Health Professions Division, Rumbaugh Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33313, USA.
J Cell Mol Med. 2012 Aug;16(8):1750-7. doi: 10.1111/j.1582-4934.2011.01472.x.
On the basis of increasing roles for HDM2 oncoprotein in cancer growth and progression, we speculated that HDM2 might play a major role in hypoxia-induced metastatic process. For verification of this hypothesis, wild-type LNCaP prostate cancer cells and HDM2 transfected LNCaP-MST (HDM2 stably transfected) cells were studied. The data obtained from our experiments revealed that the HDM2 transfected LNCaP-MST cells possessed an ability to multiply rapidly and show distinct morphological features compared to non-transfected LNCaP cells. During exposures to hypoxia HDM2 expression in the LNCaP and LNCaP-MST cells was significantly higher compared to the normoxic levels. The LNCaP-MST cells also expressed higher levels of HIF-1α (hypoxia-inducible factor-1α) and p-STAT3 even under the normoxic conditions compared to the non-transfected cells. The HIF-1α and p-STAT3 expressions were increased several fold when the cells were subjected to hypoxic conditions. The HIF-1α and p-STAT3 protein expressions observed in HDM2 transfected LNCaP-MST cells were 20 and 15 folds higher, respectively, compared to the non-transfected wild-type LNCaP cells. These results demonstrate that HDM2 may have an important regulatory role in mediating the HIF-1α and p-STAT3 protein expression during both normoxic and hypoxic conditions. Furthermore, the vascular endothelial growth factor (VEGF) expression that is typically regulated by HIF-1α and p-STAT3 was also increased significantly by 136% (P < 0.01) after HDM2 transfection. The overall results point towards a novel ability of HDM2 in regulating HIF-1α and p-STAT3 levels even in normoxic conditions that eventually lead to an up-regulation of VEGF expression.
基于 HDM2 癌蛋白在癌症生长和进展中的作用不断增加，我们推测 HDM2 可能在缺氧诱导的转移过程中发挥主要作用。为了验证这一假说，我们研究了野生型 LNCaP 前列腺癌细胞和 HDM2 转染的 LNCaP-MST（HDM2 稳定转染）细胞。我们的实验数据表明，与未转染的 LNCaP 细胞相比，HDM2 转染的 LNCaP-MST 细胞具有快速增殖和明显形态特征的能力。在暴露于缺氧环境下时，LNCaP 和 LNCaP-MST 细胞中的 HDM2 表达水平明显高于常氧水平。与未转染的细胞相比，LNCaP-MST 细胞在常氧条件下甚至表达更高水平的 HIF-1α（缺氧诱导因子-1α）和 p-STAT3。当细胞处于缺氧条件下时，HIF-1α 和 p-STAT3 的表达增加了数倍。在 HDM2 转染的 LNCaP-MST 细胞中观察到的 HIF-1α 和 p-STAT3 蛋白表达水平分别比未转染的野生型 LNCaP 细胞高 20 倍和 15 倍。这些结果表明，HDM2 可能在介导常氧和缺氧条件下的 HIF-1α 和 p-STAT3 蛋白表达中具有重要的调节作用。此外，通常受 HIF-1α 和 p-STAT3 调节的血管内皮生长因子（VEGF）表达在 HDM2 转染后也显著增加了 136%（P<0.01）。总体结果表明，HDM2 具有一种新的能力，即使在常氧条件下也能调节 HIF-1α 和 p-STAT3 水平，最终导致 VEGF 表达上调。
