Artemin is hypoxia responsive and promotes oncogenicity and increased tumor initiating capacity in hepatocellular carcinoma
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Min Zhang1,2,*, Weijie Zhang1,2,*, Zhengsheng Wu3, Shumin Liu1,2, Linchong Sun1,2, Yanghao Zhong1,2, Xiao Zhang1,2, Xiangjun Kong1,2, Pengxu Qian1,2, Huafeng Zhang1,2, Peter E. Lobie4, Tao Zhu1,2
1The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China
2Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China
3Department of Pathology, Anhui Medical University, Hefei, China
4Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore
*These authors have contributed equally to this work
Tao Zhu, e-mail: firstname.lastname@example.org
Peter Lobie, e-mail: email@example.com
Keywords: hypoxia, ARTN, hepatocellular carcinoma, cancer stem cell
Received: July 29, 2015 Accepted: November 21, 2015 Published: December 12, 2015
Hypoxia has been reported to regulate the cancer stem cell (CSC) population yet the underlying mechanism is poorly characterized. Herein, we show that Artemin (ARTN), a member of the glial cell derived neurotrophic factor family of ligands, is a hypoxia-responsive factor and is essential for hypoxia-induced CSC expansion in hepatocellular carcinoma (HCC). Clinically, elevated expression of ARTN in HCC was associated with larger tumor size, faster relapse and shorter survival. In vitro, HCC cells with forced expression of ARTN exhibited reduced apoptosis, increased proliferation, epithelial-mesenchymal transition (EMT) and enhanced motility. Additionally, ARTN dramatically increased xenograft tumor size and metastasis in vivo. Moreover, ARTN also enhanced tumorsphere formation and the tumor initiating capacity of HCC cells, consequent to expansion of the CD133+ CSC population. ARTN transcription was directly activated by hypoxia-induced factor-1α (HIF-1α) and hypoxia induced ARTN promoted EMT and increased the CSC population via AKT signaling. We herein identify a novel HIF-1α/ARTN axis promoting CSC-like behavior in hypoxic environments which implicates ARTN as a valuable therapeutic target for HCC.
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