Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biologic and toxic effects of its xenobiotic ligands. In recent years it has become evident that in the absence of ligand the AHR promotes cell cycle progression and that its activation by high-affinity ligands results in interactions with the retinoblastoma protein (RB) that lead to perturbation of the cell cycle, G 0 /G 1 arrest, diminished capacity for DNA replication and inhibition of cell proliferation. Hence, the AHR has diametrically opposed pro-proliferative and anti-proliferative functions that have yet to be reconciled at the molecular level. Work from our own and from other laboratories suggests that the AHR may function as a tumor suppressor gene that becomes silenced in the process of tumor formation. To develop preliminary support for a more thorough examination of this hypothesis we characterized the expression levels of various tumor suppressor genes, transforming growth factor-β (Tgfb) genes and the Ahr gene in liver tumor samples from mice with a liver-specific RB ablation and their wild-type littermates. In tumors arising in RB-positive livers, Cdkn2d and Tgfb1 were repressed and Cdkn2c, Tgfb2, Tgfb3 and Pai1 were induced, whereas in RB-negative tumors, only Cdkn2c and Tgfb3 were induced. Ahr was significantly repressed in tumors from both sets of mice, supporting the concept that Ahr silencing may be associated with cancer progression.

Dioxin Receptor Deficiency Impairs Angiogenesis by a Mechanism Involving VEGF-A Depletion in the Endothelium and Transforming Growth Factor-β Overexpression in the Stroma

“…In this context, the fact that natural AhR antagonists such as resveratrol can inhibit tumor angiogenesis (66) by interfering with VEGF expression and HIF-1␣ accumulation in human squamous carcinoma SCC-9 and hepatoma HepG2 cells (67) identifies AhR as novel potential therapeutic target to block angiogenesis in certain diseases such as cancer. From a mechanistic point of view, it is clear that AhR modulates TGF␤ activity by regulating its location and activation in the ECM through the transcriptional control of the latency protein LTBP-1 and the activity of ECM proteases (25,37,51) and by controlling the expression of TGF␤-related genes (68,69). Regarding the regulation of VEGF-A, our data suggest the involvement of HIF-1␣, a major regulatory protein for this growth factor (70,71) that is also down-modulated in AhR Ϫ/Ϫ MAECs.…”

The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways

“…Elevated expression of the AHR and hyperphosphorylated RB were also found in DMBA-induced mammary tumors and in rat oval cells treated with TCDD [74], contrasting the idea that AHR signaling induces growth arrest through RB in every context [75]. AHR expression was also found to be significantly repressed in DEN-induced liver tumors from RB-positive and RB-negative mice [76] and in several primary human acute lymphoblastic leukemias [77], indicating that AHR silencing may be associated with cancer progression. Finally, at least one report suggests that the RB is required for maximal transcriptional activity mediated by the AHR-ARNT complex at the Cyp1a1 promoter [63], suggesting that RB can function as an AHR coactivator protein under certain contexts.…”

The Aryl Hydrocarbon Receptor Functions as a Tumor Suppressor of Liver Carcinogenesis

“…Epigenetic AHR silencing by promoter hypermethylation has recently been reported in a significant number of human acute lymphoblastic leukemia cases (24). Ahr repression was also substantial in DEN-induced liver tumors of mice, albeit in the absence of any significant promoter hypermethylation (25). Furthermore, AHR-null TRAMP mice show increased susceptibility to prostate tumorigenesis and develop prostate tumors with greater frequency than Ahr +/+ TRAMP mice, suggesting that the AHR possesses tumor suppressor properties (26).…”