Clinicopathological and prognostic significance of HIF-1α and HIF-2α expression in small cell lung cancer.

Previous work from our laboratory has demonstrated that urokinase plasminogen activator receptor (uPAR) may be a potential stem-like cell marker in SCLC. Hypoxia inducible factor (HIF) has been shown to transcriptionally regulate uPAR expression. Therefore, the aim of this study was to evaluate the relationship between HIF-1α/HIF-2α and uPAR expression, and to investigate the role of HIF-1α/HIF-2α in the clinical pathology and prognosis of patients with SCLC. Immunohistochemical analysis showed that HIF-1α/HIF-2α staining was mainly present in the nuclei of cancer cells. HIF-1α-positive cells were diffusely distributed in the nests of the tumor, while HIF-2α-positive cells were frequently distributed around necrotic regions. HIF-1α and HIF-2α were expressed in 22/45 (48.9%) and in 11/45 (24.4%) of SCLC patients, respectively; HIF-1α did not correlate with any of the clinicopathological parameters as evaluated in our study. In contrast, a significant association of HIF-2α with uPAR expression, tumor growth and distant metastasis (p=0.001, 0.010 and 0.008, respectively) was noted; Kaplan-Meier survival analysis demonstrated that HIF-1α and HIF-2α expressions were related to shortened overall survival (p=0.027 and 0.001, respectively). However, in multivariate analysis, only HIF-2α expression and distant metastasis were the independent prognostic indicators of SCLC (p=0.004 and 0.018, respectively). Our results suggest that HIF-2α may represent a more aggressive phenotype in SCLC. HIF-2α, in addition to HIF-1α, needs to be considered when developing drugs that target HIF pathway.