p66Shc promotes HCC progression in the tumor microenvironment via STAT3 signaling.

The development of hepatocellular carcinoma (HCC) is strongly associated with chronic inflammation. p66Shc is an oxidase previously shown to promote androgen-independent cell growth through generation of reactive oxygen species. However, the importance and biologic functions of p66Shc in HCC are unclear. The clinical significance of p66Shc was assessed in a large cohort of patients with HCC. High Shc1 expression was closely correlated with poor clinical outcomes and early recurrence of HCC. p66Shc expression was also determined in HCC samples and cell lines and found to be increased. Moreover, knockdown of p66Shc significantly inhibited cell proliferation, motility in vitro and tumor growth in vivo and could attenuate the proliferation, and motility of cells stimulated by activated macrophage conditioned media. Mechanically, p66Shc knockdown inhibited phosphorylation of STAT3 on serine 727 in vitro and in vivo. Our results show that high p66Shc expression in HCC predicts a worse prognosis for survival. Furthermore, p66Shc may serve as a novel candidate target for HCC therapy.