TXNDC5 is a cervical tumor susceptibility gene that stimulates cell migration, vasculogenic mimicry and angiogenesis by down-regulating SERPINF1 and TRAF1 expression

Abstract

TXNDC5 (thioredoxin domain-containing protein 5) catalyzes disulfide bond formation, isomerization and reduction. Studies have reported that TXNDC5 expression is increased in some tumor tissues and that its increased expression can predict a poor prognosis. However, the tumorigenic mechanism has not been well characterized. In this study, we detected a significant association between the rs408014 and rs7771314 SNPs at the TXNDC5 locus and cervical carcinoma using the Taqman genotyping method. We also detected a significantly increased expression of TXNDC5 in cervical tumor tissues using immunohistochemistry and Western blot analysis. Additionally, inhibition of TXNDC5 expression using siRNA prevented tube-like structure formation, an experimental indicator of vasculogenic mimicry and metastasis, in HeLa cervical tumor cells. Inhibiting TXNDC5 expression simultaneously led to the increased expression of SERPINF1 (serpin peptidase inhibitor, clade F) and TRAF1 (TNF receptor-associated factor 1), which have been reported to inhibit angiogenesis and metastasis as well as induce apoptosis. This finding was confirmed in Caski and C-33A cervical tumor cell lines. The ability to form tube-like structures was rescued in HeLa cells simultaneously treated with anti-TXNDC5, SERPINF1 and TRAF1 siRNAs. Furthermore, the inhibition of TXNDC5 expression significantly attenuated endothelial tube formation, a marker of angiogenesis, in human umbilical vein endothelial cells. The present study suggests that TXNDC5 is a susceptibility gene in cervical cancer, and high expression of this gene contributes to abnormal angiogenesis, vasculogenic mimicry and metastasis by down-regulating SERPINF1 and TRAF1 expression.