Expressions of genes and proteins were determined by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. Their functions were assessed by endothelial cell recruitment, tube formation, wound healing, flow cytometry, immunostaining, immunoprecipitation, and xenograft assay. A tissue microarray followed by univariate and multivariate analyses was performed to indicate the clinical significance.
In HCC specimens, overexpression of 14-3-3η was observed not only in tumors but also in intratumoral vessels. In HCC and vascular endothelial cells, 14-3-3η stimulated proliferation and angiogenesis, but attenuated the functions of sorafenib. Briefly, 14-3-3η facilitated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). Then, by binding to the phosphorylated-ERK1/2 (p-ERK1/2), formed a functional positive feed-back loop. A xenograft model showed that, blockage of either 14-3-3η or ERK1/2 inhibited the tumor growth. Finally, tissue microarray analyses showed that overexpression of 14-3-3η, either in tumors or intratumoral vessels, contributed to the poor survival.
The 14-3-3η-ERK1/2 feedback loop played a characteristic growth-promoting role in HCC, not only in tumors but also in intratumoral vessels. Further, 14-3-3η could be a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response.
Here we found that, 14-3-3η protein exhibited a characteristic growth-promoting effect in both tumor and intratumoral vessels of hepatocellular carcinoma by interacting with ERK1/2 signaling.