β_2肾上腺素受体通过HIF-1α调控NNK诱导的胰腺癌细胞进展  

β_2-adrenogenic receptor mediates NNK-induced pancreatic cancer progression through HIF-1α

作　　者：沙焕臣[1] 雷建军[1] 王铮[1] 段万星[1] 徐勤鸿[1] 黎韡[1] 韩亮[1] 马清涌[1] 张东[1] SHA Huan-chen;LEI Jian-jun;WANG Zheng;DUAN Wan-xing;XU Qin-hong;LI Wei;HAN Liang;MA Qing-yong;ZHANG Dong(Department of Hepatobiliary Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an 710061,China)

机构地区：[1]西安交通大学第一附属医院肝胆外科,陕西西安710061

出　　处：《西安交通大学学报（医学版）》2018年第5期670-674,697,共6页Journal of Xi’an Jiaotong University（Medical Sciences）

基　　金：国家自然科学基金资助项目(No.81302153)~~

摘　　要：目的探讨β_2肾上腺素受体在4-甲基亚硝氨基-3-吡啶-1-丁酮(NNK)诱导胰腺癌细胞进展中的具体作用机制。方法采用NNK干预胰腺癌MIA PaCa-2和BxPC-3细胞,通过HIF-1α-shRNA稳定转染胰腺癌细胞及运用ICI118551,以NNK组作为对照,Transwell小室侵袭试验检测各组胰腺癌细胞的侵袭能力,Western blot检测HIF-1α、Cyclin D1和VEGF蛋白表达水平。流式细胞技术检测各组细胞周期变化。结果 NNK能够显著上调MIA PaCa-2和BxPC-3细胞HIF-1α水平及促进胰腺癌细胞的增殖及侵袭能力;β_2肾上腺素受体抑制剂ICI 118551及sh-HIF-1α能够显著下调NNK所诱导的MIA PaCa-2和BxPC-3细胞HIF-1α水平,以及抑制胰腺癌细胞的增殖及侵袭能力。另外,运用CoCl2上调HIF-1α表达水平后能够逆转ICI 118551对NNK效应的抑制作用,重新上调胰腺癌细胞的侵袭能力。结论β_2肾上腺素受体通过HIF-1α来介导NNK诱导的胰腺癌细胞增殖及侵袭。Objective To explore the mechanism ofβ2-adrenogenic receptor mediating the progression of NNK-induced pancreatic cancer cells.Methods Pancreatic cancer cell lines(MIA PaCa-2 and BxPC-3)were incubated with NNK.ShRNA targeting HIF-1αwas applied to knockdown HIF-1αexpression.ICI 118551 was used to inhibitβ2-adrenogenic receptor signaling.Invasion of MIA PaCa-2 and BxPC-3 cells was detected by Transwell assay.The protein expressions of HIF-1α,Cyclin D1 and VEGF were determined by Western blot.Cell cycle was determined by flow cytometric analysis.Results NNK could significantly upregulate HIF-1αexpression in MIA PaCa-2 and BxPC-3 cells and increase the invasion and proliferation of pancreatic cancer cells.However,ICI 118551 or sh-HIF-1αcould reverse the effect of NNK on MIA PaCa-2 and BxPC-3 cells.Furthermore,when HIF-1αexpression was upregulated by CoCl 2,the inhibitory effect of ICI 118551 on NNK was reversed,with a prominent increase in pancreatic cancer cell invasion.Conclusionβ2-adrenogenic receptor mediates the invasion and proliferation of NNK-induced pancreatic cancer cells through HIF-1α.

关 键 词：4-甲基亚硝氨基-3-吡啶-1-丁酮 Β2肾上腺素受体 HIF-1Α 胰腺癌 

分 类 号：R735.9[医药卫生—肿瘤]