YT521 promotes metastases of endometrial cancer by differential splicing of vascular endothelial growth factor A

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.

Pan-Cancer Analysis Reveals the Prognostic Potential of the THAP9/THAP9-AS1 Sense–Antisense Gene Pair in Human Cancers

“…Genes overrepresented in these clusters include YTHDC1, SRSF10, BLCAF1, MFSD8, and ABHD18. YTHDC1 is a nuclear protein involved in splicing cancer-causing transcripts [ 73 ] and plays a regulatory role in several cancers such as breast and prostate cancer [ 74 , 75 , 76 , 77 ]. SRSF10 is an SR protein and splicing regulator that activates splicing when phosphorylated and inhibits splicing when dephosphorylated [ 78 , 79 ].…”

Genetic identification of the m6A-related gene YTHDF3 as a putative biomarker for breast cancer

“…Our study found that the mRNA expression levels of YTHDF1, YTHDF2 and YTHDF3 were upregulated in breast cancer compared with that in normal tissues from healthy population. Although a signi cant downregulation in the expression of YTHDC1 and YTHDC2 was found in breast cancer, it has been reported that YT521 (YTHDC1) was over-expressed in endometrial carcinoma and promoted the metastatic process by regulating the mRNA splicing of VEGFA (53). Furthermore, YTHDC2 is involved in the metastasis of colon cancer by promoting the translation of HIF-1α (54).…”

Inflammatory Biomarker in Adipose Stem Cells of Women With Endometrial Cancer

“…The biomarkers investigated in this study (angiopoietin-2, EGF, IL-8, leptin, VEGFA, VEGFC, and VEGFD) have been chosen based on the association with a proinflammatory milieu, as well as with EC risks in previously published cohort and cross-sectional studies [24][25][26][27]. These seven biomarkers were analyzed by xMAP™ immunoassays, and measured in the culture medium.…”