| Summary: | 博士 === 國立臺灣大學 === 毒理學研究所 === 101 === Metastasis is the most important contributor to mortality in cancer patients. Identification of novel tumor metastasis suppressors and elucidation of the molecular mechanisms can provide new insights into the pathogenesis and development of effective anticancer drugs. Angiopoietin-like protein 1 (ANGPTL1), a member of the angiopoietin-like protein family, has been reported as an anti-angiogenic molecule that inhibits proliferation, migration, tube formation, and adhesion of endothelial cells. Growing evidence suggests that certain ANGPTL proteins not only target endothelial cells but also affect tumor cell behaviors. Whether ANGPTL1 can influence the malignant properties of cancer cells remains unclear. In this study, we show that ANGPTL1 expression inversely correlates with invasion, lymph node metastasis, and poor clinical outcomes in cancer patients. We also found that ANGPTL1 significantly suppresses the migratory, invasive, and metastatic capabilities of cancer cells through downregulation of the zinc-finger protein Slug. Further evidence has shown that ANGPTL1-mediated Slug protein downregulation is not attributed to decreased mRNA levels or facilitated protein degradation. Meanwhile, we have determined that ANGPTL1-mediated suppression of the Slug protein is due to the induction of miR-630 transcripts in the Sp-1–dependent ERK pathway. Furthermore, we show that ANGPTL1 interacts with integrin α1β1 and represses its downstream signaling, FAK/ERK to reduce cancer cell motility and invasiveness. These findings indicate that ANGPTL1 inhibits cancer cell motility and metastasis by inducing the mesenchymal-epithelial transition via the integrin α1β1−FAK−ERK−Sp-1−miR-630−Slug signal cascade. Therefore, ANGPTL1 may act as a potential powerful therapeutic protein drug for cancer treatment.
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