β2-adrenogenic signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α
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Dong Zhang1,*, Jianjun Lei1,*, Jiguang Ma2, Xin Chen1, Liang Sheng1, Zhengdong Jiang1, Ligang Nan1, Qinhong Xu1, Wanxing Duan1, Zheng Wang1, Xuqi Li3, Zheng Wu1, Erxi Wu4, Qingyong Ma1, Xiongwei Huo3
1Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
2Department of Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
3Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
4Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, 76508, USA
*These authors have contributed equally to this work
Xiongwei Huo, e-mail: firstname.lastname@example.org
Qingyong Ma, e-mail: email@example.com
Keywords: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, smoking, β2-adrenogenic signaling, HIF-1α, pancreatic cancer
Received: May 04, 2015 Accepted: September 13, 2015 Published: October 16, 2015
Cigarette smoking is a risk factor for pancreatic cancer. It is suggested that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, we show that smoking, HIF-1α expression and β2-adrenogenic receptor (β2-AR) expression are negatively correlated with the overall survival of pancreatic cancer patients. Moreover, HIF-1α expression and β2-AR expression are positively correlated with smoking status, different histological differentiation and among the tumor node metastasis (TNM) stages in pancreatic cancer patients. NNK increases HIF-1α expression in pancreatic cancer in vitro and in vivo. Furthermore, knockdown of HIF-1α and ICI118, 551 (a β2-AR selective antagonist) abrogates NNK-induced pancreatic cancer proliferation and invasion in vitro and inhibits NNK-induced pancreatic cancer growth in vivo. However, using CoCl2 (a HIF-1α stabilizing agent which decreases HIF-1α degradation under normoxia conditions) reverses ICI118, 551 induced effects under NNK exposure. Thus, our data indicate that β2-AR signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. Taken together, β2-AR signaling and HIF-1α may represent promising therapeutic targets for preventing smoking induced pancreatic cancer progression.
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