Department of Pathology, Tianjin Medical University, Tianjin, China.
Pathol Res Pract. 2013 Mar;209(3):184-9. doi: 10.1016/j.prp.2012.10.017. Epub 2013 Feb 1.
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.
先前我们实验室的工作表明，尿激酶型纤溶酶原激活物受体（uPAR）可能是 SCLC 中潜在的干细胞样细胞标志物。缺氧诱导因子（HIF）已被证明可转录调控 uPAR 的表达。因此，本研究旨在评估 HIF-1α/HIF-2α 与 uPAR 表达之间的关系，并研究 HIF-1α/HIF-2α 在 SCLC 患者临床病理和预后中的作用。免疫组织化学分析表明，HIF-1α/HIF-2α 染色主要存在于癌细胞的核内。HIF-1α 阳性细胞在肿瘤巢中弥漫分布，而 HIF-2α 阳性细胞常分布在坏死区周围。HIF-1α 和 HIF-2α 在 45 例 SCLC 患者中的表达分别为 22/45（48.9%）和 11/45（24.4%）；在我们的研究中，HIF-1α 与评估的任何临床病理参数均无相关性。相比之下，HIF-2α 与 uPAR 表达、肿瘤生长和远处转移显著相关（p=0.001、0.010 和 0.008）；Kaplan-Meier 生存分析表明，HIF-1α 和 HIF-2α 的表达与总生存期缩短相关（p=0.027 和 0.001）。然而，在多变量分析中，只有 HIF-2α 表达和远处转移是 SCLC 的独立预后指标（p=0.004 和 0.018）。我们的研究结果表明，HIF-2α 可能代表 SCLC 中更具侵袭性的表型。在开发靶向 HIF 通路的药物时，除了 HIF-1α 之外，还需要考虑 HIF-2α。
