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SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer

Oncogene volume 30, pages 3682–3693 (2011)Cite this article

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Abstract

Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is overexpressed in lung cancer tumor tissues and is correlated with the invasive ability in a lung cancer cell line model. These observations suggest that SCUBE3 may have a role in lung cancer progression. By exogenous SCUBE3 treatment or knockdown of SCUBE3 expression, we found that SCUBE3 could promote lung cancer cell mobility and invasiveness. Knockdown of SCUBE3 expression also suppressed tumorigenesis and cancer metastasis in vivo. The secreted SCUBE3 proteins were cleaved by gelatinases (matrix metalloprotease-2 (MMP-2) and MMP-9) in media to release two major fragments: the N-terminal epidermal growth factor-like repeats and the C-terminal complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain. Both the purified SCUBE3 protein and the C-terminal CUB domain fragment, bound to transforming growth factor-β (TGF-β) type II receptor through the C-terminal CUB domain, activated TGF-β signaling and triggered the epithelial-mesenchymal transition (EMT). This process includes the induction of Smad2/3 phosphorylation, the increase of Smad2/3 transcriptional activity and the upregulation of the expression of target genes involved in EMT and cancer progression (such as TGF-β1, MMP-2, MMP-9, plasminogen activator inhibitor type-1, vascular endothelial growth factor, Snail and Slug), thus promoting cancer cell mobility and invasion. In conclusion, in lung cancer cells, SCUBE3 could serve as an endogenous autocrine and paracrine ligand of TGF-β type II receptor, which could regulate TGF-β receptor signaling and modulate EMT and cancer progression.

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Acknowledgements

We thank Ker-Chau Li (Institute of Statistical Science, Academia Sinica) for providing EKVX and Hop62 cells and Shih-Han Kao for English language editing. This work was supported by Academia Sinica (Grant AS-97-FP-L16) and the National Science Council, Taiwan (Grants NSC98-2628-B-002-086-MY3 and NSC97-2314-B-002-146-MY3). shRNA constructs were obtained from the National RNAi Core Facility at the Institute of Molecular Biology/Genomic Research Center, Academia Sinica, Taipei, Taiwan. T-M H and P-C Y co-directed the project and contributed equally to this work.

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  1. T-M Hong and P-C Yang: These authors co-directed the project and contributed equally to this work.

Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC

    Y-Y Wu

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC

    K Peck, S-H Pan, Y-F Cheng, R-B Yang & P-C Yang

  3. Department of Pathology and Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan, ROC

    Y-L Chang

  4. Department of Respiratory Therapy, Fu-Jen Catholic University, Taipei, Taiwan, ROC

    J-C Lin

  5. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

    T-M Hong

  6. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

    T-M Hong

  7. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC

    P-C Yang

  8. NTU Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan, ROC

    P-C Yang

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Wu, YY., Peck, K., Chang, YL. et al. SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer. Oncogene 30, 3682–3693 (2011). https://doi.org/10.1038/onc.2011.85

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