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.

A signature of 33 immune‐related gene pairs predicts clinical outcome in hepatocellular carcinoma

“…It has been reported that macrophages can be recruited into HCC tissue by SEMA3A, and overexpression of SEMA3A indicates poor prognosis in hepatocellular carcinoma . Artemin was shown to be related to early relapse, shortened overall survival and large tumor size . The involvement of all the above mentioned genes indicates that immune processes contribute to tumor development and prognosis.…”

Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma

“…Artemin promotes the metastatic properties and tumor-initiating capacity of HCC by AKT modulation of factors involved in EMT and stemness [83]. Chronic hepatitis C virus (HCV) infection, an important factor in the etiology of HCC, is also associated with EMT and CSC pathways.…”

“…A recent study suggested that during hypoxia, HIF-1α upregulated Artemin expression and this in turn promoted CSC and EMT functions in HCC [83]. Won et al demonstrated that hypoxia could trigger Stat3-mediated CD133 upregulation with concomitant enhanced HIF-1α levels [96].…”

Aberrant erythropoiesis fuels tumor growth

“…Over the past few years, pro-tumor functions of artemin have gain prominence. 8,9 In this study, authors provide robust evidence that artemin promotes HCC progression and could be a potential therapeutic target. More importantly, it is noteworthy that artemin production is predominantly regulated by an erythroid lineage subset, namely Ter-cells.…”