title: Artemin is hypoxia responsive and promotes oncogenicity and increased tumor initiating capacity in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Anhui Medical University, Hefei, China.
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Shumin
authors.initials: S
authors.lastname: Liu
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Linchong
authors.initials: L
authors.lastname: Sun
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Yanghao
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Kong
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Pengxu
authors.initials: P
authors.lastname: Qian
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
authors.affiliation: The 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.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C490886:ARTN protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger
keywords: ARTN; cancer stem cell; hepatocellular carcinoma; hypoxia