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Tumor cell endogenous HIF-1alpha activity induces aberrant angiogenesis and interacts with TRAF6 pathway required for colorectal cancer development

ABSTRACT: Hypoxia and inflammation are key factors for colorectal cancer tumorigenesis. The colonic epithelium belongs to the tissues with the lowest partial pressure of oxygen in the body, and chronic inflammation is associated with an increased chance to develop colon cancer. How the colonic epithelium responds to hypoxia and inflammation during tumorigenesis remains to be elucidated. Here we show, that murine colon adenocarcinoma cells with attenuated response to hypoxia, due to a knock-down (KD) of HIF-1alpha produce smaller and less hypoxic tumors in an orthotopic mouse model when compared to tumors induced with control cells. HIF-1alpha-KD tumors showed more functional perfused vasculature associated with increased levels of vessel-stabilizing factors and reduced levels of pro-angiogenic factors, including extracellular matrix protein Cyr61/CCN1. Intratumoral injection of Cyr61 in HIF-1alpha-KD tumors revealed an in increased vessel permeability and tumor hypoxia. Further bioinformatics analysis identified a possible interaction between HIF-1alpha and TRAF6, an upstream effector of the NF-kappaB pathway that was confirmed by co-immunoprecipitation in MC-38 and CT26 colon adenocarcinoma cells. Down-regulation of TRAF6 resulted in virtual abrogation of orthotopic tumor growth. Subcutaneous TRAF6-KD tumors were smaller and contained reduced vessel size and differently polarized macrophages. These data demonstrate that the tumor cell response to increased hypoxia in the colon leads to promotion of non-functional angiogenesis, regulated by both hypoxia and TRAF6 pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE155104 | GEO | 2020/11/09

REPOSITORIES: GEO

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Project description:To identify the precise molecular mechanisms that could contribute to the increase in colon carcinogenesis, microarray gene expression analysis was performed on colon RNA isolated from 5-week-old VhlF/F and VhlΔIE, VhlΔIE/Apcmin/+ and VhlF/F/Apcmin/+ mice. Hypoxia-inducible factor (HIF) is a key modulator of the transcriptional response to hypoxia and is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. 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 Apcmin/+ 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 Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistent with this result, BrdU incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis demonstrated 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 demonstrate that a chronic increase in HIF-2α in the colon initiates pro-tumorigenic signaling which may have important implications in developing preventive and therapeutic strategies for colon cancer. Global gene expression profiling in colon RNAs isolated from 5-week-old VhlF/F (n=4, Shah 001), VhlF/F/Apcmin/+(n=3, Shah 003), VhlΔIE (n=3, Shah 002) and VhlΔIE/Apcmin/+ mice (n=5, Shah 004).

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Tumor cell endogenous HIF-1alpha activity induces aberrant angiogenesis and interacts with TRAF6 pathway required for colorectal cancer development

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