Angiopoietin-like protein 1 suppresses SLUG to inhibit cancer cell motility
Tsang-Chih Kuo, … , Jen-Liang Su, Min-Liang Kuo
Tsang-Chih Kuo, … , Jen-Liang Su, Min-Liang Kuo
Published February 22, 2013
Citation Information: J Clin Invest. 2013;123(3):1082-1095. https://doi.org/10.1172/JCI64044.
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Angiopoietin-like protein 1 suppresses SLUG to inhibit cancer cell motility

Abstract

Angiopoietin-like protein 1 (ANGPTL1) is a potent regulator of angiogenesis. Growing evidence suggests that ANGPTL family proteins not only target endothelial cells but also affect tumor cell behavior. In a screen of 102 patients with lung cancer, we found that ANGPTL1 expression was inversely correlated with invasion, lymph node metastasis, and poor clinical outcomes. ANGPTL1 suppressed the migratory, invasive, and metastatic capabilities of lung and breast cancer cell lines in vitro and reduced metastasis in mice injected with cancer cell lines overexpressing ANGPTL1. Ectopic expression of ANGPTL1 suppressed the epithelial-to-mesenchymal transition (EMT) by reducing the expression of the zinc-finger protein SLUG. A microRNA screen revealed that ANGPTL1 suppressed SLUG by inducing expression of miR-630 in an integrin α1β1/FAK/ERK/SP1 pathway–dependent manner. These results demonstrate that ANGPTL1 represses lung cancer cell motility by abrogating the expression of the EMT mediator SLUG.

Authors

Tsang-Chih Kuo, Ching-Ting Tan, Yi-Wen Chang, Chih-Chen Hong, Wei-Jiunn Lee, Min-Wei Chen, Yung-Ming Jeng, Jean Chiou, Pei Yu, Pai-Sheng Chen, Ming-Yang Wang, Michael Hsiao, Jen-Liang Su, Min-Liang Kuo

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Figure 5

ANGPTL1 interacts with integrin α1β1 and inhibits the downstream FAK/ERK pathway.

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ANGPTL1 interacts with integrin α1β1 and inhibits the downstream FAK/ERK...
(A) CL1-5 cells were treated with ANGPTL1 CM for 2 hours. Cell lysates were immunoprecipitated with anti-V5 and normal IgG. Western blot analysis was of V5 and integrin α1, -α2, -α3, -α5, -α6, -αV, -α8, -β1, -β3, -β4, and -β5 in this immunoprecipitation. The arrowhead indicates IgG. (B) Dose-dependent ANGPTL1 binding to immobilized integrin α1β1 (top) and relative binding of collagen I, ANGPTL1, ANGPTL1, and indicated antibodies and BSA (bottom) with immobilized integrin α1β1 by ELISA. (C) Surface plasmon resonance assay shows the binding profiles between immobilized integrin α1β1 and ANGPTL1. Sensorgram was corrected against a reference flow cell with no immobilized protein. KD = 6.35 × 10–8 M was determined after global fitting (Langmuir 1:1 model) using Scrubber2. (D) Western blot analysis of activated integrin β1 in ANGPTL1-overexpressing CL1-5 cells. (E) Western blot analysis of phosphorylation of FAK, ERK, AKT, JNK, and p38 in CL1-5 cells treated with 50 ng/ml rANGPTL1 for various periods of time. (F) Western blot analysis of phosphorylation of FAK, ERK, and AKT in ANGPTL1-overexpressing CL1-5 cells and ANGPTL1 knockdown H928 cells.