_0003204) in oxidized low-density lipoprotein (ox-LDL)-induced dysfunction of endothelial cells (ECs). RNA and protein levels were determined by reverse transcription-quantitative polymerase chain reaction and Western blot assay, respectively. Cell proliferation was analyzed by 5-ethynyl-2'-deoxyuridine assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry was conducted to analyze cell cycle progression and cell apoptosis. The release of tumor necrosis factor α in the supernatant was measured by enzyme linked immunosorbent assay. Cell death was evaluated by lactate dehydrogenase assay. Intermolecular interaction was verified by dual-luciferase reporter assay. Circ_USP36 expression was significantly up-regulated in the serum of atherosclerosis patients and ox-LDL-stimulated HUVECs than that in their corresponding controls. ox-LDL exposure inhibited the proliferation ability and cell cycle progression and triggered the apoptosis and inflammation of HUVECs, and these effects were largely overturned by the knockdown of circ_USP36. microRNA-197-3p (miR-197-3p) was a target of circ_USP36, and circ_USP36 knockdown-mediated protective role in ox-LDL-induced HUVECs was largely counteracted by the silence of miR-197-3p. miR-197-3p interacted with the 3' untranslated region of roundabout guidance receptor 1 (ROBO1). Circ_USP36 knockdown reduced ROBO1 expression partly by up-regulating miR-197-3p in HUVECs. ROBO1 overexpression reversed miR-197-3p accumulation-mediated effects in ox-LDL-induced HUVECs. In conclusion, circ_USP36 interference alleviated ox-LDL-induced dysfunction in HUVECs by targeting miR-197-3p/ROBO1 axis.
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Affiliation(s)
- Yixin Zhang
- Department of Endocrinology, the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar City, Heilongjiang, China; and
| | - Wenhua Li
- Department of Cardiovascular Medicine, the Third Affiliated Hospital of Qiqihar Medical University, Qiqihar City, Heilongjiang, China
| | - Hui Li
- Department of Endocrinology, the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar City, Heilongjiang, China; and
| | - Min Zhou
- Department of Endocrinology, the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar City, Heilongjiang, China; and
| | - Jian Zhang
- Department of Endocrinology, the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar City, Heilongjiang, China; and
| | - Yongli Fu
- Department of Endocrinology, the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar City, Heilongjiang, China; and
| | - Chunhui Zhang
- Department of Endocrinology, the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar City, Heilongjiang, China; and
| | - Xiaozhu Sun
- Department of Endocrinology, the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar City, Heilongjiang, China; and
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Scavo MP, Rizzi F, Depalo N, Armentano R, Coletta S, Serino G, Fanizza E, Pesole PL, Cervellera A, Carella N, Curri ML, Giannelli G. Exosome Released FZD10 Increases Ki-67 Expression via Phospho-ERK1/2 in Colorectal and Gastric Cancer. Front Oncol 2021; 11:730093. [PMID: 34671555 PMCID: PMC8522497 DOI: 10.3389/fonc.2021.730093] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 09/03/2021] [Indexed: 12/18/2022] Open
Abstract
Frizzled (FZD) proteins are primary receptors for Wnt signaling that activates the mitogen-activated protein kinase (MAPK) pathways. Dysfunction of Wnt signals with consequently abnormal activation of MAPK3 pathways was found in colorectal cancer (CRC) and gastric cancer (GC). Upregulation of FZD10 protein, localized in the exosomes isolated from plasma of CRC and GC patients, was associated with a poor prognosis. Herein, the expression levels of circulating FZD10 were found to be strongly correlated to their expression levels in the corresponding tissues in CRC and GC patients. Bioinformatic prediction revealed a link between FZD10 and Ki-67 through MAPK3. In both CRC and GC tissues, pERK1/2 levels were significantly increased at more advanced disease stages, and pERK1/2 and Ki-67 were correlated. Silencing of FZD10 in CRC and GC cells resulted in a significant reduction of pERK1/2 and Ki-67 expression, while subsequent treatment with exogenous exosomes partially restored their expression levels. The strong correlation between the expression of Ki-67 in tissues and of FZD10 in exosomes suggests that the exosome-delivered FZD10 may be a promising novel prognostic and diagnostic biomarker for CRC and GC.
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Affiliation(s)
- Maria Principia Scavo
- Personalized Medicine Laboratory, National Institute of Gastroenterology “S. De Bellis” Research Hospital, Bari, Italy
| | - Federica Rizzi
- University of Bari “A. Moro,” Chemistry Department, Bari, Italy
- Institute for Chemical–Physical Processes (IPCF)–National Research Council Secondary Site (CNR SS) Bari, Bari, Italy
| | - Nicoletta Depalo
- Institute for Chemical–Physical Processes (IPCF)–National Research Council Secondary Site (CNR SS) Bari, Bari, Italy
| | - Raffaele Armentano
- Department of Pathology, National Institute of Gastroenterology “S. de Bellis,” Research Hospital, Bari, Italy
| | - Sergio Coletta
- Department of Pathology, National Institute of Gastroenterology “S. de Bellis,” Research Hospital, Bari, Italy
| | - Grazia Serino
- Experimental Immunopathology Laboratory, National Institute of Gastroenterology “S. de Bellis,” Research Hospital, Bari, Italy
| | - Elisabetta Fanizza
- University of Bari “A. Moro,” Chemistry Department, Bari, Italy
- Institute for Chemical–Physical Processes (IPCF)–National Research Council Secondary Site (CNR SS) Bari, Bari, Italy
| | - Pasqua Letizia Pesole
- Laboratory of Clinical Pathology, National Institute of Gastroenterology, “S de Bellis” Research Hospital, Bari, Italy
| | - Alessandra Cervellera
- Laboratory of Clinical Pathology, National Institute of Gastroenterology, “S de Bellis” Research Hospital, Bari, Italy
| | - Nicola Carella
- Laboratory of Clinical Pathology, National Institute of Gastroenterology, “S de Bellis” Research Hospital, Bari, Italy
| | - Maria Lucia Curri
- University of Bari “A. Moro,” Chemistry Department, Bari, Italy
- Institute for Chemical–Physical Processes (IPCF)–National Research Council Secondary Site (CNR SS) Bari, Bari, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology “S. De Bellis” Research Hospital, Bari, Italy
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MiR-200b Suppresses Gastric Cancer Cell Migration and Invasion by Inhibiting NRG1 through ERBB2/ERBB3 Signaling. JOURNAL OF ONCOLOGY 2021; 2021:4470778. [PMID: 34531912 PMCID: PMC8440071 DOI: 10.1155/2021/4470778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/20/2021] [Indexed: 12/09/2022]
Abstract
Purpose Accumulating evidence indicates that miRNAs (miRs) play crucial roles in the modulation of tumors development. However, the accurately mechanisms have not been entirely clarified. In this study, we aimed to explore the role of miR-200b in the development of gastric cancer (GC). Methods Western blot and RT-PCR were applied to detect epithelial-mesenchymal transition (EMT) marker expression and mRNA expression. Transwell assay was used for measuring the metastasis and invasiveness of GC cells. TargetScan system, luciferase reporter assay, and rescue experiments were applied for validating the direct target of miR-200b. Results MiR-200b was prominently decreased in GC tissues and cells, and its downregulation was an indicator of poor prognosis of GC patients. Reexpression of miR-200b suppressed EMT along with GC cell migration and invasion. Neuregulin 1 (NRG1) was validated as the target of miR-200b, and it rescued miR-200b inhibitory effect on GC progression. In GC tissues, the correlation of miR-200b with NRG1 was inverse. Conclusion MiR-200b suppressed EMT-related migration and invasion of GC through the ERBB2/ERBB3 signaling pathway via targeting NRG1.
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Zhao S, Li W, Yu W, Rao T, Li H, Ruan Y, Yuan R, Li C, Ning J, Li S, Chen W, Cheng F, Zhou X. Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys. Am J Cancer Res 2021; 11:8660-8673. [PMID: 34522205 PMCID: PMC8419054 DOI: 10.7150/thno.62820] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Rationale: Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and progressive chronic kidney disease (CKD). Exosome-mediated cell-cell communication has been suggested to be involved in various diseases, including renal fibrosis. However, little is known regarding how exosomes regulate renal fibrosis in obstructed kidneys. Methods: We first examined the secretion of exosomes in UUO (unilateral ureteral obstruction) mouse kidneys and TGF-β1-stimulated tubular epithelial cells (NRK-52E). Exosomes from NRK-52E cells were subsequently harvested and incubated with fibroblasts (NRK-49F) or injected into UUO mice via the tail vein. We next constructed Rab27a knockout mice to further confirm the role of exosome-mediated epithelial-fibroblast communication relevant to renal fibrosis in UUO mice. High-throughput miRNA sequencing was performed to detect the miRNA profiles of TGFβ1-Exos. The roles of candidate miRNAs, their target genes and relevant pathways were predicted and assessed in vitro and in vivo by setting specific miRNA mimic, miRNA inhibitor, siRNA or miRNA LNA groups. Results: Increased renal fibrosis was associated with prolonged UUO days, and the secretion of exosomes was markedly increased in UUO kidneys and TGF-β1-stimulated NRK-52E cells. Purified exosomes from TGF-β1-stimulated NRK-52E cells could activate fibroblasts and aggravate renal fibrosis in vitro and in vivo. In addition, the inhibition of exosome secretion by Rab27a knockout or GW4869 treatment abolished fibroblast activation and ameliorated renal fibrosis. Exosomal miR-21 was significantly increased in TGFβ1-Exos compared with Ctrl-Exos, and PTEN is a certain target of miR-21. The promotion or inhibition of epithelial exosomal miR-21 correspondingly accelerated or abolished fibroblast activation in vitro, and renal fibrosis after UUO was alleviated by miR-21-deficient exosomes in vivo through the PTEN/Akt pathway. Conclusion: Our findings reveal that exosomal miR-21 from tubular epithelial cells may accelerate the development of renal fibrosis by activating fibroblasts via the miR-21/PTEN/Akt pathway in obstructed kidneys.
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MicroRNA-200b Regulates the Proliferation and Differentiation of Ovine Preadipocytes by Targeting p27 and KLF9. Animals (Basel) 2021; 11:ani11082417. [PMID: 34438874 PMCID: PMC8388755 DOI: 10.3390/ani11082417] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 01/18/2023] Open
Abstract
Simple Summary The miR-200b has been shown to play an important role in preadipocyte proliferation and differentiation. Herein, we explored the role of miR-200b in ovine adipocyte development, using Oil Red O staining, cell viability analysis, EdU and RT-qPCR. The results showed that miR-200b facilitated proliferation and suppressed the differentiation of preadipocytes. The dual fluorescent reporter vector experiments showed that miR-200b directly targeted p27 and KLF9. Meanwhile, we demonstrated that p27 significantly inhibited the proliferation, while KLF9 significantly promoted the differentiation of preadipocytes. Abstract MicroRNAs (miRNAs) are crucial regulatory molecules in lipid deposition and metabolism. However, the effect of miR-200b on the regulation of proliferation and adipogenesis of ovine preadipocytes is unknown in the sheep (Ovis aries). In this study, the expression profiles of miR-200b were investigated in the seven tissues of Tibetan ewes and differentiated preadipocytes. The effect of miR-200b, as well as its target genes p27 and KLF9, on the proliferation of ovine preadipocytes and adipogenesis was also investigated, using cell viability analysis, EdU staining, Oil Red O staining and reverse transcription-quantitative PCR (RT-qRCR). The miR-200b was expressed in all the tissues investigated, and it was highly expressed in lung, liver, subcutaneous adipose and spleen tissues. The expression of miR-200b continuously decreased when the differentiation of ovine preadipocytes initiated. The miR-200b mimic dramatically accelerated the proliferation but inhibited differentiation of ovine preadipocytes. The miR-200b inhibitor resulted in an opposite effect on the proliferation and differentiation of ovine preadipocytes. The dual luciferase reporter assay results showed that miR-200b mimic significantly decreased the luciferase activity of p27 and KLF9 in HEK293 cells transfected with wild-type dual luciferase reporter vectors. This suggests that p27 and KLF9 are the target genes of miR-200b. In over-expressed-p27 preadipocytes, the number of EdU-labeled preadipocytes and the expression levels of proliferation marker genes CDK2, CDK4, CCND1 and PCNA significantly decreased. In addition, the transfection of over-expressed-KLF9 vector into adipocytes remarkably increased the accumulation of lipid droplets and the expression levels of differentiation marker genes aP2, PPARγ, LPL and GLUT4. These results suggest that miR-200b accelerated the proliferation but inhibited the adipogenic differentiation of ovine preadipocytes by targeting p27 and KLF9, respectively.
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Wang J, Yao R, Luo Q, Tan L, Jia B, Ouyang N, Li Y, Tong J, Li J. miR‑200b upregulation promotes migration of BEAS‑2B cells following long‑term exposure to cigarette smoke by targeting ETS1. Mol Med Rep 2021; 24:562. [PMID: 34109431 PMCID: PMC8201442 DOI: 10.3892/mmr.2021.12201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 05/18/2021] [Indexed: 12/24/2022] Open
Abstract
Cigarette smoking is the leading cause of all histological types of lung cancer, and the role that microRNAs (miRNAs) serve in its pathogenesis is being increasingly recognized. The aim of the present study was to investigate the role of miR‑200b on migration in cigarette smoke‑induced malignant transformed cells. In the present study, miR‑200b expression was found to be increased in cigarette smoke (CS)‑exposed BEAS‑2B cells, lung cancer cell lines and tumor tissue samples. Using wound healing and Transwell migration assays, the migratory ability was shown to be increased in miR‑200b‑overexpressing cells, whereas miR‑200b knockdown resulted in reduced migration. Additionally, the expression of E‑Cadherin was downregulated, whereas that of N‑Cadherin was upregulated in miR‑200b mimic‑transfected cells, suggesting an increase in epithelial‑mesenchymal transition. Downstream, using four target gene prediction tools, six target genes of miR‑200b were predicted, amongst which, ETS proto‑oncogene 1 transcription factor (ETS1) was shown to be significantly associated with tumor invasion depth and negatively associated with miR‑200b expression. The interaction between miR‑200b and ETS1 was confirmed using a dual‑luciferase reporter assay. Using rescue experiments, the increased migratory ability of the miR‑200b‑overexpressing cells was reversed by ETS1 overexpression. In summary, this study showed that miR‑200b overexpression serves a carcinogenic role and promotes the migration of BEAS‑2B cells following long‑term exposure to CS by targeting ETS1.
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Affiliation(s)
- Jin Wang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Ruixin Yao
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Qiulin Luo
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Lirong Tan
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Beibei Jia
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Nan Ouyang
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yezhou Li
- School of Medicine, University of Manchester, M13 9PL Manchester, UK
| | - Jian Tong
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Jianxiang Li
- Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
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Shen Q, Huang Z, Yao J, Jin Y. Extracellular vesicles-mediated interaction within intestinal microenvironment in inflammatory bowel disease. J Adv Res 2021; 37:221-233. [PMID: 35499059 PMCID: PMC9039646 DOI: 10.1016/j.jare.2021.07.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
EVs derived from different sources play modulatory functions in the intestine, especially interaction associated with microbiota. An EV-mediated interaction system was established to describe the possible mechanism of IBD pathogenesis and its cure. EVs-based treatments show great potential of clinical applications in IBD diagnosis and therapy. Background The intestinal tract is a complicated ecosystem with dynamic homeostasis via interaction of intestine and microbiota. Inflammatory bowel disease (IBD) is chronic intestinal inflammation involving dysbiosis of intestinal microenvironment. Extracellular vesicles (EVs), as vital characteristics of cell–cell and cell-organism communication, contribute to homeostasis in intestine. Recently, EVs showed excellent potential for clinical applications in disease diagnoses and therapies. Aim of Review Our current review discusses the modulatory functions of EVs derived from different sources in intestine, especially their effects and applications in IBD clinical therapy. EV-mediated interaction systems between host intestine and microbiota were established to describe possible mechanisms of IBD pathogenesis and its cure. Key Scientific Concepts of Review EVs are excellent vehicles for delivering molecules containing genetic information to recipient cells. Multiple pieces of evidence have illustrated that EVs participate the interaction between host and microbiota in intestinal microenvironment. In inflammatory intestine with dysbiosis of microbiota, EVs as regulators target promoting immune response and microbial reconstruction. EVs-based immunotherapy could be a promising therapeutic approach for the treatment of IBD in the near future.
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Affiliation(s)
- Qichen Shen
- Department of Biotechnology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Zhuizui Huang
- Department of Biotechnology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Jiachen Yao
- Faculty of Technology, University of Turku, Turku 20014, Finland
| | - Yuanxiang Jin
- Department of Biotechnology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
- Corresponding author at: 18, Chaowang Road, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
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You X, Wang Y, Meng J, Han S, Liu L, Sun Y, Zhang J, Sun S, Li X, Sun W, Dong Y, Zhang Y. Exosomal miR‑663b exposed to TGF‑β1 promotes cervical cancer metastasis and epithelial‑mesenchymal transition by targeting MGAT3. Oncol Rep 2021; 45:12. [PMID: 33649791 PMCID: PMC7877003 DOI: 10.3892/or.2021.7963] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 01/18/2021] [Indexed: 12/24/2022] Open
Abstract
Transforming growth factor (TGF)‑β1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor‑derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF‑β1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF‑β1 stimulated cervical cancer cells to secrete more miR‑663b‑containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR‑663b directly targets the 3'-untranslated regions (3'‑UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial‑mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR‑663b, causing increased expression of epithelial differentiation marker E‑cadherin and decreased expression of mesenchymal markers N‑cadherin and β‑catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR‑663b. Exosome PKH67‑labeling experiment verified that exosomal miR‑663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR‑663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real‑time transcription‑polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell‑derived exosomal miR‑663b is endocytosed by cervical cancer cells adjacent or distant after TGF‑β1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.
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Affiliation(s)
- Xuewu You
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Ying Wang
- Department of Obstetrics and Gynecology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China
| | - Jinyu Meng
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Sai Han
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Lu Liu
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yu Sun
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Junhua Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Shuqin Sun
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xinyue Li
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Wenxiong Sun
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yajie Dong
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Youzhong Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
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Noh GT, Kwon J, Kim J, Park M, Choi DW, Cho KA, Woo SY, Oh BY, Lee KY, Lee RA. Verification of the role of exosomal microRNA in colorectal tumorigenesis using human colorectal cancer cell lines. PLoS One 2020; 15:e0242057. [PMID: 33175885 PMCID: PMC7657557 DOI: 10.1371/journal.pone.0242057] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
Exosomes are a group of small membranous vesicles that are shed into the extracellular environment by tumoral or non-tumoral cells and contribute to cellular communication by delivering micro RNAs (miRNAs). In this study, we aimed to evaluate the role of exosomal miRNAs from colorectal cancer cell lines in tumorigenesis, by affecting cancer-associated fibroblasts (CAFs), which are vital constituents of the tumor microenvironment. To analyze the effect of exosomal miRNA on the tumor microenvironment, migration of the monocytic cell line THP-1 was evaluated via Transwell migration assay using CAFs isolated from colon cancer patients. The migration assay was performed with CAFs ± CCL7-blocking antibody and CAFs that were treated with exosomes isolated from colon cancer cell lines. To identify the associated exosomal miRNAs, miRNA sequencing and quantitative reverse transcription polymerase chain reaction were performed. The migration assay revealed that THP-1 migration was decreased in CCL7-blocking antibody-expressing and exosome-treated CAFs. Colon cancer cell lines contained miRNA let-7d in secreted exosomes targeting the chemokine CCL7. Exosomes from colorectal cancer cell lines affected CCL7 secretion from CAFs, possibly via the miRNA let-7d, and interfered with the migration of CCR2+ monocytic THP-1 cells in vitro.
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Affiliation(s)
- Gyoung Tae Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Jiyun Kwon
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Jungwoo Kim
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Minhwa Park
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Da-Won Choi
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Kyung-Ah Cho
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - So-Youn Woo
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Bo-Young Oh
- Department of Surgery, Hallym University College of Medicine, Seoul, South Korea
| | - Kang Young Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Ryung-Ah Lee
- Department of Surgery, Ewha Womans University College of Medicine, Seoul, South Korea
- * E-mail:
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Shen Y, Yang Y, Li Y. MiR-133a acts as a tumor suppressor in lung cancer progression by regulating the LASP1 and TGF-β/Smad3 signaling pathway. Thorac Cancer 2020; 11:3473-3481. [PMID: 33074595 PMCID: PMC7705923 DOI: 10.1111/1759-7714.13678] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND MiR-133a has been confirmed to be involved in the development of multiple cancers including non-small cell lung cancer (NSCLC). However, the precise molecular mechanism has not yet been fully elucidated. The purpose of this study was to investigate the functional role and underlying mechanism of miR-133a in the progression of NSCLC. METHODS Quantitative real-time PCR (qRT-PCR) was performed to measure miR-133a and LASP1 expression in NSCLC tissues and cells. 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to detect cell viability. The protein levels were measured by western blot. The tumor growth was measured by xenograft tumor formation assay. RESULTS miR-133a was significantly decreased while LASP1 was increased in NSCLC tissues and cells compared with control groups. Moreover, overexpression of miR-133a suppressed cell viability, whereas miR-133a knockdown enhanced the viability of A549 cells. More importantly, LASP1 was verified as a direct target of miR-133a. Moreover, overexpression of miR-133a inhibited the epithelial-mesenchymal transition (EMT) and TGF-β/Smad3 pathways by regulating LASP1 in vitro. In addition, miR-133a mimic suppressed tumor growth by modulating the TGF-β/Smad3 pathway in vivo. CONCLUSIONS In conclusion, miR-133a acted as a tumor suppressor in lung cancer progression by regulating the LASP1 and TGF-β/Smad3 signaling pathway.
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Affiliation(s)
- Yuyao Shen
- Department of Respiratory Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Yan Yang
- Department of Respiratory Medicine, Shan Dong Chest Hospital, Jinan, China
| | - Yahua Li
- Department of Respiratory Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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Li D, Meng D, Niu R. Exosome-Reversed Chemoresistance to Cisplatin in Non-Small Lung Cancer Through Transferring miR-613. Cancer Manag Res 2020; 12:7961-7972. [PMID: 32943930 PMCID: PMC7481302 DOI: 10.2147/cmar.s254310] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 07/06/2020] [Indexed: 12/27/2022] Open
Abstract
Introduction Non-small lung cancer (NSCLC) is one of the most common malignant tumors in the world. Chemoresistance is the main reason of adverse effects leading to the death of patients; thus, it is important to discover the potential target of chemotherapeutic resistance. Methods The expression of differentially expressed miRNA was detected in BEAS-2B, A549 and A549/cisplatin (DDP) by qRT-PCR. Transmission electron microscopy (TEM) and exosome biomarkers were used to validate the extracted exosome. Cells incubated with miR-613 enriched exosomes were used to detect the function of exo-miR-613 in vitro. Then, exo-miR-613 was injected to mice treated with DDP to investigate the function role of exo-miR-613 in vivo. Results Comparing to BEAS-2B, the expression of miR-613 inA549 was significantly reduced, which was more obvious in A549/DDP. After incubated with exo-miR-613 and corresponding exo-negative control (NC), we found overexpression of miR-613 remarkably increased the inhibition of cell proliferation induced by cisplatin. Exo-miR-613 fused into cells to significantly enhance the inhibited effect of DDP on the proliferation, migration and showed a promotion on cell apoptosis and DNA damage. The in vivo study showed that exo-miR-613 significantly inhibited the tumor growth, and promote the sensitivity to DDP, probably by down-regulating the expressions of GJA1, TBP and EIF-4E in tumor cells and tissues. Conclusion Exo-miR-613 reversed chemoresistance to DDP in NSCLC cell to involve in the process of tumor progression, and might be a potential therapeutic strategy for NSCLC.
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Affiliation(s)
- Delong Li
- Department of Special Geriatrics, Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China
| | - Debin Meng
- Department of Special Geriatrics, Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China.,Department of General Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China
| | - Rungui Niu
- Department of Special Geriatrics, Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China
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The Role of miR-375-3p and miR-200b-3p in Gastrointestinal Stromal Tumors. Int J Mol Sci 2020; 21:ijms21145151. [PMID: 32708220 PMCID: PMC7404198 DOI: 10.3390/ijms21145151] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/10/2020] [Accepted: 07/17/2020] [Indexed: 02/06/2023] Open
Abstract
Deregulated microRNA (miRNA) expression profiles and their contribution to carcinogenesis have been observed in virtually all types of human cancer. However, their role in the pathogenesis of rare mesenchymal gastrointestinal stromal tumors (GISTs) is not well defined, yet. In this study, we aimed to investigate the role of two miRNAs strongly downregulated in GIST—miR-375-3p and miR-200b-3p—in the pathogenesis of GIST. To achieve this, miRNA mimics were transfected into GIST-T1 cells and changes in the potential target gene mRNA and protein expression, as well as alterations in cell viability, migration, apoptotic cell counts and direct miRNA–target interaction, were evaluated. Results revealed that overexpression of miR-375-3p downregulated the expression of KIT mRNA and protein by direct binding to KIT 3′UTR, reduced GIST cell viability and migration rates. MiR-200b-3p lowered expression of ETV1 protein, directly targeted and lowered expression of EGFR mRNA and protein, and negatively affected cell migration rates. To conclude, the present study identified that miR-375-3p and miR-200b-3p have a tumor-suppressive role in GIST.
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Wang M, Yu F, Li P, Wang K. Emerging Function and Clinical Significance of Exosomal circRNAs in Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 21:367-383. [PMID: 32650235 PMCID: PMC7340966 DOI: 10.1016/j.omtn.2020.06.008] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/18/2020] [Accepted: 06/09/2020] [Indexed: 02/08/2023]
Abstract
Exosomes are a type of extracellular vesicles (EVs) secreted by almost all cells, with a diameter range of 30-150 nm and a lipid bilayer membrane. Exosomes are now considered as vital mediators of intercellular communication and participate in multiple cellular processes, such as signal transduction and antigen presentation. Recently, circular RNAs (circRNAs), a novel class of noncoding RNAs (ncRNAs), have been found to be abundant and stable in exosomes. Increasing evidence indicates that exosome-derived circRNAs act as signaling molecules to regulate cancer growth, angiogenesis, invasion, metastasis, and sensitivity to chemotherapy. Moreover, circulating exosomal circRNAs can reflect the progression and malignant characteristics of cancer, implying their great potential as promising, non-invasive biomarkers for cancer diagnosis and prognosis. In this review, we summarize the recent progress on the functional roles of exosomal circRNAs in cancer progression, discussing their potential as promising biomarkers and therapeutic targets in cancer. Comprehensive elucidation of molecular mechanisms relevant to the implications of exosomal circRNAs in cancer progression will be conducive to the development of innovative diagnostic and therapeutic approaches in cancer.
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Affiliation(s)
- Man Wang
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
| | - Fei Yu
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Kun Wang
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
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45
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The Role of Extracellular Vesicles in the Hallmarks of Cancer and Drug Resistance. Cells 2020; 9:cells9051141. [PMID: 32384712 PMCID: PMC7290603 DOI: 10.3390/cells9051141] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs) mediate intercellular signaling and communication, allowing the intercellular exchange of proteins, lipids, and genetic material. Their recognized role in the maintenance of the physiological balance and homeostasis seems to be severely disturbed throughout the carcinogenesis process. Indeed, the modus operandi of cancer implies the highjack of the EV signaling network to support tumor progression in many (if not all) human tumor malignancies. We have reviewed the current evidence for the role of EVs in affecting cancer hallmark traits by: (i) promoting cell proliferation and escape from apoptosis, (ii) sustaining angiogenesis, (iii) contributing to cancer cell invasion and metastasis, (iv) reprogramming energy metabolism, (v) transferring mutations, and (vi) modulating the tumor microenvironment (TME) by evading immune response and promoting inflammation. Special emphasis was given to the role of EVs in the transfer of drug resistant traits and to the EV cargo responsible for this transfer, both between cancer cells or between the microenvironment and tumor cells. Finally, we reviewed evidence for the increased release of EVs by drug resistant cells. A timely and comprehensive understanding of how tumor EVs facilitate tumor initiation, progression, metastasis and drug resistance is instrumental for the development of innovative EV-based therapeutic approaches for cancer.
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Tan S, Xia L, Yi P, Han Y, Tang L, Pan Q, Tian Y, Rao S, Oyang L, Liang J, Lin J, Su M, Shi Y, Cao D, Zhou Y, Liao Q. Exosomal miRNAs in tumor microenvironment. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:67. [PMID: 32299469 PMCID: PMC7164281 DOI: 10.1186/s13046-020-01570-6] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023]
Abstract
Tumor microenvironment (TME) is the internal environment in which tumor cells survive, consisting of tumor cells, fibroblasts, endothelial cells, and immune cells, as well as non-cellular components, such as exosomes and cytokines. Exosomes are tiny extracellular vesicles (40-160nm) containing active substances, such as proteins, lipids and nucleic acids. Exosomes carry biologically active miRNAs to shuttle between tumor cells and TME, thereby affecting tumor development. Tumor-derived exosomal miRNAs induce matrix reprogramming in TME, creating a microenvironment that is conducive to tumor growth, metastasis, immune escape and chemotherapy resistance. In this review, we updated the role of exosomal miRNAs in the process of TME reshaping.
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Affiliation(s)
- Shiming Tan
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Pin Yi
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.,University of South China, Hengyang, 421001, Hunan, China
| | - Yaqian Han
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Lu Tang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.,University of South China, Hengyang, 421001, Hunan, China
| | - Qing Pan
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.,University of South China, Hengyang, 421001, Hunan, China
| | - Yutong Tian
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.,University of South China, Hengyang, 421001, Hunan, China
| | - Shan Rao
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Linda Oyang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Jiaxin Liang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Jinguan Lin
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Min Su
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Yingrui Shi
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Deliang Cao
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.,Department of Medical Microbiology, Immunology & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794,, USA
| | - Yujuan Zhou
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
| | - Qianjin Liao
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
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Guo QR, Wang H, Yan YD, Liu Y, Su CY, Chen HB, Yan YY, Adhikari R, Wu Q, Zhang JY. The Role of Exosomal microRNA in Cancer Drug Resistance. Front Oncol 2020; 10:472. [PMID: 32318350 PMCID: PMC7154138 DOI: 10.3389/fonc.2020.00472] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/16/2020] [Indexed: 12/19/2022] Open
Abstract
Exosomes affect the initiation and progression of cancers. In the tumor microenvironment, not only cancer cells, but also fibroblasts and immunocytes secrete exosomes. Exosomes act as a communicator between cells by transferring different cargos and microRNAs (miRNAs). Drug resistance is one of the critical factors affecting therapeutic effect in the course of cancer treatment. The currently known mechanisms of drug resistance include drug efflux, alterations in drug metabolism, DNA damage repair, alterations of energy programming, cancer stem cells and epigenetic changes. Many studies have shown that miRNA carried by exosomes is closely associated with the development of drug resistance mediated by the above-mentioned mechanisms. This review article will discuss how exosomal miRNAs regulate the drug resistance.
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Affiliation(s)
- Qiao-ru Guo
- Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, China
| | - Hui Wang
- Guangzhou Institute of Pediatrics/Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ying-da Yan
- Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yun Liu
- Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Chao-yue Su
- Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Hu-biao Chen
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yan-yan Yan
- Collaborative Innovation Center for Cancer, Institute of Respiratory and Occupational Diseases, Medical College, Shanxi Datong University, Datong, China
| | - Rameshwar Adhikari
- Research Centre for Applied Science and Technology, Tribhuvan University, Kirtipur, Nepal
| | - Qiang Wu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, China
- Key Laboratory of Emergency and Trauma of Ministry of Education, School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, China
| | - Jian-ye Zhang
- Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, China
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Ding Y, Li W, Wang K, Xu C, Hao M, Ding L. Perspectives of the Application of Liquid Biopsy in Colorectal Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6843180. [PMID: 32258135 PMCID: PMC7085834 DOI: 10.1155/2020/6843180] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 02/25/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal tumors and the second leading cause of cancer death worldwide. Since traditional biopsies are invasive and do not reflect tumor heterogeneity or monitor the dynamic progression of tumors, there is an urgent need for new noninvasive methods that can supplement and improve the current management strategies of CRC. Blood-based liquid biopsies are a promising noninvasive biomarker that can detect disease early, assist in staging, monitor treatment responses, and predict relapse and metastasis. Over time, an increasing number of experiments have indicated the clinical utility of liquid biopsies in CRC. In this review, we mainly focus on the development of circulating tumor cells and circulating tumor DNA as key components of liquid biopsies in CRC and introduce the potential of exosomal microRNAs as emerging liquid biopsy markers in clinical application for CRC.
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Affiliation(s)
- Yuhan Ding
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Wenxia Li
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Kun Wang
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Chang Xu
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Mengdi Hao
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Lei Ding
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
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49
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Farace C, Pisano A, Griñan-Lison C, Solinas G, Jiménez G, Serra M, Carrillo E, Scognamillo F, Attene F, Montella A, Marchal JA, Madeddu R. Deregulation of cancer-stem-cell-associated miRNAs in tissues and sera of colorectal cancer patients. Oncotarget 2020; 11:116-130. [PMID: 32010426 PMCID: PMC6968784 DOI: 10.18632/oncotarget.27411] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is a deadly tumour in Western countries characterized by high cellular/molecular heterogeneity. Cancer stem cells (CSC) act in cancer recurrence, drug-resistance and in metastatic epithelial-to-mesenchymal transition. microRNAs (miRNAs) contribute to cancer is increasing, and miRNA roles in CSC phenotype and fate and their utility as CRC biomarkers have also been reported. Here, we investigated miR-21, miR-221, miR-18a, miR-210, miR-31, miR-34a, miR-10b and miR-16 expression in experimental ALDH+ and CD44+/CD326+ colorectal CSCs obtained from the human CRC cell lines HCT-116, HT-29 and T-84. Then, we moved our analysis in cancer tissue (CT), healthy tissue (HT) and serum (S) of adult CRC patients (n=12), determining relationships with clinical parameters (age, sex, metastasis, biochemical serum markers). Specific miRNA patterns were evident in vitro (normal, monolayers and CSCs) and in patients’ samples stratified by TNM stage (LOW vs HIGH) or metastasis (Met vs no-Met). miR-21, miR-210, miR-34a upregulation ad miR-16 dowregulation associated with the CSCs phenotype. miR-31b robustly overexpressed in monolayers and CSCs, and in CT ad S of HIGH grade and Met patients, suggesting a role as marker of CRC progression and metastasis. miR-18a upregulated in all cancer models and associated to CSC phenotype, and to metastasis and age in patients. miR-10b downregulated in CT and S of LOW/HIGH grade and no-Met patients. Our results identify miRNAs useful as colorectal CSC biomarker and that miR-21, miR-210, miR-10b and miR-31b are promising markers of CRC. A specific role of miR-18a as metastatic CRC serum biomarker in adult patients was also highlighted.
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Affiliation(s)
- Cristiano Farace
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,National Institute of Biostructures and Biosystems, Rome, Italy
| | - Andrea Pisano
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Carmen Griñan-Lison
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain
| | - Giuliana Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Gema Jiménez
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Bio-Health Research Foundation of Eastern Andalusia - Alejandro Otero (FIBAO), Granada, Spain
| | - Marina Serra
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Esmeralda Carrillo
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
| | | | - Federico Attene
- O.U. of Surgery I (Surgical Pathology), A.O.U. Sassari, Sassari, Italy
| | - Andrea Montella
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain.,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Roberto Madeddu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,National Institute of Biostructures and Biosystems, Rome, Italy
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50
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Advances in the study of exosomal lncRNAs in tumors and the selection of research methods. Biomed Pharmacother 2019; 123:109716. [PMID: 31896067 DOI: 10.1016/j.biopha.2019.109716] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 11/19/2019] [Accepted: 11/29/2019] [Indexed: 02/07/2023] Open
Abstract
Exosomes are endosome-derived extracellular vesicles that are released upon the fusion of multivesicular bodies with the plasma membrane. These vesicles contain proteins, lipids, and nucleic acids and are found in various human body fluids. Exosomes can transfer bioactive molecules to nearby or distant recipient cells, thereby affecting their function. Recently, exosomes have gained importance as a medium of communication between tumor cells. An increasing number of studies have found that non-coding RNAs in tumor cell-derived exosomes can regulate tumor microenvironments, inhibit immune cell function, promote the growth and invasion of tumor cells, and impart resistance to chemicals in tumor cells. In this review, we focus on the effects of exosomal long non-coding RNAs (lncRNAs) on tumors. As exosomes and their parent cells have similar biological characteristics and coated lncRNAs can exist stably in vivo without being degraded by RNases, exosomal lncRNAs have emerged as novel non-invasive tumor biomarkers for use in the early diagnosis and evaluation of prognosis of tumors. Advancements in the field have led to the development of a variety of techniques in exosomal non-coding RNA research. Currently, most methods include the separation and purification of exosomes, followed by RNA extraction, reverse transcription, and subsequent analyses; thus, these processes are very tedious and vulnerable to contamination and could lead to inaccurate and inconsistent results. Thus, there has been an increase in the development of detection methods for exosomal RNAs. Here, we discuss the existing research methods, their advantages and disadvantages, and a few new techniques.
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