HIF2α cooperates with RAS to promote lung tumorigenesis in mice

Abstract

Members of the hypoxia-inducible factor (HIF) family of transcription factors regulate the cellular response to hypoxia. In non-small cell lung cancer (NSCLC), high HIF2α levels correlate with decreased overall survival, and inhibition of either the protein encoded by the canonical HIF target gene VEGF or VEGFR2 improves clinical outcomes. However, whether HIF2α is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2α and a mutant form of Kras (Kras G12D ) that induces lung tumors. Mice expressing both Hif2a and Kras G12D in the lungs developed larger tumors and had an increased tumor burden and decreased survival compared with mice expressing only Kras G12D . Additionally, tumors expressing both Kras G12D and Hif2a were more invasive, demonstrated features of epithelial-mesenchymal transition (EMT), and exhibited increased angiogenesis associated with mobilization of circulating endothelial progenitor cells. These results implicate HIF2α causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2α can promote expression of markers of EMT, and define HIF2α as a promoter of tumor growth and progression in a solid tumor other than renal cell carcinoma. They further suggest a possible causal relationship between HIF2α and prognosis in patients with NSCLC.

Alveolar Hypoxia Promotes Murine Lung Tumor Growth through a VEGFR-2/EGFR-Dependent Mechanism

“…We found a preferential stabilization of HIF-2α accompanied by a decrease in HIF-1α expression both in lungs and tumors from hypoxic mice. HIF-2α overexpression in a conditionally expressed mutant Kras G12D model of lung carcinogenesis resulted in larger tumors, similar to our findings with alveolar hypoxia (9). In patient non small cell lung cancer samples, HIF-1α and HIF-2α overexpression is frequently observed and correlates with the expression of angiogenic factors and poor outcome (35).…”

“…It has been shown that the chronic inflammation characteristic of COPD can promote HIF stabilization by activation of NFκB (8). Mice that conditionally express both a non-degradable variant of HIF-2α and a mutant form of Kras (Kras G12D ) in the lungs developed larger and more invasive tumors, had an increased tumor burden and decreased survival compared with mice expressing only Kras G12D (9). Experiments with HIF-2α deletion unexpectedly demonstrated an increase in tumor burden, associated with a decrease in the candidate tumor suppressor gene Scgb3a1, revealing the complexity of the relationship between HIF-2α expression and tumorigenesis, in which either up or down regulation from basal expression can have similar effects (10).…”

EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming

“…A significant increase in HIF2α was observed in the RP-R-02LM. Increase in HIF2α has been reported to correlate with gene signatures of EMT in lung cancer models (42). We also observed an increase in expression of metastasis associated genes ALDH1A , E2F-1 , SETD2 and EZH2 (42–45).…”

The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network

“…HIF-2α is over expressed in non-small lung carcinoma, renal carcinoma, and glioblastoma. Interestingly, HIF-2α cooperates with K-ras mutant to promote more invasive lung cancer [226]. This cancer is characterized by increased EMT, angiogenesis, and mobilization of endothelial progenitor cells [226].…”

“…Interestingly, HIF-2α cooperates with K-ras mutant to promote more invasive lung cancer [226]. This cancer is characterized by increased EMT, angiogenesis, and mobilization of endothelial progenitor cells [226]. Further, HIF-2α has shown to be predominantly expressed in glioma stem cells compared with non-stem tumor cells and normal neural progenitors [227].…”