Activation of HIF-1α does not increase intestinal tumorigenesis

Xue, Xiang; Ramakrishnan, S; Shah, Yatrik M.

doi:10.1152/ajpgi.00112.2014

Cited by 45 publications

(41 citation statements)

References 55 publications

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“…Microarray analysis was done as previously described (Xue et al, 2014). The full data set is available on the Gene Expression Omnibus database accession number GSE65104.…”

Section: Methodsmentioning

confidence: 99%

Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

et al. 2016

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Summary Dietary iron intake and systemic iron balance are implicated in colorectal cancer (CRC) development, but the means by which iron contributes to CRC are unclear. Gene expression and functional studies demonstrated that the cellular iron importer, divalent metal transporter 1 (DMT1), is highly expressed in CRC through hypoxia inducible factor 2α-dependent transcription. Colon-specific Dmt1 disruption resulted in a tumor-selective inhibitory effect of proliferation in mouse colon tumor models. Proteomic and genomic analysis identified an iron-regulated signaling axis mediated by cyclin dependent kinase 1 (CDK1), JAK1 and STAT3 in CRC progression. A pharmacological inhibitor of DMT1 antagonized the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model. Our studies implicate a growth-promoting signaling network instigated by elevated intracellular iron levels in tumorigenesis, offering molecular insights into how a key dietary component may contribute to CRC.

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“…Microarray analysis was done as previously described (Xue et al, 2014). The full data set is available on the Gene Expression Omnibus database accession number GSE65104.…”

Section: Methodsmentioning

confidence: 99%

Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

et al. 2016

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“…Karhausen et al 8 showed that loss of epithelial HIF-1a led to severe intestinal inflammation, whereas an increase in epithelial HIF protein was protective. Xue et al 9 recently reported that activation of HIF-1a in intestinal epithelial cells did not increase intestinal tumorigenesis. Reduction of epithelial cell apoptosis in murine colitis by 1 inhibition of HIF-1 degradation by the hydroxylase inhibitor dimethyloxalylglycine underscores the importance of HIF-1 in the intestinal epithelium.…”

Section: Introductionmentioning

confidence: 98%

Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis

et al. 2016

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Dendritic cells (DCs) serve as a bridge between innate and adaptive immunity and help to maintain intestinal homeostasis. Inflammatory bowel disease (IBD) is associated with dysregulation of the mucosal immune response. The concomitant hypoxic inflammation in IBD will activate the transcription factor hypoxia-inducible factor-1 (HIF-1) to also drive gene expression in DCs. Recent studies have described a protective role for epithelial HIF-1 in mouse models of IBD. We investigated the role of HIF-1 in DC function in a dextran sodium sulfate (DSS)-induced model of murine colitis. Wild-type and dendritic cell-specific HIF-1α knockout mice were treated with 3% DSS for 7 days. Knockout of HIF-1α in DCs led to a significantly larger loss of body weight in mice with DSS-induced colitis than in control mice. Knockout mice exhibited more severe intestinal inflammation with increased levels of proinflammatory cytokines and enhanced production of mucin. Induction of regulatory T cells (Tregs) was impaired, and the number of forkhead box P3 (Foxp3) Tregs was diminished by dendritic HIF-1α knockout. Our findings demonstrate that in DCs HIF-1α is necessary for the induction of sufficient numbers of Tregs to control intestinal inflammation.

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“…Additionally, HIF-2␣ is a transcriptional regulator of proinflammatory cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase (mPGES) to in-crease tumor inflammation, and treatment of HIF-2␣-overexpressing mice with the anti-inflammatory nimesulide can reduce colon tumorigenesis (47). Interestingly, HIF-1␣ activation has no effect on colon tumorigenesis (48). Similarly, we found that HIF-1␣ has no effect on the expression of Cxcl1.…”

Section: Discussionmentioning

confidence: 67%

Epithelial Hypoxia-Inducible Factor 2α Facilitates the Progression of Colon Tumors through Recruiting Neutrophils

Triner

Xue

Schwartz

et al. 2017

Molecular and Cellular Biology

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Inflammation is a significant risk factor for colon cancer. Recent work has demonstrated essential roles for several infiltrating immune populations in the metaplastic progression following inflammation. Hypoxia and stabilization of hypoxiainducible factors (HIFs) are hallmark features of inflammation and solid tumors. Previously, we demonstrated an important role for tumor epithelial HIF-2␣ in colon tumors; however, the function of epithelial HIF-2␣ as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2␣ was essential in tumor growth. Concurrently, epithelial disruption of HIF-2␣ significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2␣-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2␣ signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2␣-overexpressing mice in conjunction with data mining from the Cancer Genome Atlas showed that the neutrophil chemokine CXCL1 gene was highly upregulated in colon tumor epithelium in a HIF-2␣-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2␣-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2␣ is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer.KEYWORDS HIF-2␣, inflammation, colon cancer, cancer, colon, hypoxia, neutrophils C olon cancer remains a significant public health concern and is the second leading cause of cancer-associated deaths in the United States (1). Patients with chronic inflammation associated with inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, are at an increased lifetime risk of developing colon cancer; these tumors are termed colitis-associated cancers (CAC) (2). The genetic changes of sporadic colon cancer have been well defined, and a comprehensive genetic analysis of CAC was recently reported (3). In contrast to sporadic colon cancer, CAC are associated with early loss of the TP53 tumor suppressor and less frequent inactivation of adenomatous polyposis coli (APC) (4). Inflammation is an important component of the progression of sporadic cancer, and the inflammatory response is essential in the initiation and progression of CAC (5). The precise mechanisms that initiate the protumorigenic response following inflammation remain unknown.Hypoxia is a characteristic feature of IBD and nearly all solid tumors, including those of the colon (6). Hypoxia promotes activation of the hypoxia-inducible factors (HIFs). HIFs consist of a heterodimer of an O 2 -labile ␣-subunit (HIF-1␣, HIF-2␣, and HIF-3␣) and an O 2 -stable ␤-subunit (ARNT) (7). HIFs regulate transcription of target genes that mediate cellular responses to hypoxic microenvironments. HIFs are also essenti...

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Activation of HIF-1α does not increase intestinal tumorigenesis

Cited by 45 publications

References 55 publications

Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis

Epithelial Hypoxia-Inducible Factor 2α Facilitates the Progression of Colon Tumors through Recruiting Neutrophils

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