Abstract
Follistatin-related protein 1 (FSTL1) plays a critical role in lung development through regulating BMP4-p-Smad1/5/8-Smad4 pathway. Regarding that many developmental pathways in embryogenesis are dysregulated in cancer, we aim to unravel the role of FSTL1-BMP4-Smad pathway in lung cancer. Our results showed low FSTL1 immunoexpression was significantly correlated with poor prognosis while patients with low BMP4 or low Smad4 immunoexpression showed a trend toward poor prognosis. When stratified by different histological types, low FSTL1, BMP4, and Smad4 expression retained their trends in predicting poor prognosis in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma (SCC). Low FSTL1, BMP4, and Smad4 expression were more frequently observed in LUAD patients with smoking history. To determine smoking effect on FSTL1, normal cell BEAS2B and lung cancer cell lines was treated with nicotine and the results showed nicotine increased the proliferation of these cells. Interestingly, FSTL1 attenuated nicotine-induced BEAS2B and lung cancer cell line proliferation. Altogether, low FSTL1, BMP4, and Smad4 expression significantly correlated with poor prognosis in LUAD but not in SCC. Frequent decrease of FSTL1 expression in smokers LUAD further indicates its importance and therapeutic potential for lung cancer patients with specific subtypes. FSTL1 may prevent nicotine-induced lung cancer cell proliferation.
Highlights
Lung cancer as one of the most common cancer type worldwide has a high mortality rate in spite of the improvement of therapeutic strategies[1]
We revealed that Follistatin-related protein 1 (FSTL1)-Bone morphogenetic proteins 4 (BMP4)-Smad pathway plays an important role in cancer progression in lung adenocarcinoma but not in squamous cell carcinoma
The difference between the significance of FSTL1-BMP4-Smad pathway in adenocarcinoma and squamous cell carcinoma may be explained by its role in lung development
Summary
Lung cancer as one of the most common cancer type worldwide has a high mortality rate in spite of the improvement of therapeutic strategies[1]. Targeted therapies used in adenocarcinoma are mostly ineffective for patients with squamous cell carcinoma[4, 5] These valuable experiences give us a lesson that discovering novel targets specific for certain histologic or molecular subtypes lead to the greatest therapeutic benefit[6]. Premature senescence induced by BMP4 mediated Smad signaling pathway decreases cell growth rate in vitro and tumorigenicity in vivo[17,18,19]. Markers in FSTL1-BMP4-p-Smad1/5/8-Smad[4] pathway have no prognostic value in lung squamous cell carcinoma patients. Frequent decrease of FSTL1-BMP4-p-Smad1/5/8-Smad[4] pathway observed in smokers and in ALK-fusion or KRAS mutant adenocarcinoma patients may facilitate the understanding of the molecular pathogenesis of lung adenocarcinoma. We presented in vitro and in vivo experiments to decipher the interplay between nicotine and FSTL1
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