Lung cancer is the main cause of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) is one of the major molecular mechanisms inducing tumor invasion and metastasis. Paired-related homeobox 1 (Prrx1) is a newly found EMT-inducing transcription factor. The prognostic value of Prrx1 in lung cancer has not been well demonstrated.
H1299-Prrx1 cell lines were generated by transfecting the pcDNA3.1-Prrx1 plasmid into H1299 cells. The H1299-Prrx1-Twisti cell lines were generated by transfecting the pSUPER-Twisti plasmid into H1299-Prrx1 cells. Immunofluorescence staining was done to demonstrate expression of E-cadherin and vimentin in these cells. Soft agar clonogenicity assay was done in these cell lines to demonstrate anchorage-independent growth. Cell migration and invasiveness assay were done in these cells to demonstrate their invasion and migration ability. In vivo tail vein metastasis assay was done to demonstrate the ability of Prrx1 overexpression in metastasis in vivo. Immunohistochemistry analysis of Prrx1 expression was done in 110 specimens of lung cancer patients.
Prrx1 overexpression increased transformation activity, induced EMT and increased migration/invasiveness of H1299 cells. Prrx1 overexpression also increased metastatic ability in vivo. Prrx1 overexpression upregulated the expression of Twist and its downstream target matrix metalloproteinase 1 (MMP1). EMT phenotypes, increased migration/invasiveness of H1299-Prrx1 cells, and increase MMP1 expression were reversed by siRNA-mediated repression of Twist expression or a phosphatidylinositol (PI) 3-kinase inhibitor. Prrx1 overexpression predicted lower recurrence-free survival in patients with lung adenocarcinoma.
Prrx1 overexpression induces EMT through upregulation of PI 3-kinase/Akt/Twist/MMP1 axis. Prrx1 overexpression also predicts recurrence in lung cancer patients.
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