The splicing factor YBX1 promotes the progression of osteosarcoma by upregulating VEGF(165) and downregulating VEGF(165b)

VEGF(165) and its isoform VEGF(165b) have the same length but opposite functions in cancer. Some studies have indicated the important role of VEGF(165) in osteosarcoma (OS); however, VEGF(165b) has not been taken into consideration. This study aims to clarify the roles of the two isoforms in OS and the mechanism controlling their formation from an alternative splicing perspective. By in vivo and in vitro experiments, we assessed the expression and function of VEGF(165) and VEGF(165b), screened the underlying splicing factors, and verified the regulatory function of splicing factor YBX1 on the two isoforms and its role in OS. The results showed that in OS, VEGF(165) was upregulated but VEGF(165b) was downregulated. VEGF(165) promoted the proliferation, migration and invasion of OS cells and induced angiogenesis in OS tumours; however, VEGF(165b) showed the opposite function. Of the four screened splicing factors, YBX1 was upregulated in OS tissues. It was positively correlated with VEGF(165) but negatively correlated with VEGF(165b). Further study indicated that YBX1 could upregulate VEGF(165) but downregulate VEGF(165b). Moreover, YBX1 promoted the proliferation, migration and invasion of OS cells and induced angiogenesis in OS tumours. OS patients with higher YBX1 had a poor prognosis within five years, but this difference disappeared in a longer follow-up. In conclusion, VEGF(165b) was antineoplastic and downregulated in OS, in contrast to VEGF(165). YBX1 was found to be an important splicing factor that increased VEGF(165) but decreased VEGF(165b). Targeting YBX1 could endogenously alter the levels of VEGF(165) and VEGF(165b) simultaneously.