The splicing factor YBX1 promotes the progression of osteosarcoma by upregulating VEGF ₁₆₅ and downregulating VEGF _165b

Abstract

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.