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.
Highlights
Hepatocellular carcinoma (HCC), the most prevalent primary malignancy of the liver, has become the second leading cause of cancer death globally
In an attempt to define the clinical relevance of ARTN expression in HCC, we evaluated the abundance of ARTN protein in archived HCC specimens (n = 150) and adjacent non-tumorous liver tissues (n = 20) by immunohistochemistry (IHC)
Thirteen of twenty patients were positive for expression of ARTN protein in tumors compared with five of twenty adjacent nontumorous tissues (P = 0.0284), which further exemplifies that the expression of ARTN is elevated in HCC (Supplementary Figure S1A)
Summary
Hepatocellular carcinoma (HCC), the most prevalent primary malignancy of the liver, has become the second leading cause of cancer death globally. The incidence of HCC has been rising in the past decade [1]. The prevalence of HCC in parts of Africa and Asia is predominantly due to chronic hepatitis B and hepatitis C virus infection induced liver cirrhosis [2]. It is apparent that specific growth factors may be involved in HCC progression. IGF signaling is activated in HCC and IGF-1R blockage provides effective anti-tumor activity [5]. High levels of TGF-β and CXCR4 confer HCC cells with a mesenchymallike phenotype, which contributes to tumor progression and dissemination [6]. Growth factors orchestrate signaling pathways to regulate HCC progression
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