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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-11, Vol.77 (21), p.5831-5845
• Main Authors: Yan, Qian, Jiang, Lingxi, Liu, Ming, Yu, Dandan, Zhang, Yu, Li, Yan, Fang, Shuo, Zhu, Ying-Hui, Yuan, Yun-Fei, Guan, Xin-Yuan
• Format: Article
• Language: English
• Subjects: AKT protein; Angiogenesis; Angiopoietin; Angiopoietin-like Proteins - genetics; Angiopoietin-like Proteins - metabolism; Animals; Apoptosis; Apoptosis - genetics; Bcl-2 protein; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Chemical compounds; Ectopic expression; Hepatocellular carcinoma; Humans; Integrin alpha1beta1 - genetics; Integrin alpha1beta1 - metabolism; Janus kinase 2; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Metastases; Metastasis; Mice, Inbred BALB C; Mice, Nude; Microscopy, Confocal; Neoplasm Metastasis; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal transduction; Signal Transduction - genetics; Snail protein; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Thrombosis; Transcription factors; Transplantation, Heterologous; Tumor suppressor genes; Tumorigenicity
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-0579

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 is associated with vascular invasion, tumor thrombus, metastasis, and poor prognosis in HCC. Ectopic expression of in HCC cells effectively decreased their and tumorigenicity, cell motility, and angiogenesis. shRNA-mediated depletion of exerted opposing effects. 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, 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 as a prognostic biomarker and novel therapeutic agent in HCC. .