FSTL1 Inhibits Tumor Growth and Metastatic Progression via Blocking Proteolytic Activation of SPP1 in Lung Adenocarcinoma

Abstract

Follistatin‐related protein 1 (FSTL1) plays a critical role in lung development through the interaction with bone morphogenetic protein (BMP) 4 and transforming growth factor β1 (TGF‐β1) signaling pathways. Although the supplement of FSTL1 was appeared to inhibit the in vitro cell growth of lung cancer cells, the precise mechanism and its role in lung cancer aggressiveness remains unclear. Here we found that low‐level FSTL1 is extensively detected in tumor tissues and significantly correlates with poor prognosis in patients with non‐small cell lung cancer, particularly lung ademonocarcinoma. Moreover, the expression of FSTL1 was inversely associated with the in vitro migration ability of several lung adenocarcinoma cell lines. Robustly, the treatment with recombinant FSTL1 protein significantly decreased migration and invasion of highly metastatic CL1‐5 cells in a dose‐dependent manner. In contrast, the mobility of poorly metastatic CL1‐0 cells was dose‐dependently enhanced by neutralizing FSTL1 using its specific antibody. Furthermore, the enforced expression of exogenous FSTL1 gene suppressed but the knockdown of FSTL1 promoted the in vitro and in vivo metastatic potential of CL1‐5 and CL1‐0 cells, respectively. Importantly, the administration of FSTL1 effectively inhibited the lung metastasis of CL1‐5 cells in an orthotropic animal model. The mass spectrometric analysis of FSTL1‐interacting proteins revealed that FSTL1 is capable of binding to the secreted phosphoprotein 1 (SPP1), Furthermore our results showed that FSTL1 binds to the matrix metalloproteinase‐3/7 (MMP3/7)‐recognition site and thereby blocks the proteolytic activation of pro‐SPP1 and its downstream signaling to ultimately inhibit lung cancer cell invasion and metastasis.These results suggest that the downregulation of predicts a poor prognosis in lung adenocarcinoma and the administration of FSTL1 could be a new therapeutic strategy to inhibit tumor growth and combat metastatic progression in lung adenocarcinoma via preventing the proteolytically processing of pro‐SPP1 into its active form.