Purpose HSP70/HSP90-organizing protein(HOP)is an adaptor protein that mediates HSP70 and HSP90 folding.Recent studies reported that HOP can be secreted by(some)cancer cells and promote malignant cell growth in an autocrine manner.Here,we studied the role of HOP in gastric cancer(GC).Experimental design MRNA and protein expression of HOP was assessed in GC tumor and adjacent normal tissues,and circulating HOP levels were measured in serum of GC patients and age-matched normal controls by ELISA.HOP expression was analyzed in 117 GC patients by immunohistochemistry and correlated with clinical outcomes.Functional role of HOP in regulating cell proliferation and apoptosis was interrogated using antibody neutralization or addition of exogenous recombinant HOP to GC cell lines cultures in vitro.Results HOP mRNA and protein levels were significantly higher in GC tissues than those in normal tissues in our medical center(P<0.001)and TCGA database(P<0.001).GC patients have higher serum HOP than age-matched healthy controls(P<0.001).Strikingly,once tumors were removed,serum HOP significantly decreased(P=0.0012).In human GC tissues,increased HOP expression was associated with tumor progression and poor survival.Notably,we demonstrated that autocrine HOP promoted cell proliferation through phospholipase Cγ1(PLCγ1)-ERK1/2 dependent pathways,and inhibited cell apoptosis via regulating the activity of caspase-9,caspase-3 and BCL-2.Blocking extracellular HOP with neutralizing antibody reduced proliferation and enhanced 5-fluorouracil-induced apoptosis of GC cells.Conclusions Our findings identified HOP as an important molecular marker and prognostic factor for GC,that functionally contributes to tumor cell growth and survival.Our data provide the rationale for considering HOP a potential therapeutic target and chemosensitizer in GC.