Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer

Masaru Ishida, Shuji Mikami, Eiji Kikuchi, Takeo Kosaka, Akira Miyajima, Ken Nakagawa, Makio Mukai, Yasunori Okada, Mototsugu Oya

Research output: Contribution to journalArticle

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Abstract

Aryl hydrocarbon receptor (AhR) and the activation of the AhR pathway are involved in xenobiotic-induced toxicity and carcinogenesis. Although xenobiotics, such as cigarette smoke, contribute to the development of urothelial carcinoma (UC), the relationship between AhR and UC is unclear. In the present study, we investigated AhR expression in 209 patients with upper urinary tract UC. The nuclear expression of AhR was significantly associated with histological grade, pathological T stage, lymphovascular invasion and lymph node involvement. A multivariate Cox analysis revealed that nuclear AhR expression was a significant and independent predictor for disease-specific survival (hazard ratio = 2.469, P = 0.013). To determine whether the AhR pathway can be activated in the T24 UC cell line, we examined the expression of cytochrome P450 (CYP) 1A1 and CYP1B1, which are target genes of the AhR pathway, following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR. TCDD treatment upregulated the expression levels of AhR, CYP1A1 and CYP1B1. TCDD enhanced T24 cell invasion associated with the upregulation of matrix metalloproteinase (MMP)-1 and MMP-9. Furthermore, targeting AhR messenger RNA (mRNA) expression in T24 cells with small interfering RNA (siRNA) downregulated the mRNA expression of AhR, CYP1A1, CYP1B1, MMP-1, MMP-2 and MMP-9; furthermore, the cells transfected with siRNA for AhR showed decreased invasion activity in comparison with the cells transfected with a non-targeting siRNA. Our results therefore suggest that AhR plays a role in the invasiveness of UC cells and can serve as a marker for the prognosis of upper urinary tract UC.

Original languageEnglish
Article numberbgp222
Pages (from-to)287-295
Number of pages9
JournalCarcinogenesis
Volume31
Issue number2
DOIs
Publication statusPublished - 2010 Feb

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Urologic Neoplasms
Aryl Hydrocarbon Receptors
Matrix Metalloproteinases
Neoplasms
Carcinoma
Small Interfering RNA
Matrix Metalloproteinase 1
Cytochrome P-450 CYP1A1
Matrix Metalloproteinase 9
Xenobiotics
Urinary Tract
Messenger RNA
Matrix Metalloproteinase 2

ASJC Scopus subject areas

  • Cancer Research

Cite this

Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer. / Ishida, Masaru; Mikami, Shuji; Kikuchi, Eiji; Kosaka, Takeo; Miyajima, Akira; Nakagawa, Ken; Mukai, Makio; Okada, Yasunori; Oya, Mototsugu.

In: Carcinogenesis, Vol. 31, No. 2, bgp222, 02.2010, p. 287-295.

Research output: Contribution to journalArticle

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