Hypoxia Inducible Factor 1α and Hypoxia Inducible Factor 2α Play Distinct and Functionally Overlapping Roles in Oral Squamous Cell Carcinoma

Abstract

Purpose: This study aimed to investigate the functional difference between hypoxia inducible factor (HIF)-1α and HIF-2α in oral squamous cell carcinomas (OSCC).Experimental Design: We evaluated the correlations between HIF-1α and HIF-2α expression and the clinical-pathologic characteristics of 97 patients with OSCC by immunohistochemical staining. OSCC cell lines transfected with lentivirus encoding short hairpin RNA against HIF-1α/2α were used to investigate the HIF-1α/2α-dependent target genes. Xenograft tumors in nude mice were established using cells affected by lentivirus, and tumor growth, angiogenesis, proliferation, and apoptosis were measured.Results: HIF-1α expression was significantly associated with T stage (P = 0.004), lymph node involvement (P = 0.006), histologic differentiation (P = 0.013), and microvessel density (P = 0.014), whereas that of HIF-2α was associated with T stage (P = 0.011) and microvessel density (P = 0.005). Patients with positive HIF-1α nuclear staining had a significantly worse overall survival (P < 0.001) and disease-free survival (P < 0.001) than those with negative HIF-1α staining. When OSCC cells were cultured at 5% O 2 , only HIF-2α contributed to the expression of vascular endothelial growth factor. At 1% O 2 , vascular endothelial growth factor was regulated by both HIF-1α and HIF-2α, but glucose transporter 1, carbonic anhydrase 9, and urokinase-type plasminogen activator receptor were regulated by HIF-1α rather than by HIF-2α. Knocking down HIF-1α or HIF-2α individually inhibited the xenograft tumor angiogenesis and growth, and knocking them down simultaneously revealed a better inhibitory effect than knocking down either unit alone.

Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype

“…HIF-1a and HIF-2a activate a set of genes that facilitate tumor growth, angiogenesis, and metastasis (8,9). Although HIF-1a and HIF-2a have striking similarities in structure, function, and regulation, many lines of evidence suggest that these two HIF-a proteins play distinct and functionally overlapping roles in tumor progression (10).…”

HIF-2α as a prognostic marker for breast cancer progression and patient survival

“…Both the univariate and multivariate analyses indicated that HIF-2α expression was an independent prognostic factor for breast cancer progression. Several recent studies have demonstrated that the expression of HIF-2α is upregulated in several types of solid tumors, including colorectal, gastric, oral squamous cell carcinoma, and non-small cell lung cancer (Wang et al, 2010;Zhu et al, 2010;Xue et al, 2012). The widespread overexpression of HIF-2α in cancer has led to the belief that HIF-2α is an oncogenic gene.…”

The Cellular Microenvironment of Head and Neck Squamous Cell Carcinoma

“…Tumor hypoxia also plays an important role in the release of angiogenic growth factors. Under hypoxic conditions stabilization of the hypoxia inducible factor 1 (HIF-1 ) in tumor cells allows transcription of genes involved in angiogenesis and other critical aspects of tumor maintenance [66,67]. Semaphorin 4D strongly induced by HIF-1 , binds to plexin B1 on endothelial cells inducing migration [68].…”