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

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.

Citation

Zheng Zhang, Li Min, Hengcun Li, Lei Chen, Yu Zhao, Si Liu, Qingdong Guo, Shengtao Zhu, Peng Li, Shutian Zhang. Asporin represses gastric cancer apoptosis via activating LEF1-mediated gene transcription independent of β-catenin. Oncogene. 2021 Jul;40(27):4552-4566

Mesh Tags

Substances

PMID: 34127813

search → result