Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasionviathe PI3K/GSK-3β/β-catenin pathway in hepatocellular carcinoma

// Yun Zhu 1,* , Yang Cheng 2,* , YaBin Guo 3 , JinZhang Chen 3 , FengSheng Chen 1 , RongCheng Luo 1 and AiMin Li 1 1 Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, China 2 Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China 3 Liver Tumor Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China * These authors have contributed equally to this work Correspondence to: AiMin Li, email: // RongCheng Luo, email: // Keywords : protein kinase D2, hepatocellular carcinoma, epithelial mesenchymal transition, PI3K, β-catenin Received : April 13, 2015 Accepted : December 09, 2015 Published : December 16, 2015 Abstract Although protein kinase D (PKD) has been shown to contribute to invasion and metastasis in several types of cancer, the role of PKD in the epithelial mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) has remained unclear. We found that PKD2 is up-regulated in HCC and is correlated with the metastasis of HCC. PKD2 positively regulated TNF-α-induced EMT and metastasis of HCC. Mechanistic studies revealed TNF-α-induced PKD2 activation is mediated by the formation of a TNFR1/TRAF2 complex. PKD2 bound directly to the p110α and p85 subunits of PI3K and promoted the PI3K/Akt/GSK-3β signaling cascade to stimulate EMT. In conclusion, our results have uncovered a novel role for the regulation of EMT and suggest inhibition of PKD2 as a potential therapeutic strategy for HCC.