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      MiR‐1246 is responsible for lung cancer cells‐derived exosomes‐mediated promoting effects on lung cancer stemness via targeting TRIM17

      1 , 2 , 1
      Environmental Toxicology
      Wiley

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          Abstract

          The stemness of lung cancer cells contributes to drug resistance, tumor occurrence, progression, and recurrence; however, the underlying mechanisms are still fragmentary. In the present study, it was found that exosomes from cisplatin‐resistant cells and spheres derived from lung cancer cells enhanced the stemness of the parental lung cancer cells. Then we screened the upregulated miRNAs in spheres derived from lung cancer cells and cisplatin‐resistant lung cancer cells/exosomes compared to that in the parental lung cancer cells. It was found that miR‐1246 was remarkably enriched in cisplatin‐resistant lung cancer cells/exosomes and spheres. Additionally, inhibition of miR‐1246 attenuated the stemness of lung cancer cells induced by exosomes from cisplatin‐resistant cells and spheres. Furthermore, TRIM17 was identified to the direct target of miR‐1246 in lung cancer cells. Our findings suggest that exosomal miR‐1246 could be as a potential target for lung cancer treatment.

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          Most cited references28

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          Is Open Access

          Exosome Theranostics: Biology and Translational Medicine

          Exosomes are common membrane-bound nanovesicles that contain diverse biomolecules, such as lipids, proteins, and nucleic acids. Exosomes are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Exosome secretion is a constitutive phenomenon that is involved in both physiological and pathological processes and determines both the exosomal surface molecules and the contents. Hence, we can exploit exosomes as biomarkers, vaccines and drug carriers and modify them rationally for therapeutic interventions. However, it is still a challenge to identify, isolate and quantify exosomes accurately, efficiently and selectively. Further studies on exosomes will explore their potential in translational medicine and provide new avenues for the creation of effective clinical diagnostics and therapeutic strategies; the use of exosomes in these applications can be called exosome theranostics. This review describes the fundamental processes of exosome formation and uptake. In addition, the physiological and pathological roles of exosomes in biology are also illustrated with a focus on how exosomes can be exploited or engineered as powerful tools in translational medicine.
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            CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer

            Background Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic. Methods Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential. Results Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity. Conclusions The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC. Graphical abstract
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              Effect of exosomal miRNA on cancer biology and clinical applications

              Exosomes, extracellular vesicles with diameters ranging from 30 to 150 nm, are widely present in various body fluids. Recently, microRNAs (miRNAs) have been identified in exosomes, the biogenesis, release, and uptake of which may involve the endosomal sorting complex required for transport (ESCRT complex) and relevant proteins. After release, exosomes are taken up by neighboring or distant cells, and the miRNAs contained within modulate such processes as interfering with tumor immunity and the microenvironment, possibly facilitating tumor growth, invasion, metastasis, angiogenesis and drug resistance. Therefore, exosomal miRNAs have a significant function in regulating cancer progression. Here, we briefly review recent findings regarding tumor-derived exosomes, including RNA sorting and delivering mechanism. We then describe the intercommunication occurring between different cells via exosomal miRNAs in tumor microenvironmnt, with impacts on tumor proliferation, vascularization, metastasis and other biological characteristics. Finally, we highlight the potential role of these molecules as biomarkers in cancer diagnosis and prognosis and tumor resistance to therapeutics.
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                Author and article information

                Contributors
                Journal
                Environmental Toxicology
                Environmental Toxicology
                Wiley
                1520-4081
                1522-7278
                November 2022
                July 27 2022
                November 2022
                : 37
                : 11
                : 2651-2659
                Affiliations
                [1 ] Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing Jiangsu Province China
                [2 ] Department of Biomedical Sciences and Tung Biomedical Sciences Centre City University of Hong Kong Kowloon Hong Kong
                Article
                10.1002/tox.23625
                35894553
                bc7d67e4-3fd7-497c-ac20-e43f19707561
                © 2022

                http://onlinelibrary.wiley.com/termsAndConditions#vor

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