Ren He, Jia Lingling, Zhao Tiansuo, Zhang Huan, Chen Jing, Yang Shaoguang, Liu Jingcheng, Yu Ming, Hao Jihui
National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
School of Public Health, Tianjin Medical University, Tianjin, China.
Cancer Lett. 2014 Nov 1;354(1):172-80. doi: 10.1016/j.canlet.2014.08.001. Epub 2014 Aug 15.
The aim of this study is to investigate the regulatory mechanism of leptin receptors (Ob-R) in pancreatic cancer. We found that the over-expression of hypoxia inducible factor (HIF-1)α and hypoxia up-regulated the expression of Ob-R in pancreatic cancer cells. When HIF-1α gene was silenced in vitro, the expression of Ob-R was significantly decreased. Xenograft mouse models showed that the inhibition of HIF-1α resulted in the concomitant decrease of Ob-R in vivo. In addition, HIF-1α expression was correlated with Ob-R in pancreatic cancer tissues by immunohistochemical staining. Clinical data showed that over-expression of HIF-1 was associated with pathological tumor node metastasis stage, lymph node metastasis and overall survival. HIF-1α directly bound to the hypoxia-responsive element (HRE) located in Ob-R gene promoter (-828/-832) and activated the transcription. Finally, we demonstrated that the silence of HIF-1α gene reversed the inhibitory effect of leptin/Ob-R in pancreatic cancer cells. Taken together, our results indicate that HIF-1α directly regulated Ob-R expression in pancreatic cancer, which might be a valuable therapeutic target for pancreatic cancer.
本研究旨在探讨瘦素受体（Ob-R）在胰腺癌中的调控机制。我们发现缺氧诱导因子（HIF-1）α的过表达以及缺氧上调了胰腺癌细胞中Ob-R的表达。当在体外沉默HIF-1α基因时，Ob-R的表达显著降低。异种移植小鼠模型显示，抑制HIF-1α会导致体内Ob-R随之减少。此外，通过免疫组织化学染色发现胰腺癌组织中HIF-1α表达与Ob-R相关。临床数据表明，HIF-1的过表达与肿瘤病理分期、淋巴结转移及总生存期相关。HIF-1α直接结合位于Ob-R基因启动子（-828/-832）的缺氧反应元件（HRE）并激活转录。最后，我们证明沉默HIF-1α基因可逆转瘦素/Ob-R对胰腺癌细胞的抑制作用。综上所述，我们的结果表明HIF-1α直接调控胰腺癌中Ob-R的表达，这可能是胰腺癌一个有价值的治疗靶点。
