A disintegrin and metalloproteinase-17 (ADAM17) is a member of the 
metalloproteinase superfamily and involved in the cleavage of ectodomain of many 
transmembrane proteins. ADAM17 is overexpressed in a variety of human tumors, 
which is associated with tumor development and progression. In the present 
study, we sought to investigate the expression and function of ADAM17 in 
hypoxia-treated hepatocellular carcinoma (HCC) cells. Western blot analysis was 
used to measure the expression of ADAM17 in HCC cell lines (Hep3B and HepG2 
cells). Annexin V/PI double staining was performed to analyze the effects of 
ADAM17 on hypoxia-mediated cisplatin resistance. ADAM17 expression was 
upregulated by hypoxia treatment in HCC cells at both mRNA and protein levels. 
Overexpression of ADAM17 reduced cisplatin-induced apoptosis in HCC cells, 
accompanies by less cleavage of caspase-3 and poly (ADP-ribose) polymerase 
(PARP). Forced expression of ADAM17 enhanced the phosphorylation of epidermal 
growth factor receptor (EGFR) and Akt without affecting the expression of total 
EGFR and Akt. Pretreatment with EGFR inhibitor AG1478 or phosphatidylinositol 
3-kinase (PI3K) inhibitor LY294002 rescued ADAM17-mediated cisplatin resistance 
of HCC cells. ADAM17 silencing attenuated hypoxia-induced cisplatin resistance 
and enhanced the accumulation of cleaved caspase-3 and PARP. Western blot 
analysis showed that overexpression of hypoxia-inducible factor-1α (HIF-1α), a 
transcription factor, upregulated the expression of ADAM17 and HIF-1α silencing 
downregulated the expression of ADAM17 in hypoxia-treated HCC cells, indicating 
the regulation of ADAM17 by HIF-1α. Taken together, our results indicated that 
ADAM17 is upregulated by hypoxia and contributes to hypoxia-induced cisplatin 
resistance via EGFR/PI3K/Akt pathway.