RESUMO
Caveolae are specialized microdomains on membranes that are critical for signal transduction, cholesterol transport, and endocytosis. Caveolin-1 (CAV1) is a multifunctional protein and a major component of caveolae. Cav1 is directly activated by hypoxia-inducible factor (HIF). HIFs are heterodimers of an oxygen-sensitive α subunit, HIF1α or HIF2α, and a constitutively expressed ß subunit, aryl hydrocarbon receptor nuclear translocator (ARNT). Whole-genome expression analysis demonstrated that Cav1 is highly induced in mouse models of constitutively activated HIF signaling in the intestine. Interestingly, Cav1 was increased only in the colon and not in the small intestine. Currently, the mechanism and role of HIF induction of CAV1 in the colon are unclear. In mouse models, mice that overexpressed HIF1α or HIF2α specifically in intestinal epithelial cells demonstrated an increase in Cav1 gene expression in the colon but not in the duodenum, jejunum, or ileum. HIF2α activated the Cav1 promoter in a HIF response element-independent manner. myc-associated zinc finger (MAZ) protein was essential for HIF2α activation of the Cav1 promoter. Hypoxic induction of CAV1 in the colon was essential for intestinal barrier integrity by regulating occludin expression. This may provide an additional mechanism by which chronic hypoxia can activate intestinal inflammation.
Assuntos
Caveolina 1/biossíntese , Colo/metabolismo , Proteínas de Ligação a DNA/genética , Inflamação/imunologia , Ocludina/antagonistas & inibidores , Fatores de Transcrição/genética , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Caveolina 1/genética , Hipóxia Celular/imunologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Duodeno/metabolismo , Receptores ErbB/metabolismo , Células HCT116 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Íleo/metabolismo , Intestino Delgado/metabolismo , Jejuno/metabolismo , Camundongos , Camundongos Transgênicos , Ocludina/biossíntese , Permeabilidade , Regiões Promotoras Genéticas , Transdução de Sinais/genética , Junções Íntimas/genética , Junções Íntimas/patologia , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
Hypoxia-inducible factor (HIF), a key modulator of the transcriptional response to hypoxia, is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. In this study, we found that intestinal epithelium-specific disruption of the von Hippel-Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apc(min/+) intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and HIF-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue; however, tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apc(min/+) mice in which HIF-2α was activated in the intestine. Consistent with this result, bromodeoxyuridine incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis showed that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α-mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings show that a chronic increase in HIF-2α in the colon initiates protumorigenic signaling, which may have important implications in developing preventive and therapeutic strategies for colon cancer.