B7-H4 Expression is Upregulated by PKCδ Activation and Contributes to PKCδ-Induced Cell Mobility in Colorectal Cancer

Abstract Background B7-H4 is overexpressed in colorectal cancer (CRC) and plays important roles in tumour growth and immunosuppression. However, the exact mechanism that regulates B7-H4 expression remains largely unknown. Protein kinase δ (PKCδ) plays a significant role in a range of cancers, including CRC. Here, we investigated whether PKCδ regulates the expression of B7-H4 in CRC.Methods By using immunohistochemical and immunofluorescence (IF) staining, we analysed the expression of B7-H4 and phospho-PKCδ (p-PKCδ) in 225 colorectal tumour samples, and the clinical significance of these expression patterns was determined. In vitro experiments were performed with the CRC cell lines HCT116 and SW620 to detect the effect of PKCδ activation on B7-H4 expression.Results B7-H4 expression was significantly correlated with p-PKCδ expression (r=0.378, P<0.001) in tumour tissues. The co-expression of p-PKCδ and B7-H4 was significantly associ­ated with moderate/poor differentiation (P=0.024), lymph node metastasis (P=0.001) and an advanced Dukes’ stage (P=0.002). Western blot analysis showed that TPA increased B7-H4 levels in a concentration-dependent manner and rottlerin also abrogated TPA-induced B7-H4 enhancement. The expression of B7-H4 and p-STAT3 were significantly reduced by PKCδ-specific siRNA. Moreover, STAT3 inhibitor cryptotanshinone significantly decreased B7-H4 protein levels in HCT116 cells. Knockdown of B7-H4 or PKCδ expression suppressed cell migration and mobility.Conclusion B7-H4 expression was significantly correlated with p-PKCδ expression in CRC samples. B7-H4 expression was upregulated by STAT3 activation via PKCδ and played roles in PKCδ-induced cancer cell mobility and metastasis.