Pröstler, Eva (2023)
The different functions of sEV-derived miR-574-5p in PGE2-dependent tumors correlate with the tetraspanin composition on the sEV envelope.
Technische Universität Darmstadt
doi: 10.26083/tuprints-00024601
Ph.D. Thesis, Primary publication, Publisher's Version
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Item Type: | Ph.D. Thesis | ||||
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Type of entry: | Primary publication | ||||
Title: | The different functions of sEV-derived miR-574-5p in PGE2-dependent tumors correlate with the tetraspanin composition on the sEV envelope | ||||
Language: | English | ||||
Referees: | Saul, Dr. Meike Julia ; Süß, Prof. Dr. Beatrix | ||||
Date: | 5 October 2023 | ||||
Place of Publication: | Darmstadt | ||||
Collation: | 123 Seiten | ||||
Date of oral examination: | 22 September 2023 | ||||
DOI: | 10.26083/tuprints-00024601 | ||||
Abstract: | Small extracellular vesicles (sEV) are essential for intracellular communication in the tumor microenvironment (TME). They can transport biological molecules, such as proteins or nucleic acids, including microRNAs (miRs), a class of short non-coding RNAs. MiRs can exert various functions in gene regulation of target cells. This work aimed to elucidate the transferability of the diverse functions of miR-574-5p to different tumor models. For this purpose, the two prostaglandin E2 (PGE2)-dependent tumor types, non-small cell lung cancer (NSCLC) and neuroblastoma (NB), were investigated. In NSCLC, miR-574-5p regulates the microsomal prostaglandin E2 synthase 1 (mPGES-1)-dependent PGE2 synthesis, which contributes to tumor progression. At the intracellular level, miR-574-5p binds to the CUG-RNA binding protein 1 (CUGBP1), thereby upregulating the synthesis of mPGES-1 and its enzymatic product PGE2. In this thesis, this function of intracellular miR-574-5p was also shown in NB with 11q deletion. Furthermore, NB cells were shown to specifically secrete miR-574-5p into their sEV upon stimulation with PGE2, similar to NSCLC cells. The autocrine role of sEV-derived miR-574-5p in mPGES-1 regulation was not confirmed in NB. However, sEV-miR-574-5p derived from NB cells was shown to exert a novel paracrine role by specific upregulation of the differentiation marker α-smooth muscle actin (α-SMA) of fibroblasts in the TME via Toll-like receptors (TLR) 7/8. Another point investigated in this study was the influence of the tetraspanins CD9, CD63, and CD81 on the functional transfer of sEV-miR-574-5p. In both tumor types, NB and NSCLC, inhibition of specific tetraspanins was shown to alter the function of sEV-miR-574-5p. A difference in the rate of internalization of sEV was excluded as the cause of this functional change. The link between tetraspanins and the functional mediation of sEV-derived miRs is a novel and promising aspect of cancer research. Overall, this work revealed a new paracrine function of sEV-miR-574-5p, regulating the α-SMA levels of fibroblasts in the TME. Furthermore, the transferability of intracellular and extracellular miR-574-5p functions to different tumor models were analyzed. The interaction of miR-574-5p and CUGBP1 was shown to be transferable from NSCLC to NB, whereas the role of sEV-derived miR-574-5p differed. Investigating the transferability of miR functions to different tumor types is an important approach to maximize the therapeutic benefit of miRs with the least effort and the greatest impact. |
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Status: | Publisher's Version | ||||
URN: | urn:nbn:de:tuda-tuprints-246018 | ||||
Classification DDC: | 500 Science and mathematics > 570 Life sciences, biology | ||||
Divisions: | 10 Department of Biology > Extracellular vesicles / miRNA Research | ||||
Date Deposited: | 05 Oct 2023 12:05 | ||||
Last Modified: | 06 Oct 2023 09:01 | ||||
URI: | https://tuprints.ulb.tu-darmstadt.de/id/eprint/24601 | ||||
PPN: | 512062013 | ||||
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