Her3 is associated with poor survival of gastric adenocarcinoma: Her3 promotes proliferation, survival and migration of human gastric cancer mediated by PI3K/AKT signaling pathway

Abstract

ErbB3 (Her3) is a membrane-bound protein which can form heterodimers with other EGF receptor family members with kinase activity. Previous reports identified Her3 as a significant predictor of poor survival in human gastric cancer (GC), but its mechanism has remained unclear. We sought to investigate the mechanism of Her3 in GC and its association with clinical characteristics. Her3 was detected by both real-time PCR and immunohistochemistry (IHC) in 161 GC patients, and its related downstream signaling PI3K/AKT activity and clinical characteristics were accessed by statistical analysis. Her3 siRNA was used in both in vitro and in vivo assay to investigate the mechanism. Her3 expression was significantly increased in human GC compared with adjacent normal gastric tissues as observed by both real-time PCR and IHC. Her3 expression was associated with downstream AKT activation and increased tumor size, metastasis and poor survival in GC patients. Knockdown of Her3 in human GC cell line can inhibit cell proliferation and tumor growth both in vitro and in vivo by inactivation of AKT. Her3 knockdown had no observed impact on Her2 expression or activity. G2/M arrest was investigated due to decreased CyclinB1 and p27(kip1) at T157. Increased apoptosis occurred in Her3 silenced GC cell treated with cisplatin due to decreased BAD at S112. Moreover, Her3 silence can inhibit cell migration in vitro and metastasis in vivo by down-regulating MMPs via PI3K/AKT signaling. Her3 is a new prognostic factor associated with tumor growth and metastasis via PI3K/AKT signaling.