Oncotarget

Research Papers:

Gemcitabine-induced heparanase promotes aggressiveness of pancreatic cancer cells via activating EGFR signaling

Jin-Wen Song, Ying-Xia Tan, Su-Bo Li, Shi-Kun Zhang, Lu-Ming Wan, Shou-Ping Ji, Hong Zhou, Zhi-Hang Zhou and Feng Gong _

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Oncotarget. 2017; 8:58417-58429. https://doi.org/10.18632/oncotarget.16911

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Abstract

Jin-Wen Song1, Ying-Xia Tan1, Su-Bo Li1, Shi-Kun Zhang1, Lu-Ming Wan1, Shou-Ping Ji1, Hong Zhou2, Zhi-Hang Zhou3 and Feng Gong1

1Department of Tissue Engineering, Beijing Institute of Transfusion Medicine, Beijing, China

2Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China

3Department of Pathology, The 309th Hospital of People’s Liberation Army, Beijing, China

Correspondence to:

Feng Gong, email: gongfeng@bmi.ac.cn

Zhi-Hang Zhou, email: zhouzhihang@yeah.net

Keywords: gemcitabine, pancreatic cancer, HPA1, EGFR, NF-κ B

Received: December 14, 2016     Accepted: March 16, 2017     Published: April 07, 2017

ABSTRACT

Pancreatic cancer (PC), characterized by aggressive local invasion and metastasis, is one of the most malignant cancers. Gemcitabine is currently used as the standard drug for the treatment of advanced and metastatic PC, but with limited efficacy. In this study, we demonstrated that gemcitabine increased the expression of heparanase (HPA1), the only known mammalian endoglycosidase capable of cleaving heparan sulfate, both in vitro and in vivo. Furthermore, overexpression of HPA1 in PC cell lines enhanced proliferation and invasion, accompanied with elevated phosphorylation of EGFR. In addition, we showed that the NF-κB pathway mediated the gemcitabine-induced HPA1 expression. Importantly, we found that an HPA1 inhibitor attenuated gemcitabine-induced invasion of PC cells. Finally, we showed that HPA1 was of negative prognostic value for PC patients. Taken together, our results demonstrated that gemcitabine-induced HPA1 promotes proliferation and invasion of PC cells through activating EGFR, implying that HPA1 may serve as promising therapeutic target in the treatment of PC.


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