Abstract
The high mortality rate associated with melanoma primarily results from metastasis and recurrence. However, the precise mechanisms driving these processes remain poorly understood. Intercellular communication between cancer cells and non-cancer cells significantly influences the tumor microenvironment and plays a crucial role in metastasis. Therefore, our current study aims to investigate the role and mechanism of long non-coding RNAs (lncRNAs) in regulating the interaction between melanoma cancer stem cells (CSCs) and non-CSCs during the metastatic colonization process. This study has characterized a novel lncRNA called Gm33149. Importantly, we provide evidence for the first time that Gm33149, originating from highly metastatic melanoma stem cells (OL-SD), can be packaged into exosomes and transferred to low-metastatic nonstem cells (OL). Once internalized by OL cells, Gm33149 exerts its function through a competitive endogenous RNA mechanism (ceRNA) involving miR-5623-3p. Specifically, Gm33149 competitively binds to miR-5623-3p, thereby activating the Wnt signaling pathway and promoting the acquisition of a more aggressive metastatic phenotype by OL cells. In summary, our findings suggest that targeting lncRNA Gm33149 within extracellular vesicles could potentially serve as a therapeutic strategy for the treatment of metastatic melanoma.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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Acknowledgements
Throughout the writing of this dissertation, I have received a great deal of support and assistance. I would first like to thank my supervisor, H. Rosie Xing, whose expertise was invaluable in formulating the research questions and methodology. I would also like to thank my tutor, Jian-Yu Wang, for their valuable guidance throughout my studies. I would particularly like to acknowledge my team members, Yu-Han Zhang, Jie Li, Lei Shi, Jia-Cheng Xie, Xue Han, Yuting Chen, Meng Xiang, and Bo-Wen Li, for their wonderful collaboration and patient support.
Funding
This work was supported by the National Natural Science Fund (Grant No. 82073277 and 82173247), the Science and Technology Project Affiliated to the Education Department of Chongqing (Grant No. KJQN202100404), and Project of Chongqing Natural Science Foundation Innovation and Development Fund (Municipal Education Commission) (Grant No. CSTB2022NS CQ-LZX0023).
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YC, YH Z and JL conducted the experiments and analyzed the data. YC was responsible for writing the manuscript. LS, JC X, XH, YT C, MX and BW L participated in the conduction of this study. JY W and HR X designed and oversaw the execution of this study, and contributed to the writing of this manuscript.
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Animal experiments were approved by the Chongqing Medical University committee for animal experiments. All experiments were performed with relevant guidelines and regulations. Title: Novel lncRNA Gm33149 Modulates Metastatic Heterogeneity in Melanoma by Regulating the miR-5623-3p/Wnt Axis via Exosomal Transfer; the institutional approval committee: Chongqing Medical University committee; approval number: SYXK2018-0003; date: 2022-02-22\2022-06-23.
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Chen, Y., Zhang, YH., Li, J. et al. Novel lncRNA Gm33149 modulates metastatic heterogeneity in melanoma by regulating the miR-5623-3p/Wnt axis via exosomal transfer. Cancer Gene Ther 31, 364–375 (2024). https://doi.org/10.1038/s41417-023-00707-x
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DOI: https://doi.org/10.1038/s41417-023-00707-x
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