Abstract
The malignancy of endometrial carcinoma (EC) largely results from its high invasive feature. The regulation of the mRNA splicing of vascular endothelial growth factor A (VEGF-A) is critical for EC-associated cancer vascularization and invasion. Recently, we have reported that poorly prognostic EC had high levels of YT521, a newly defined RNA splicing protein. However, whether YT521 may similarly regulate the splicing of VEGF-A in EC is unknown. Here, we showed that EC specimens contained significantly higher levels of YT521, compared to the adjacent non-tumor endometrial tissue. Higher levels of YT521 were detected in EC specimens with metastases. High-YT521 EC is associated with poor patient survival. In order to examine whether YT521 may regulate VEGF-A mRNA splicing in EC, we transfected an EC cell line HEC-1A with different doses of YT521 mimics. We found that YT521 dose-dependently increased the ratio of VEGF-165 vs VEGF-121 at both mRNA and protein level, suggesting that YT521 may promote VEGF-A mRNA splicing to favor a VEGF-165 isoform. Moreover, the increases in the ratio of VEGF-165 vs VEGF-121 by YT521 overexpression resulted in increases in EC cell invasion, while decreases in the ratio of VEGF-165 vs VEGF-121 by YT521 depletion resulted in decreases in EC cell invasion in a transwell cell migration assay. Further, overexpression of VEGF-165, but not overexpression of VEGF-121, increased EC cell invasiveness. Finally, a strong correlation was detected between the ratio of VEGF-165 vs VEGF-121 and the levels of YT521 in EC specimens. Together, these data suggest that YT521 may promote EC metastases by regulating mRNA splicing of VEGF-A.
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The project was supported by Grants from the National Natural Science Foundation of China (NSFC Nos. 81202045) and the Shanghai Science and Technology Committee Foundation (13ZR1432000).
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Bo Zhang and Xiaowen Shao contributed equally to this work.
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Zhang, B., Shao, X., Zhou, J. et al. YT521 promotes metastases of endometrial cancer by differential splicing of vascular endothelial growth factor A. Tumor Biol. 37, 15543–15549 (2016). https://doi.org/10.1007/s13277-015-3908-y
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DOI: https://doi.org/10.1007/s13277-015-3908-y