Diacylglycerol kinase alpha enhances hepatocellular carcinoma progression by activation of Ras-Raf-MEK-ERK pathway

Background & Aims: Diacylglycerol kinases (DGKs) were recently recognized as key regulators in cell signaling pathways. We investigated whether DGK alpha is involved in human hepatocellular carcinoma (HCC) progression. Methods: We silenced or overexpressed DGK alpha in HCC cells and assessed its effect on tumor progression. DGK alpha expression in 95 surgical samples was analyzed by immunohistochemistry, and the expression status of each sample was correlated with clinicopathological features. Results: DGK alpha was detected in various HCC cell lines but at very low levels in the normal liver. Knockdown of DGK alpha significantly suppressed cell proliferation and invasion. Overexpression of wild type (WT) DGK alpha, but not its kinase-dead (KD) mutant, significantly enhanced cell proliferation. DGK alpha knockdown impaired MEK and ERK phosphorylation, but did not inhibit Ras activation in HCC cells. In a xenograft model, WT DGK alpha overexpression significantly enhanced tumor growth compared to the control, but KD DGK alpha mutant had no effect. Immunohistochemical studies showed that DGK alpha was expressed in cancerous tissue, but not in adjacent non-cancerous hepatocytes. High DGK alpha expression (>= 20%) was associated with high Ki67 expression (p < 0.05) and a high rate of HCC recurrence (p = 0.033) following surgery. In multivariate analyses, high DGK alpha expression was an independent factor for determining HCC recurrence after surgery. Conclusions: DGK alpha is involved in HCC progression by activation of the MAPK pathway. DGK alpha could be a novel target for HCC therapeutics as well as a prognostic marker. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.