Wang Hsiu-Hua, Wang Yao-Chen, Wu De-Wei, Hung Chin-Sheng, Chen Chih-Yi, Lee Huei
1 Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
2 Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
Tumour Biol. 2017 Apr;39(4):1010428317694316. doi: 10.1177/1010428317694316.
Insulin-like growth factor-binding protein-3 acts as a tumor suppressor that inhibits the PI3K/AKT signaling pathway due to blocking insulin growth factor-1 binding to its receptor. We hypothesized that insulin-like growth factor-binding protein-3 might be targeted by microRNA-125b and promote tumor invasion and poor outcome in non-small-cell lung cancer via activation of the PI3K/AKT signaling pathway. Real-time polymerase chain reaction and immunohistochemistry were performed to determine the level of microRNA-125b, insulin-like growth factor-binding protein-3 messenger RNA, and phosphorylated-AKT expression in 105 tumors from non-small-cell lung cancer patients. Low insulin-like growth factor-binding protein-3 messenger RNA levels and positive phosphorylated-AKT expression were more commonly found in patients with high microRNA-125b tumors than low microRNA-125b tumors. A poorer overall survival and relapse-free survival were observed in patients with high microRNA-125b tumors than low-microRNA-125b tumors in p53-mutated patients, but not in p53-wild-type patients. Mechanistically, microRNA-125b promotes invasion ability in p53-mutated cells via the PI3K/AKT activation by targeting of insulin-like growth factor-binding protein-3, but this effect was not observed in p53-wild-type cells. An increase in phosphorylated-AKT expression due to targeting of insulin-like growth factor-binding protein-3 by microRNA-125b was responsible for cell invasion in p53-mutated cells. In conclusion, the microRNA-125b level promotes invasive ability in p53-mutated cells via PI3K/AKT activation by targeting of insulin-like growth factor-binding protein-3, thereby resulting in p53-mutated non-small-cell lung cancer patients with poor outcomes.
胰岛素样生长因子结合蛋白3作为一种肿瘤抑制因子，通过阻止胰岛素生长因子1与其受体结合来抑制PI3K/AKT信号通路。我们推测，微小RNA-125b可能靶向胰岛素样生长因子结合蛋白3，并通过激活PI3K/AKT信号通路促进非小细胞肺癌的肿瘤侵袭和不良预后。采用实时聚合酶链反应和免疫组织化学方法，检测了105例非小细胞肺癌患者肿瘤组织中微小RNA-125b、胰岛素样生长因子结合蛋白3信使核糖核酸水平以及磷酸化AKT的表达。微小RNA-125b水平高的肿瘤患者比微小RNA-125b水平低的患者更常出现胰岛素样生长因子结合蛋白3信使核糖核酸水平低和磷酸化AKT表达阳性的情况。在p53突变的患者中，微小RNA-125b水平高的肿瘤患者比微小RNA-125b水平低的患者总生存期和无复发生存期更差，但在p53野生型患者中未观察到这种情况。机制上，微小RNA-125b通过靶向胰岛素样生长因子结合蛋白3激活PI3K/AKT，促进p53突变细胞的侵袭能力，但在p53野生型细胞中未观察到这种效应。微小RNA-125b靶向胰岛素样生长因子结合蛋白3导致磷酸化AKT表达增加，这是p53突变细胞发生侵袭的原因。总之，微小RNA-125b水平通过靶向胰岛素样生长因子结合蛋白3激活PI3K/AKT，促进p53突变细胞的侵袭能力，从而导致p53突变的非小细胞肺癌患者预后不良。
