WITHDRAWN: NNK promotes chronic pancreatitis to pancreatic intraepithelial neoplasia and accelerates pancreatic cancer migration

Abstract

// Xin Chen 1,* , Liang Sheng 1,* , Jiguang Ma 2 , Zhengdong Jiang 1 ,Qinhong Xu 1 , Jianjun Lei 1 , Wanxing Duan 1 , Ligang Nan 1 , Xuqi Li 3 , Zheng Wang 1 , Zheng Wu 1 , Jun Xu 1 , Fengfei Wang 4,5,6,7 , Jason H. Huang 4,6,7 , Erxi Wu 4,6,7,8 , Qingyong Ma 1 and Dong Zhang 1 1 The Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China 2 The Department of Anesthesiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China 3 The Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China 4 Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, USA 5 Department of Neurology, Baylor Scott & White Health, Temple, TX, USA 6 Neuroscience Institute, Baylor Scott & White Health, Temple, TX, USA 7 Department of Surgery, Texas A & M University College of Medicine, Temple, TX, USA 8 Department of Pharmaceutical Sciences, Texas A & M University College of Pharmacy, College Station, TX, USA * These authors have contributed equally to this work Correspondence to: Erxi Wu, email: erxi.wu@bswhealth.org Qingyong Ma, email: qyma56@mail.xjtu.edu.cn Dong Zhang, email: pavilion1021@hotmail.com Keywords : 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; sonic hedgehog pathway; chronic pancreatitis; pancreatic cancer Received: October 21, 2017     Accepted: December 11, 2017     Epub: December 25, 2017 Abstract Smoking has been identified as a categorical environmental risk factor for pancreatic cancer, while the underlying mechanism remains unclear. In the present study, we collect 62 patient samples to explore the effect of smoking on chronic pancreatitis and pancreatic cancer. The biological effect of cigarette carcinogen 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) on pancreatic cancer cells and chronic pancreatitis is determined in vitro and in vivo . We show that smoking promotes Kras mutation and P16 methylation. Through activating Sonic Hedgehog signaling, NNK greatly facilitates the growth and migration of pancreatic cancer cells. More importantly, NNK promotes acinar-to-ductal metastasis (ADM) and pancreatic intraepithelial neoplasia (PanINs) formation in chronic pancreatitis rats, accompanied by desmoplastic reaction and Gli 1 overexpression. Taken together, we reveal that NNK not only promotes the initiation but also accelerates the biological behavior of pancreatic cancer.