Abstract
Fibulins (FBLNs), interacting with cell adhesion receptors and extracellular matrix (ECM) components, play multiple roles in ECM structures and tissue functions. Abnormal expression of FBLN2, one of the fibulin family members, contributes to tumor initiation and development. However, the function of FBLN2 in human non-small cell lung cancer (NSCLC) has not yet been elucidated. In this study, we found that FBLN2 was downregulated in 9 out of 11 lung cancer cell lines compared to normal bronchial epithelial cells, which was associated with DNA hypermethylation. Primary lung squamous cell carcinoma expressed significantly more FBLN2 protein compared to adenocarcinoma (p = 0.047). Ectopic expression of FBLN2 led to decreased cell proliferation, migration and invasion, accompanied by inactivated MAPK/ERK and AKT/mTOR pathways, while FBLN2 siRNA knockdown resulted in an opposite biological behaviour in NSCLC cells. Additionally, overexpression of FBLN2 led to dysregulation of cell adhesion molecules, ECM markers and a panel of lysate/exosome-derived-microRNAs, which are involved in cell adhesion and ECM remodelling. Taken together, our data indicate that FBLN2 is methylated and exerts a tumor suppressor function through modulation of MAPK/ERK and AKT pathways and regulation of cell adhesion and ECM genes. Moreover, FBLN2 might be a potential biomarker for the sub-classification of NSCLC.
Highlights
The Human fibulin family, as one of the participators in elastic fiber assembly, is closely associated with basement membrane integrity, and is involved in multiple cellular processes, including cell shape, motility, and growth, that are crucial for the regulation of tissue morphogenesis [1,2]
Severe disruption of the elastic lamina has been observed in double knockout mice for fbln2 and fbln5, suggesting that fbln2 and fbln5 may cooperatively contribute to the formation of extracellular matrix (ECM) [6]
It was found that the short isoform is the dominant isoform in the majority of lung cancer cells, while in human brachial epithelial cells (HBEC), both isoforms were present (Supplementary Figure S1)
Summary
The Human fibulin family, as one of the participators in elastic fiber assembly, is closely associated with basement membrane integrity, and is involved in multiple cellular processes, including cell shape, motility, and growth, that are crucial for the regulation of tissue morphogenesis [1,2]. Single knockout mice for fbln were found to be viable and fertile and did not show obvious anatomical abnormalities, indicating that fbln might be dispensable for mouse development due to a compensatory mechanism that upregulates other fibulin family members, such as fbln1 [5] and fbln5 [6]. Severe disruption of the elastic lamina has been observed in double knockout mice for fbln and fbln, suggesting that fbln and fbln may cooperatively contribute to the formation of ECM [6].
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