Downregulation of tumor suppressor signaling plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). Here, we report that downregulation of the angiopoietin- like protein ANGPTL1 is associated with vascular invasion, tumor thrombus, metastasis, and poor prognosis in HCC. Ectopic expression of ANGPTL1 in HCC cells effectively decreased their in vitro and in vivo tumorigenicity, cell motility, and angiogenesis. shRNA-mediated depletion of ANGPTL1 exerted opposing effects. ANGPTL1 promoted apoptosis via inhibition of the STAT3/Bcl-2-mediated antiapoptotic pathway and decreased cell migration and invasion via downregulation of transcription factors SNAIL and SLUG. Furthermore, ANGPTL1 inhibited angiogenesis by attenuating ERK and AKT signaling and interacted with integrin alpha 1 beta 1 receptor to suppress the downstream FAK/Src-JAK-STAT3 signaling pathway. Taken together, these results suggest ANGPTL1 as a prognostic biomarker and novel therapeutic agent in HCC. (C) 2017 AACR.