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

Abstract

Diacylglycerol kinases (DGKs) were recently recognized as key regulators in cell signaling pathways. We investigated whether DGKα is involved in human hepatocellular carcinoma (HCC) progression. We silenced or overexpressed DGKα in HCC cells and assessed its effect on tumor progression. DGKα expression in 95 surgical samples was analyzed by immunohistochemistry, and the expression status of each sample was correlated with clinicopathological features. DGKα was detected in various HCC cell lines but at very low levels in the normal liver. Knockdown of DGKα significantly suppressed cell proliferation and invasion. Overexpression of wild type (WT) DGKα, but not its kinase-dead (KD) mutant, significantly enhanced cell proliferation. DGKα knockdown impaired MEK and ERK phosphorylation, but did not inhibit Ras activation in HCC cells. In a xenograft model, WT DGKα overexpression significantly enhanced tumor growth compared to the control, but KD DGKα mutant had no effect. Immunohistochemical studies showed that DGKα was expressed in cancerous tissue, but not in adjacent non-cancerous hepatocytes. High DGKα 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 DGKα expression was an independent factor for determining HCC recurrence after surgery. DGKα is involved in HCC progression by activation of the MAPK pathway. DGKα could be a novel target for HCC therapeutics as well as a prognostic marker.