Fibrinogen Alpha Chain Knockout Promotes Tumor Growth and Metastasis through Integrin-AKT Signaling Pathway in Lung Cancer

Fibrinogen is an extracellular matrix protein composed of three polypeptide chains with fibrinogen alpha (FGA), beta (FGB) and gamma (FGG). Although fibrinogen and its related fragments are involved in tumor angiogenesis and metastasis, their functional roles are incompatible. A recent genome-scale...

Full description

Saved in:
Bibliographic Details
Published in:Molecular cancer research 2020-07, Vol.18 (7), p.943-954
Main Authors: Wang, Meng, Zhang, Guangxin, Zhang, Yue, Cui, Xuelian, Wang, Shuaibin, Gao, Song, Wang, Yicun, Liu, Ying, Bae, Jeeyoo H, Yang, Wei-Hsiung, Qi, Lei S, Wang, Lizhong, Liu, Runhua
Format: Article
Language:English
Subjects:
A549 Cells
Adenocarcinoma of Lung - genetics
Adenocarcinoma of Lung - metabolism
Adenocarcinoma of Lung - pathology
Animals
Cell Line, Tumor
Cell Movement
Cell Proliferation
CRISPR-Cas Systems
Down-Regulation
Epithelial-Mesenchymal Transition
Female
Fibrinogen - genetics
Fibrinogen - metabolism
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Humans
Integrins - metabolism
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Male
Mice
Neoplasm Metastasis
Neoplasm Transplantation
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Fibrinogen is an extracellular matrix protein composed of three polypeptide chains with fibrinogen alpha (FGA), beta (FGB) and gamma (FGG). Although fibrinogen and its related fragments are involved in tumor angiogenesis and metastasis, their functional roles are incompatible. A recent genome-scale screening reveals that loss of affects the acceleration of tumor growth and metastasis of lung cancer, but the mechanism remains elusive. We used CRISPR/Cas9 genome editing to knockout (KO) in human lung adenocarcinoma (LUAD) cell lines A549 and H1299. By colony formation, transwell migration and matrix invasion assays, KO increased cell proliferation, migration, and invasion but decreased the expressions of epithelial-mesenchymal transition marker E-cadherin and cytokeratin 5/8 in A549 and H1299 cells. However, administration of FGA inhibited cell proliferation and migration but induced apoptosis in A549 cells. Of note, KO cells indirectly cocultured by transwells with wild-type cells increased FGA in the culture medium, leading to decreased migration of KO cells. Furthermore, our functional analysis identified a direct interaction of FGA with integrin α5 as well as FGA-integrin signaling that regulated the AKT-mTOR signaling pathway in A549 cells. In addition, we validated that KO increased tumor growth and metastasis through activation of AKT signaling in an A549 xenograft model. IMPLICATIONS: These findings demonstrate that that loss of facilities tumor growth and metastasis through the integrin-AKT signaling pathway in lung cancer.
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.mcr-19-1033