Fibulin 2 Is Hypermethylated and Suppresses Tumor Cell Proliferation through Inhibition of Cell Adhesion and Extracellular Matrix Genes in Non-Small Cell Lung Cancer

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.

ITGBL1 promotes anoikis resistance and metastasis in human gastric cancer via the AKT/FBLN2 axis

“…Fibulin‐2 (FBLN2) is an extracellular glycoprotein and was initially discovered in embryonic endocardial cushion tissue and adult mouse and human heart valves, and FBLN2 may be involved in tissue development and remodelling 26,27 . According to reports, FBLN2 has been identified to exhibit tumour suppressor properties in several cancer types, such as breast cancer, 28 non‐small cell lung cancer, 29 and nasopharyngeal carcinoma 30 . In contrast, FBLN2 was reported to act as an oncogene in urothelial carcinoma 31 and colorectal cancer 32 .…”

TMT-based quantitative proteomic analysis revealed that FBLN2 and NPR3 are involved in the early osteogenic differentiation of mesenchymal stem cells (MSCs)

“…The FBLN2 gene encodes an extracellular matrix (ECM) protein, which binds multiple extracellular ligands and calcium [ 25 ], and it has a wide range of physiological functions. Some studies revealed a strong relationship between FBLN2 and the occurrence and progression of tumors [ 26 , 27 ]. Other studies reported that FBLN2 is likely associated with cardiovascular disease [ 28 , 29 ].…”

Current treatments for non-small cell lung cancer

“…There are also some proteins that overexpress in the NSCLC patients, which could become new targets in clinical trials. Fibulin2 (FBLN2) is decreased in the lung cancer cell lines, and the overexpression of FBLN2 would inhibit the activation of MAPK/ERK and AKT/mTOR signaling pathways, accompanied by the decreased migration and invasion of cells ( 64 ). This means that FBLN2 could be a potential biomarker for detecting NSCLC in the clinic.…”