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Novel lncRNA Gm33149 modulates metastatic heterogeneity in melanoma by regulating the miR-5623-3p/Wnt axis via exosomal transfer

Cancer Gene Therapy volume 31, pages 364–375 (2024)Cite this article

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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.

Schematic representation of the mechanisms underlying the pro-metastatic activity of lncRNA Gm33149 mediated by exosomal transfer. The figure illustrates the key mechanisms involved in the pro-metastatic activity of lncRNA Gm33149 through exosomal transfer. Melanoma stem cells (OLSD) release exosomes containing lncRNA Gm33149. These exosomes are taken up by non-stem melanoma cells (OL), delivering lncRNA Gm33149 to the recipient cells. Within OL cells, lncRNA Gm33149 functions as a competitive endogenous RNA (ceRNA), sequestering miR-5623-3p. This sequestration prevents miR-5623-3p from binding to its target genes, thereby activating the Wnt signaling pathway. The activated Wnt signaling pathway enhances the migration, invasion, and metastatic colonization capabilities of OL cells. The transfer of lncRNA Gm33149 via exosomes contributes to OL cells acquiring “metastatic competency” while promoting their metastatic colonization. These findings underscore the importance of lncRNA Gm33149 in intercellular communication and the metastatic progression of melanoma.

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Fig. 1: Exosomes secreted by melanoma stem cells (CSCs) can promote the metastasis of no-CSC melanoma cells.
Fig. 2: Prioritization of novel lncRNA Gm33149.
Fig. 3: miR-5623-3p promotes metastatic colonization of non-CSC melanoma cells.
Fig. 4: lncRNA Gm33149 sequesters miR-5623-3p to promote the metastatic colonization of non-CSC melanoma cells.
Fig. 5: The Wnt signaling pathway functions downstream of lncRNA Gm33149 to mediate its pro-metastatic activity.

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Data availability

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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  1. These authors contributed equally: Yan Chen, Yu-Han Zhang, Jie Li.

Authors and Affiliations

  1. State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China

    Yan Chen, Yu-Han Zhang, Lei Shi, Jia-Cheng Xie, Yu-Ting Chen, Meng Xiang, Bo-Wen Li & H. Rosie Xing

  2. Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China

    Yan Chen, Yu-Han Zhang, Lei Shi, Jia-Cheng Xie, Yu-Ting Chen, Meng Xiang, Bo-Wen Li & H. Rosie Xing

  3. Institute of Life Sciences, Chongqing Medical University, Chongqing, China

    Jie Li, Xue Han & Jian-Yu Wang

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Contributions

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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Correspondence to H. Rosie Xing or Jian-Yu Wang.

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The Author confirms: that the work described has not been published before; that it is not under consideration for publication elsewhere; and that its publication has been approved by all authors.

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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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