Follistatin Is a Novel Biomarker for Lung Adenocarcinoma in Humans

Chen, Fangfang; Ren, Ping; Feng, Yan; Liu, Haiyan; Sun, Yang; Liu, Zhonghui; Ge, Jingyan; Cui, Xueling

doi:10.1371/journal.pone.0111398

Cited by 18 publications

(23 citation statements)

References 36 publications

(41 reference statements)

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“…Moreover, despite IR-induced secretion of activin A in A549 cells, blocking activin signaling in these cells by dominant-negative interference with ALK4 function, unlike ALK5 function, failed to alter the IR-induced migratory activity. The reason for this discrepancy is not known but is possibly explained by the recent finding that lung carcinoma cells also secrete follistatin [30,31], which may have inactivated the IR-induced activin A. To solve this issue, it will be necessary to determine by bioassay the amount of free, biologically active activin A in irradiated A549 cultures.…”

Section: Discussionmentioning

confidence: 99%

Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway

Carl

Flindt²,

Hartmann³

et al. 2015

Cell. Mol. Life Sci.

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Radiotherapy, a major treatment modality against cancer, can lead to secondary malignancies but it is uncertain as to whether tumor cells that survive ionizing radiation (IR) treatment undergo epithelial-mesenchymal transition (EMT) and eventually become invasive or metastatic. Here, we have tested the hypothesis that the application of IR (10 MeV photon beams, 2-20 Gy) to lung and pancreatic carcinoma cells induces a migratory/invasive phenotype in these cells by hyperactivation of TGF-β and/or activin signaling. In accordance with this assumption, IR induced gene expression patterns and migratory responses consistent with an EMT phenotype. Moreover, in A549 cells, IR triggered the synthesis and secretion of both TGF-β1 and activin A as well as activation of intracellular TGF-β/activin signaling as evidenced by Smad phosphorylation and transcriptional activation of a TGF-β-responsive reporter gene. These responses were sensitive to SB431542, an inhibitor of type I receptors for TGF-β and activin. Likewise, specific antibody-mediated neutralization of soluble TGF-β, or dominant-negative inhibition of the TGF-β receptors, but not the activin type I receptor, alleviated IR-induced cell migration. Moreover, the TGF-β-specific approaches also blocked IR-dependent TGF-β1 secretion, Smad phosphorylation, and reporter gene activity, collectively indicating that autocrine production of TGF-β(s) and subsequent activation of TGF-β rather than activin signaling drives these changes. IR strongly sensitized cells to further increase their migration in response to recombinant TGF-β1 and this was accompanied by upregulation of TGF-β receptor expression. Our data raise the possibility that hyperactivation of TGF-β signaling during radiotherapy contributes to EMT-associated changes like metastasis, cancer stem cell formation and chemoresistance of tumor cells.

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Section: Discussionmentioning

confidence: 99%

Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway

Carl

Flindt²,

Hartmann³

et al. 2015

Cell. Mol. Life Sci.

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“…Follistatin (FST) has been reported to be a prognostic biomarker for lung adenocarcinoma (10). Similar proteins in the follistatinlike (FSTL) protein family, including FSTL1, IGFBP7, FSTL3, FSTL4, and FSTL5, play different roles in cancers (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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 in vitro and in vivo. 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.

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“…Under such circumstances, it is quite important to characterize the subtypes of NSCLC before designing appropriate treatment strategies. Previous studies have demonstrated that follistatin and the family with sequence similarity 83, member B (FAM83B) are candidate biomarkers for lung adenocarcinoma and squamous cell carcinoma, respectively [3,4]. Whether there exist additional potential prognostic biomarkers for different subtypes of NSCLC is of great interest.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of bone morphogenetic protein 5 in human lung squamous cell carcinoma and adenocarcinoma

Deng

Lin

Zhang

et al. 2015

ABBS

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Bone morphogenetic proteins (BMPs) play important roles in tumor cell proliferation, metastasis, and invasion. However, the expression patterns of BMPs in patients with non-small-cell lung cancer (NSCLC) and their correlations with NSCLC pathogenesis have not been examined yet. In this study, the mRNA levels of BMP family members in NSCLC tissues were analyzed and results showed that the mRNA levels of BMP5 and BMP7 were significantly down-regulated and up-regulated, respectively, in tumor tissues compared with those in the corresponding noncancerous tissues. Interestingly, the mRNA level of BMP5 was significantly higher in lung adenocarcinoma tissues than that in lung squamous cell carcinoma tissues. Furthermore, results from immunohistochemistry analysis confirmed stronger expression of BMP5 protein in lung adenocarcinoma than in lung squamous cell carcinoma. Our findings suggested that BMP5 might be a potential prognostic biomarker or therapeutic target for patients with NSCLC.

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Follistatin Is a Novel Biomarker for Lung Adenocarcinoma in Humans

Cited by 18 publications

References 36 publications

Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway

Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway

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

Differential expression of bone morphogenetic protein 5 in human lung squamous cell carcinoma and adenocarcinoma

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