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MiR-629-5p promotes the invasion of lung adenocarcinoma via increasing both tumor cell invasion and endothelial cell permeability

Oncogene volume 39, pages 3473–3488 (2020)Cite this article

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Abstract

Tumor invasion underlies further metastasis, the leading cause for cancer-related deaths. Deregulation of microRNAs has been identified associated with the malignant behavior of various cancers, including lung adenocarcinoma (LUAD), the major subtype of lung cancer. Here, we showed the significantly positive correlation between miR-629-5p level and tumor invasion in LUAD specimens (n = 49). In a human LUAD metastasis mouse model, H1650 cells (high level of miR-629-5p) were more aggressive than A549 cells (low level of miR-629-5p) in vivo, including higher incidence of vascular invasion and pulmonary colonization. Ectopic expression of miR-629-5p in A549 cells also increased their invasive capability. Then we identified that miR-629-5p promotes LUAD invasion in a mode of dual regulation via tumor cells invasion and endothelial cells permeability, respectively. In tumor cells, miR-629-5p enhanced motility and invasiveness of tumor cells by directly targeting PPWD1 (a cyclophilin), which clinically related to tumor invasion in LUAD specimens. Restoring PPWD1 protein significantly attenuated the invasion-promoting effects of miR-629-5p. Besides, exosomal-miR-629-5p secreted from tumor cells could be transferred to endothelial cells and increased endothelial monolayers permeability by suppressing CELSR1 (a nonclassic-type cadherin), which had a low level in the endothelial cells of invasive LUAD specimens. Activating the expression of CELSR1 in endothelial cells markedly blocked the effect of miR-629-5p. Our study suggests the dual roles of miR-629-5p in tumor cells and endothelial cells for LUAD invasion, implying a therapeutic option to targeting miR-629-5p using the “one stone, two birds” strategy in LUAD.

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Fig. 1: MiR-629-5p was upregulated in LUAD and associated with LUAD invasion.
Fig. 2: Endogenous miR-629-5p promoted LUAD cells invasion in vitro and in vivo.
Fig. 3: Overexpression of miR-629-5p promoted A549 cells invasion in vitro and vivo.
Fig. 4: miR-629-5p targets PPWD1 in LUAD cells.
Fig. 5: Clinical relevance of miR-629-5p and PPWD1.
Fig. 6: LUAD-secreted exosomal-miR-629-5p induced HUVEC monolayers leakiness.
Fig. 7: MiR-629-5p targets CELSR1 in HUVECs.
Fig. 8: Clinical relevance of miR-629-5p and CELSR1.

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Acknowledgements

This work was supported by the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program,” China (2018ZX09101001-003-007 and 2018ZX09711002-010-001), “the National Natural Science Foundation of china (91859106),” One Hundred Talent Program of Chinese Academy of Sciences, the Fundamental and Open Research Funds from the State Key Laboratory of Drug Research, and the grant from Shanghai Committee of Science and Technology, China (Grant No.: 18DZ2290200). We thank the Electron Microscopy System and Animal Facility at the National Facility for Protein Science in Shanghai (NFPS), Zhangjiang Lab, China, and the Institutional Technology Service Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences for technical supports.

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  1. These authors contributed equally: Yu Li, Huibiao Zhang

Authors and Affiliations

  1. Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China

    Yu Li, Lei Fan, Jiahui Mou, Yuxiang Chen, Henglei Lu, Zhouteng Tao, Jing Chen, Xinming Qi & Jin Ren

  2. University of Chinese Academy of Sciences, 100049, Beijing, China

    Yu Li, Lei Fan, Jiahui Mou, Zhouteng Tao, Jing Chen, Xinming Qi, Ruimin Huang & Jin Ren

  3. Department of Thoracic Surgery, Huadong Hospital, Fudan University, 200040, Shanghai, China

    Huibiao Zhang

  4. National Facility for Protein Science in Shanghai, Zhangjiang Lab, 201210, Shanghai, China

    Yue Yin

  5. Shanghai Science Research Center, Chinese Academy of Sciences, 201204, Shanghai, China

    Chao Peng

  6. Shanghai University of Chinese Medicine, 201203, Shanghai, China

    Henglei Lu

  7. Department of Nursing, Huadong Hospital, Fudan University, 200040, Shanghai, China

    Liting Zhao

  8. The Brain Science Center, Beijing Institute of Basic Medical Sciences, 100730, Beijing, China

    Yizheng Wang

  9. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China

    Ruimin Huang

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Li, Y., Zhang, H., Fan, L. et al. MiR-629-5p promotes the invasion of lung adenocarcinoma via increasing both tumor cell invasion and endothelial cell permeability. Oncogene 39, 3473–3488 (2020). https://doi.org/10.1038/s41388-020-1228-1

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