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Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke
Author(s) -
Ishida Masaru,
Mikami Shuji,
Shinojima Toshiaki,
Kosaka Takeo,
Mizuno Ryuichi,
Kikuchi Eiji,
Miyajima Akira,
Okada Yasunori,
Oya Mototsugu
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29398
Subject(s) - aryl hydrocarbon receptor , carcinogenesis , cancer research , biology , tumor progression , cancer , medicine , transcription factor , gene , biochemistry
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 TM 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.