Role for TNFAIP2: Relationships with Outcomes and EMT in Urothelial Cancers under the Control of Cisplatin

Background: Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many cancer types. However, the phenotypic hallmark of tumors often changes after CDDP, with the acquisition of Epithelial-to-mesenchymal transition (EMT) and platinum resistance. Yet, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Methods: Following an investigation of urothelial cancers (UCs) before and after the acquisition of platinum resistance, we offered the new target TNFAIP2, which led to EMT and tumor invasion. TNFAIP2 expression in cancers were examined at the protein and transcription levels. Results: Clinically, up-regulated TNFAIP2 expression was identified as a significant predictor of mortality in upper urinary tract UCs. TNFAIP2 knockdown resulted in up-regulated E-cadherin expression and down-regulated TWIST expression in cancers, which decreased motile function. TNFAIP2 overexpression led to down-regulated E-cadherin expression and up-regulated TWIST expression. Clinical investigations on matched pre- and post-CDDP-treated sections confirmed up-regulated TNFAIP2 expression in CDDP-treated tumors, but down-regulated E-cadherin expression. A global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition. Conclusions: Our results suggest a relationship between TNFAIP2 and EMT in cancers, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition. To investigate the relationship between TNFAIP2 and EMT, we compared changes in global gene expression between before and after the knockdown of TNFAIP2 in platinum-resistant 5637PR cells.