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

Naoya Niwa, Nobuyuki Tanaka, Hiroshi Hongo, Yasumasa Miyazaki, Kimiharu Takamatsu, Ryuichi Mizuno, Eiji Kikuchi, Shuji Mikami, Takeo Kosaka, Mototsugu Oya

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
JournalLaboratory Investigation
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Epithelial-Mesenchymal Transition
Platinum
Carcinoma
Neoplasms
Cadherins
Up-Regulation
Down-Regulation
Cisplatin
Gene Expression
Drug Therapy
Mortality

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells. / Niwa, Naoya; Tanaka, Nobuyuki; Hongo, Hiroshi; Miyazaki, Yasumasa; Takamatsu, Kimiharu; Mizuno, Ryuichi; Kikuchi, Eiji; Mikami, Shuji; Kosaka, Takeo; Oya, Mototsugu.

In: Laboratory Investigation, 01.01.2019.

Research output: Contribution to journalArticle

@article{3c8a99e947b34beeb575db7050e40823,
title = "TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells",
abstract = "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-na{\"i}ve 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.",
author = "Naoya Niwa and Nobuyuki Tanaka and Hiroshi Hongo and Yasumasa Miyazaki and Kimiharu Takamatsu and Ryuichi Mizuno and Eiji Kikuchi and Shuji Mikami and Takeo Kosaka and Mototsugu Oya",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41374-019-0285-y",
language = "English",
journal = "Laboratory investigation; a journal of technical methods and pathology",
issn = "0023-6837",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells

AU - Niwa, Naoya

AU - Tanaka, Nobuyuki

AU - Hongo, Hiroshi

AU - Miyazaki, Yasumasa

AU - Takamatsu, Kimiharu

AU - Mizuno, Ryuichi

AU - Kikuchi, Eiji

AU - Mikami, Shuji

AU - Kosaka, Takeo

AU - Oya, Mototsugu

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85068390229&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068390229&partnerID=8YFLogxK

U2 - 10.1038/s41374-019-0285-y

DO - 10.1038/s41374-019-0285-y

M3 - Article

AN - SCOPUS:85068390229

JO - Laboratory investigation; a journal of technical methods and pathology

JF - Laboratory investigation; a journal of technical methods and pathology

SN - 0023-6837

ER -