The EDA-containing cellular fibronectin induces epithelial-mesenchymal transition in lung cancer cells through integrin α9β1-mediated activation of PI3-K/AKT and Erk1/2.
Cellular fibronectin (cFN) is one of the main components of tissue extracellular matrices and is involved in multiple physiologic and pathologic processes such as embryogenesis, wound healing, inflammation and tumor progression. The function of fibronectin in regulating normal cell adhesion and migration is well documented, but its function in cancer progression is only partially unraveled. We have reported previously that fibronectin stimulates the proliferation and survival of non-small lung carcinoma cells through upregulation of pro-oncogenic signals related to cyclooxygenase-2/phosphatidylinositol-3-kinase/protein kinase B (COX-2/PI3-K/AKT)/mammalian target of rapamycin triggered by activation of the integrin α5β1. Here, we extend these studies by showing that fibronectin promotes epithelial-mesenchymal transition (EMT) in lung cancer cells. We found that cFN, but not plasma fibronectin or type 1 collagen, induces lung carcinoma cell scattering in vitro, promotes cell migration and invasion of Matrigel and stimulates the expression of the mesenchymal marker α-smooth muscle actin while decreasing the expression of the epithelial marker E-cadherin through PI3-K and Erk pathways. Interestingly, the extra domain A (EDA) within cFN was found to be crucial for this process, as confirmed by testing cells overexpressing EDA or cells exposed to EDA-containing matrices. We found that the integrin α9, but not α5, mediated cFN-induced EMT as silencing integrin α9 neutralized cFN-induced EMT. Overall, our findings show that the EDA domain within cFN induces EMT in lung carcinoma cells through integrin α9-mediated activation of PI3-K and Erk.
Department of Biobank, Shenzhen Tumor Clinical Immune Gene Therapy Engineering Lab, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Xiaojuan
X
Sun
Pingping
P
Fa
Zhiwen
Z
Cui
Ye
Y
Xia
Liang
L
Sun
Zesong
Z
Li
Aifa
A
Tang
Yaoting
Y
Gui
Zhiming
Z
Cai
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D005353:Fibronectins; D016023:Integrins; C113256:integrin alpha 9 beta 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3