Follistatin-like Protein 1 Inhibits Lung Cancer Metastasis by Preventing Proteolytic Activation of Osteopontin

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-12, Vol.79 (24), p.6113-6125
• Main Authors: Chiou, Jean, Chang, Yu-Chan, Tsai, Hsing-Fang, Lin, Yuan-Feng, Huang, Ming-Shyan, Yang, Chih-Jen, Hsiao, Michael
• Format: Article
• Language: English
• Subjects: A549 Cells; Actin Cytoskeleton - pathology; Adenocarcinoma of Lung - mortality; Adenocarcinoma of Lung - pathology; Adenocarcinoma of Lung - surgery; Animals; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - surgery; Down-Regulation; Female; Follistatin-Related Proteins - genetics; Follistatin-Related Proteins - metabolism; Gene Knockdown Techniques; Humans; Lung - pathology; Lung - surgery; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Lung Neoplasms - surgery; Male; Mice; Osteopontin - metabolism; Pneumonectomy; Prognosis; Protein Binding; Proteolysis; Recombinant Proteins - metabolism; RNA, Small Interfering - metabolism; Signal Transduction; Survival Analysis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-19-0842

Follistatin-like protein 1 (FSTL1) plays a critical role in lung organogenesis, but is downregulated during lung cancer development and progression. The prognostic significance and functional consequences of FSTL1 downregulation in lung cancer are unclear. Here, reduced levels of FSTL1 were detected in various tumors compared with normal tissues and were associated with poor clinical outcome in patients with non-small cell lung cancer, particularly those with lung adenocarcinoma. FSTL1 expression negatively correlated with the metastatic potential of lung cancer cells. Antibody-based neutralization of extracellular FSTL1 increased cellular migration/invasion while addition of recombinant FSTL1 protein diminished the metastatic capacity of lung cancer cells and . Notably, treatment with FSTL1 effectively prevented the metastatic progression of lung cancer cells in an orthotopic animal model. Mechanistically, FSTL1 directly bound to the proform of secreted phosphoprotein 1 (SPP1)/osteopontin, restraining proteolytic activation of SPP1, which led to inactivation of integrin/CD44-associated signaling and rearrangement of the actin cytoskeleton. Combined low expression of FSTL1 and high expression of SPP1 predicted a poorer prognosis for patients with lung cancer. This study highlights the novel interaction between FSTL1 and SPP1 and new opportunities to effectively target SPP1-driven metastatic cancers characterized by FSTL1 downregulation. SIGNIFICANCE: These findings describe the novel interaction between FSTL1 and SPP1 and its role in the metastatic progression of lung adenocarcinoma.