<p>Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide because of metastasis. The class II α-isoform of phosphatidylinositol 3-kinase (PIK3C2A) was found to be a regulator in proliferation and migration of endothelial cells, but its role in cancer metastasis has less been evaluated. In this study we find it functions as a tumor suppressor. PIK3C2A was frequently down-regulated in human HCC cells and tissues. Low PIK3C2A expression correlated with elevated LRP6 phosphorylation, β-catenin nuclear accumulation, and Wnt/β-catenin hyperactivation in clinical HCC tissues. Low PIK3C2A predicted poor overall and disease-free survival and aggressive clinicopathological features. Loss of PIK3C2A significantly promoted HCC cells invasion and migration in vitro, and promoted tumor growth and metastasis in vivo. And these changed phenotypes by PIK3C2A knockdown in HCC cells could be rescued by exogenous expression of PIK3C2A. Mechanism studies demonstrated loss of PIK3C2A activated Wnt/β-catenin signaling dramatically. Further investigations showed loss of PIK3C2A gave rise to a decrease in phosphatidylinositol (3,4) bisphosphate (PI(3,4)P₂) and an increase in phosphatidylinositol (4,5) bisphosphate (PI(4,5)P₂), therefore promoting phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6). Moreover, the activated Wnt/β-catenin signaling and the significantly increased invasion and migration cells by loss of PIK3C2A were also markedly suppressed in various levels respectively by inhibiting LRP6 phosphorylation in diverse levels. Inhibiting LRP6 phosphorylation abolished PIK3C2A-mediated effects. Taken together, our results indicate PIK3C2A suppresses HCC metastasis by targeting Wnt/β-catenin signaling via inhibiting phosphorylation of LRP6, and can serve as a prognostic biomarker and therapeutic target for HCC.</p>