Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke

Masaru Ishida, Shuji Mikami, Toshiaki Shinojima, Takeo Kosaka, Ryuichi Mizuno, Eiji Kikuchi, Akira Miyajima, Yasunori Okada, Mototsugu Oya

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel<sup>TM</sup> were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

Original languageEnglish
Pages (from-to)299-310
Number of pages12
JournalInternational Journal of Cancer
Volume137
Issue number2
DOIs
Publication statusPublished - 2015 Jul 15

Fingerprint

Aryl Hydrocarbon Receptors
Renal Cell Carcinoma
Smoke
Tobacco Products
Matrix Metalloproteinases
Tumor-Infiltrating Lymphocytes
Environmental Pollutants
Neoplasms
Small Interfering RNA
Carcinogenesis
Ligands
Cytochrome P-450 CYP1A1
Immunity

Keywords

  • aryl hydrocarbon receptor
  • cigarette smoke
  • invasion
  • prognosis
  • renal cell carcinoma
  • tumor-infiltrating lymphocyte

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke. / Ishida, Masaru; Mikami, Shuji; Shinojima, Toshiaki; Kosaka, Takeo; Mizuno, Ryuichi; Kikuchi, Eiji; Miyajima, Akira; Okada, Yasunori; Oya, Mototsugu.

In: International Journal of Cancer, Vol. 137, No. 2, 15.07.2015, p. 299-310.

Research output: Contribution to journalArticle

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