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

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Follistatin-Like Protein 1 Inhibits Lung Cancer Metastasis by Preventing Proteolytic Activation of Osteopontin Author Manuscript Published OnlineFirst on October 25, 2019; DOI: 10.1158/0008-5472.CAN-19-0842 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Follistatin-like protein 1 inhibits lung cancer metastasis by 2 preventing proteolytic activation of osteopontin 3 4 Jean Chiou1#, Yu-Chan Chang1#, Hsing-Fang Tsai1, Yuan-Feng Lin2, Ming-Shyan 5 Huang3, Chih-Jen Yang4,5 and Michael Hsiao1,6 6 7 1Genomic Research Center, Academia Sinica, Taipei, Taiwan 8 2Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical 9 University, Taipei, Taiwan 10 3Department of Internal Medicine, E-DA Cancer Hospital, School of Medicine, I- 11 Shou University, Kaohsiung, Taiwan 12 4Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, 13 Kaohsiung Medical University, Kaohsiung, Taiwan. 14 5Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan. 15 6Department of Biochemistry, College of Medicine, Kaohsiung Medical University, 16 Kaohsiung, Taiwan 17 18 # These authors contributed equally to the research. 19 To whom correspondence should be addressed: 20 Michael Hsiao, Genomics Research Center, Academia Sinica, 128 Academia Road, 21 Taipei 11529, Taiwan. Tel: +886-2-2787-1243; Fax: +886-2-2789-9931; E-mail: 22 [email protected] 23 Or to 24 Chih-Jen Yang, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical 25 University, No. 68 Chunghwa 3rd Road, Cianjin District, Kaohsiung 80145, Taiwan. 1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 25, 2019; DOI: 10.1158/0008-5472.CAN-19-0842 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Phone: +886-7-320-8159; E-mail: [email protected] 2 3 Disclosure of Potential Conflicts of Interest 4 The authors have no competing financial interests to declare. 5 6 Running title: FSTL1 interacts with SPP1 to inhibit lung cancer metastasis 7 8 Abbreviations list Abbreviations Full-name FST Follistatin FSTL1 Follistatin-like protein 1 SPP1 Secreted phosphoprotein 1 PPI Protein-protein interaction TGFβ Transforming growth factor β BMP4 Bone morphogenetic protein 4 TCGA The Cancer Genome Atlas NSCLC Non-small cell lung cancer LUAD Lung Adenocarcinoma rhFSTL1 Recombinant FSTL1 protein IPA Ingenuity Pathway Analysis OE Overexpress KD Knockdown HR Hazard ratio Ab Antibody OS Overall survival DMFS Distant metastasis free survival 9 10 2 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 25, 2019; DOI: 10.1158/0008-5472.CAN-19-0842 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 Follistatin-like protein 1 (FSTL1) plays a critical role in lung organogenesis, but 3 is downregulated during lung cancer development and progression. The prognostic 4 significance and functional consequences of FSTL1 downregulation in lung cancer 5 are unclear. Here, reduced levels of FSTL1 were detected in various tumors compared 6 to normal tissues and were associated with poor clinical outcome in patients with non- 7 small cell lung cancer, particularly those with lung adenocarcinoma. FSTL1 8 expression negatively correlated with the metastatic potential of lung cancer cells. 9 Antibody-based neutralization of extracellular FSTL1 increased cellular 10 migration/invasion while addition of recombinant FSTL1 protein diminished the 11 metastatic capacity of lung cancer cells in vitro and in vivo. Notably, treatment with 12 FSTL1 effectively prevented the metastatic progression of lung cancer cells in an 13 orthotopic animal model. Mechanistically, FSTL1 directly bound to the pro-form of 14 secreted phosphoprotein 1 (SPP1)/osteopontin restraining proteolytic activation of 15 SPP1 which led to inactivation of integrin/CD44-associated signaling and 16 rearrangement of the actin cytoskeleton. Combined low expression of FSTL1 and 17 high expression of SPP1 predicted a poorer prognosis for patients with lung cancer. 18 This study highlights the novel interaction between FSTL1 and SPP1 and new 19 opportunities to effectively target SPP1-driven metastatic cancers characterized by 20 FSTL1 downregulation. 21 22 Significance 23 Findings describe the novel interaction between FSTL1 and SPP1 and its role in the 24 metastatic progression of lung adenocarcinoma 25 3 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 25, 2019; DOI: 10.1158/0008-5472.CAN-19-0842 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 2 Introduction 3 Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein that was originally 4 identified as a transforming growth factor (TGF)-inducible protein. Recently, 5 FSTL1 has increasingly been recognized as a critical developmental regulator of 6 organogenesis, particularly lung development (1). FSTL1 appears to antagonize bone 7 morphogenetic protein 4 (BMP4) signaling during lung development (2). Fstl1- 8 deficient mice have impaired alveolar maturation due to dysfunctional distal alveolar 9 differentiation and insufficient surfactant production (3). Since many developmental 10 pathways involved in embryogenesis play critical roles in oncogenesis and cancer 11 progression (4,5)and the dysregulation of BMP pathways has been detected during 12 tumorigenesis and the malignant evolution of lung cancer (6-9), perturbations in the 13 FSTL1/BMP4 pathway during lung cancer development are worth investigating. 14 Follistatin (FST) has been reported to be a prognostic biomarker for lung 15 adenocarcinoma (10). Similar proteins in the follistatin-like (FSTL) protein family, 16 including FSTL1, IGFBP7, FSTL3, FSTL4, and FSTL5, play different roles in 17 cancers (11-13). FSTL1 has been reported to be downregulated or undetectable in 18 various human cancer cells, including lung cancer cells, but it is expressed at high 19 levels in normal lung tissues (14). Similarly, FSTL1 mRNA levels are substantially 20 reduced in a panel of lung cancer cell lines compared to nontumor lung cell lines (15). 21 The neutralization of extracellular FSTL1 by its specific antibody promotes lung 22 cancer cell invasion and metastasis (16), confirming a pivotal role for FSTL1 in 23 preventing lung cancer progression. We presented the clinical relevance of FSTL1 24 downregulation in lung cancer (17). However, the practical application of the FSTL1 25 protein in combating malignant tumors has not yet been explored. 4 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 25, 2019; DOI: 10.1158/0008-5472.CAN-19-0842 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Lung cancer is the leading cause of cancer-related deaths worldwide (18) and is 2 classified into nonsmall cell lung cancer (NSCLC, ~85% of all lung cancers) and 3 small cell lung cancer (~15%). Moreover, NSCLC is divided into three major 4 histological subtypes: adenocarcinoma, squamous cell carcinoma, and large cell lung 5 cancer. Lung adenocarcinoma is currently the most common type of lung cancer in 6 patients who have never smoked (19) and accounts for approximately 40% of all lung 7 cancers. Here, FSTL1 downregulation strongly predicts a poorer prognosis in patients 8 with lung adenocarcinoma, but not squamous cell carcinoma, and strongly correlates 9 with an increased metastatic potential of lung cancer cells in vitro and in vivo. 10 Importantly, treatment with FSTL1 inhibits the metastatic progression of lung cancer 11 cells by directly binding to pro-SPP1 and thereby restraining the proteolytic activation 12 of SPP1. Since SPP1 is a critical extracellular molecule involved in eliciting cancer 13 metastasis, the identification of protein-protein interactions between FSTL1 and SPP1 14 might provide a new opportunity for developing novel anti-cancer agents to combat 15 metastatic cancers. 16 17 18 19 20 21 22 23 24 5 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 25, 2019; DOI: 10.1158/0008-5472.CAN-19-0842 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Materials and Methods 2 Chemicals and Antibodies 3 The recombinant FSTL1 protein was purchased from Sino Biological Inc., Beijing, 4 P.R. C. (10924H08H50). Recombinant pro- and mature SPP1 proteins were obtained 5 from R&D (1433-OP-050) and Abnova, Taipei, Taiwan (H00006696-Q01, 6 H00006696-Q02), respectively. The FSTL1 antibody was purchased from 7 Proteintech, IL, USA (20182-1-AP, 1:2000). The SPP1 antibody was purchased from 8 Abcam, MA, USA (ab8848, 1:1000). Antibodies against Akt (9272, 1:1000), p-AkT 9 (9275S, 1:1000), Src (2109S, 1:1000) and p-Src (2101S, 1:1000) antibodies were 10 purchased from Cell Signaling Technology, MA, USA. The antibody against β-actin 11 (A2228, 1:5000) was purchased from Sigma-Aldrich, MO, USA. 12 Cell lines and cell culture conditions 13 The lung cancer cell lines A549, H1299, PC13 and PC14 were maintained in DMEM 14 supplemented with 10% FBS and 1% penicillin-streptomycin-glutamine (PSG) 15 (Invitrogen, CA, USA). H1355, H928, CL1-0 and CL1-5 lung cancer cells were 16 maintained in RPMI-1640 medium supplemented with 10% FBS and 1% PSG. The 17 Beas2B normal lung epithelial cell line was maintained in keratinocyte-SFM medium 18 (Invitrogen, CA, USA, cat: 17005042) supplemented with 1% PSG. CL1-0 and CL1-5 19 cells were derived by Chu et al. and exhibit progressively increasing invasiveness 20 (20). The PC13 and PC14 cell lines were generated by Lee et al. at the National 21 Cancer Center Hospital, Tokyo, Japan (21). Other lung cancer cell lines and the 22 Beas2B cell line were acquired from the American Type Culture Collection, USA.
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