<i>ANGPTL1</i> Interacts with Integrin α1β1 to Suppress HCC Angiogenesis and Metastasis by Inhibiting JAK2/STAT3 Signaling

Abstract

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 <i>ANGPTL1</i> is associated with vascular invasion, tumor thrombus, metastasis, and poor prognosis in HCC. Ectopic expression of <i>ANGPTL1</i> in HCC cells effectively decreased their <i>in vitro</i> and <i>in vivo</i> tumorigenicity, cell motility, and angiogenesis. shRNA-mediated depletion of <i>ANGPTL1</i> exerted opposing effects. <i>ANGPTL1</i> 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, <i>ANGPTL1</i> inhibited angiogenesis by attenuating ERK and AKT signaling and interacted with integrin α1β1 receptor to suppress the downstream FAK/Src-JAK-STAT3 signaling pathway. Taken together, these results suggest <i>ANGPTL1</i> as a prognostic biomarker and novel therapeutic agent in HCC. <i>Cancer Res; 77(21); 5831-45. ©2017 AACR</i>.