TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells

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Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

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The authors would like to sincerely thank Ms Yukiko Nakajima for her assistance with the experiments. This study was supported in part by Grants-in-Aid for Scientific Research (#15K20110 and 18K16746 to NN, #26462429 to NT, and #26861299 to TK) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This work was also supported in part by a Keio University Grant-in-Aid for the Encouragement of Young Medical Scientists to NN from Keio University School of Medicine. The study was also supported in part by a research grant to NT from The YASUDA Medical Foundation, Japan, The Takeda Science Foundation, Japan, and The Uehara Memorial Foundation, Japan.

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Correspondence to Nobuyuki Tanaka or Takeo Kosaka or Mototsugu Oya.

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RM has received honoraria from Novartis and Pfizer. TK has received honoraria from Sanofi, Astellas, Takeda, Bayer, and Janssen. MO has received honoraria from Astellas, Bayer, Novartis, and Pfizer.

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