X‐Linked Inhibitor of Apoptosis Protein (XIAP) Contributes to ERK1/2‐Mediated Anoikis Resistance in Hepatocellular Carcinoma

ABSTRACT X‐linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein that regulates many cellular functions. Anoikis resistance is necessary for hepatocellular carcinoma (HCC) intrahepatic spread and extrahepatic metastasis. However, limited information is available regarding the mechanism of XIAP underlying the resistance of HCC cells to anoikis. Here we show an increased expression of XIAP in microvascular tumor thrombosis (MVTT) of HCC, which is positively correlated with the expression of extracellular signal‐regulated kinases 1/2 (ERK1/2). HCC cells exhibit an increase in XIAP expression when detached, leading to their resistance to anoikis. Furthermore, enhanced phosphorylation of XIAP promotes resistance to anoikis in HCC cells. In addition, the zinc‐binding baculovirus IAP repeat (BIR) domains of XIAP, instead of the highly intriguing novel gene (RING) domain, are responsible for conferring resistance to anoikis in HCC cells. Importantly, our findings indicate that ERK1/2 can control the expression of XIAP, leading to the resistance of HCC to anoikis in cell‐based and mouse models. The significance of the interaction between XIAP and ERK1/2 in resisting anoikis is emphasized by our discoveries, presenting novel avenues for HCC treatment.