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Asporin represses gastric cancer apoptosis via activating LEF1-mediated gene transcription independent of β-catenin

Oncogene volume 40, pages 4552–4566 (2021)Cite this article

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Abstract

Asporin (ASPN) presents in the tumor microenvironment and exhibits a cancer-promoting effect as a stroma protein. Even though ASPN has already been observed inside cancer cells, the functions of intracellular ASPN and its underlying mechanisms remain unknown. Here we reported that ASPN was upregulated in different stages of gastric cancer (GC), and associated with a poor prognosis. Moreover, we found that ASPN markedly inhibited GC cell apoptosis and promoted cell growth in vitro and in vivo. Further mechanism investigations revealed that ASPN directly binding to lymphoid enhancer-binding factor 1 (LEF1) and promoted LEF1-mediated gene transcription independent of β-catenin, the classic co-factor in the Wnt/LEF1 pathway. We also demonstrated that ASPN selectively facilitated LEF1 binding to and activating the promoters of PTGS2, IL6, and WISP1 to promote their transcription. The suppression of cell apoptosis by ASPN overexpression could be attenuated by LEF1 knockdown or 100 µM aspirin (PTGS2 inhibitor), and siASPN mediated apoptosis could be rescued by LEF1 ectopic expression or adding recombinant IL6. Therefore, we concluded that ASPN repressed GC cell apoptosis via activating LEF1-mediated gene transcription independent of β-catenin, which could serve as a potential prognostic biomarker in GC patients.

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Fig. 1: ASPN was upregulated inside GC cells and correlated with poor prognosis in different GC cohorts.
Fig. 2: ASPN promoted GC cell proliferation, migration and invasion.
Fig. 3: ASPN inhibited GC cell apoptosis and promoted tumorigenicity.
Fig. 4: ASPN interacted with LEF1.
Fig. 5: ASPN selectively regulated the expression of LEF1 downstream molecules in GC.
Fig. 6: Nuclear-specific ASPN indeed promote cell viability and inhibit cell apoptosis.
Fig. 7: ASPN inhibited apoptosis by activating the transcriptional activity of LEF1.

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Acknowledgements

This study was supported by National Natural Science Foundation of China (81570507, 81702314) and National Key Research and Development Program of China (2017YFC0113600).

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  1. These authors contributed equally: Zheng Zhang, Li Min

Authors and Affiliations

  1. Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China

    Zheng Zhang, Li Min, Hengcun Li, Lei Chen, Yu Zhao, Si Liu, Qingdong Guo, Shengtao Zhu, Peng Li & Shutian Zhang

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Zhang, Z., Min, L., Li, H. et al. Asporin represses gastric cancer apoptosis via activating LEF1-mediated gene transcription independent of β-catenin. Oncogene 40, 4552–4566 (2021). https://doi.org/10.1038/s41388-021-01858-7

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