Overexpression of SHANK2 contributes malignant outcomes as a Hippo pathway regulator in gastric cancer.

Abstract

Background: Recent studies identified that SH3 and multiple ankyrin repeat domains 2 (SHANK2) is located in a gene-amplified region 11q13 of various human cancers, and has oncogenic functions as a Hippo pathway suppressor in hepatocellular carcinoma. In this study, we tested whether SHANK2 acts as a cancer-promoting gene through its activation or overexpression in gastric cancer (GC).

Materials and methods: We analyzed 5 GC cell lines and 172 primary tumor samples of GC, which were curatively resected in our hospital.

Results: Overexpression of SHANK2 protein was frequently detected in GC cell lines (4/5 cell lines, 80%). Knockdown of SHANK2 inhibited cell proliferation, migration and invasion of GC cells in a TP53 mutation-independent manner, and induced the overexpression of the Hippo pathway genes. Fluorescent immunostaining showed that overexpression of SHANK2 in cytoplasm was inversely correlated with Yes1-associated transcriptional regulator (YAP) expression, suggesting that SHANK2 may play a role in suppressing the Hippo pathway in GC. In primary GC samples, both overexpression of SHANK2 in cytoplasm and low expression of SHANK2 in nucleus, which are defined as high SHANK2 index, correlated with more aggressive venous invasion, advanced tumor and nodal stage. Patients with high SHANK2 index tumors had a lower overall survival rate than those with non-expressing tumors. Multivariate analysis demonstrated that high SHANK2 index was independently associated with poor outcomes.

Conclusions: These findings suggest that SHANK2 plays a crucial role in tumor malignant potential through the Hippo pathway suppression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.