Hypoxia-Inducible Factor-1α Suppresses Squamous Carcinogenic Progression and Epithelial-Mesenchymal Transition

Abstract

Hypoxia-inducible factor-1 is a known cancer progression factor, promoting growth, spread, and metastasis. However, in selected contexts HIF-1 is a tumor suppressor coordinating hypoxic cell cycle suppression and apoptosis. Prior studies focused on HIF-1 function in established malignancy, however little is known about its role during the entire process of carcinogenesis from neoplasia induction to malignancy. Here we tested HIF-1 gain of function during multistage murine skin chemical carcinogenesis in K14-HIF-1αPro402A564G (K14-HIF-1αDPM) transgenic mice. Transgenic papillomas appeared earlier and were more numerous, 6±3 transgenic versus 2±1.5 nontransgenic papillomas per mouse, yet they were more differentiated, their proliferation was lower, and their malignant conversion was profoundly inhibited, 7% in transgenic versus 40% in non transgenic mice. Moreover, transgenic cancers maintained squamous differentiation whereas epithelial mesenchymal transformation was frequent in nontransgenic malignancies. Transgenic basal keratinocytes upregulated the HIF-1 target N-myc downstream regulated gene-1, a known tumor suppressor gene in human malignancy, and its expression was maintained in transgenic papillomas and cancer. We also discovered a novel HIF-1 target gene, selenium binding protein-1 (selenbp1), a gene of unknown function whose expression is lost in human cancer. Thus, HIF-1 can function as a tumor suppressor through transactivation of genes that are themselves targets for negative selection in human cancers.

Decreased Selenium-Binding Protein 1 Enhances Glutathione Peroxidase 1 Activity and Downregulates HIF-1α to Promote Hepatocellular Carcinoma Invasiveness

“…The expression of HIF-1a was increased by hydrogen peroxide treatment, as shown by the control groups (SMMC7721 and SMMC7721-Mock), and an increase in SBP1 expressions could also be observed in the same groups. This is consistent with the finding that SBP1 is a target gene for HIF-1a (20). However, in the SMMC7721 groups where SBP1 expression was downregulated by siRNA treatment, the expression of HIF-1a was not elevated by hydrogen peroxide treatment.…”

“…ROS could initiate the activation of HIF-1a (21), whereas HIF-1a could regulate the expression of SBP1 through a hypoxia response element in its promoter region (20). On the basis of this effect, ROS would elevate the expression of SBP1 through HIF-1a mediation.…”

“…SBP1 is also known to have a hypoxia response element in its promoter region and to be a target gene of hypoxia-inducible factor-1a (HIF-1a; ref. 20), which is a fundamental mediator of cellular adaptation to microenvironmental stress, especially oxidative stress (21). The relationship between GPX1 and oxidative stress and the multifunctional role of HIF-1a in cancer biology may be associated with the antitumor activity of SBP1.…”

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

“…Recently, it has been demonstrated that in murine keratinocytes HIF-1α may arrest cell proliferation (14). Because HIF-1α is inducible by hypoxia, a component of ischemia (Figs.…”

HIF-1α silencing suppresses growth of lung adenocarcinoma A549 cells through induction of apoptosis

“…Overexpression of HIF-1α has been detected in >70% of solid tumors. While upregulation or activation of HIF-1α promotes tumor growth, downregulation or loss of HIF-1α activity has been demonstrated to markedly decrease tumor growth, vascularization and energy metabolism (8)(9)(10)(11). The suppression of HIF-1α expression by RNA interference (RNAi) has been shown to be an effective method of cancer therapy (12).…”