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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor mediating various cellular responses to xenobiotics as well as to physiological stimuli. We previously showed that AhR-deficient mice spontaneously develop cecal tumors with severe inflammation. To further elucidate the molecular mechanism of the tumor suppressor function of AhR, we investigated cell migration in colon cancer cells transfected with siRNA against AhR. Cell motility examined in an in vitro wound healing assay was up-regulated in the AhR-knockdown (AhR-KD) cells. Migration was further studied using a real-time cell analyzer system and showed that cell migration was remarkable on substrates coated with either fibronectin or Matrigel. The GTPase Rac was activated in these cells as assessed by GST pull-down assay. The AhR knockdown phenotype also included enhanced cell spreading, increased amounts of focal adhesion kinase phosphorylation at Y397 and decreased integrin β5 as detected by immunoblotting using anti-cytoplasmic domain antibodies. Collectively, these data suggest that AhR function contributes to tumor suppression by regulating cell adhesion and migration signaling. The aryl hydrocarbon receptor (AhR) mediates various biological responses to environmental pollutants such as dioxins, PCBs, and benzo[a]pyrene (BP), as well as to natural chemical substances. When AhR is activated by ligand binding, it translocates to the nucleus to form a heterodimer with AhR nuclear translocator (ARNT). In the nucleus, AhR/ARNT binds to the xenobiotic responsive elements located in the 5′-flanking regions of target genes such as CYP1A1 and various other factors involved in cellular responses [1, 2]. Because the tumorigenic activity of BP requires metabolic activation of CYP1A1 or CYP1B1 enzymes into their ultimate DNA-damaging forms [3, 4], AhR has been investigated in the context of tumorigenesis. Apart from toxicological studies, AhR has been shown to have critical endogenous function involved in embryonic development [5, 6], cell cycle regulation [7], and immune responses [8-10]. We have reported on the tumor suppressor function of AhR using AhR-deficient mice that spontaneously develop cecal tumors [11]. In addition, treatment of ApcMin/+ mice with an AhR ligand, which is a model mouse for the study of carcinogenesis, suppresses intestinal tumorigenesis. Our study also found an up-regulation of inflammatory cytokines in the colorectal tissues of AhR-deficient mice and that suppression of inflammatory responses repressed tumor formation in these animals [12]. Immunohistochemical analysis using human colon cancer tissues has revealed that AhR expression is increased in both tumor and stromal cells [13]. Up-regulation of AhR expression has also been reported in other tissues such as lung [14], breast [15], and pancreatic cancer [16], indicating the possibility of therapeutic treatment with AhR ligands. We have also previously observed that cell growth is suppressed by treatment with methylcholanthrene or indole-3-carbinol (I3C), an AhR ligand, in human colon cancer cell lines [13]. These results indicate a tumor suppressor function of AhR. In this study, we investigated whether changes in AhR expression alter cell migration in cultured human colon cancer cells. Cell migration is a critical step during tissue formation during fetal development and wound healing, as well as in tumor formation. Migration requires Introduction

Aryl Hydrocarbon Receptor Controls Adhesion and Migration of Colon Cancer Cells