PRL-3 facilitates angiogenesis and metastasis by increasing ERK phosphorylation and up-regulating the levels and activities of Rho-A/C in lung cancer.
OBJECTIVE
The aim of this study was to investigate the mechanism of PRL-3 in inducing angiogenesis and lymphangiogenesis to promote distant and lymph node metastasis in human lung cancer tissues and cells.


METHODS
We investigated the expression of PRL-3, VEGF, and VEGF-C from 94 patients with non-small cell lung cancer (NSCLC) using immunohistochemical staining. The relationship between PRL-3 expression and microvessel density (MVD), lymphatic vessel density (LVD), clinicopathological factors, and surgical treatment outcome was also studied. Following this, we studied the effect on A549 by blocking PRL-3.


RESULTS
PRL-3 expression in NSCLC was high, and this over-expression is correlated with advanced clinical stage (p = 0.019), distant metastasis (p = 0.001), lymph node metastasis (p = 0.001), and poor post-operative survival. PRL-3 over-expression was associated with vascular endothelial growth factor (VEGF; p = 0.000) and VEGF-C (p = 0.008) expressions, MVD and LVD (p = 0.000 and p = 0.000). Blocking PRL-3 expression in A549 cell resulted in decreased cellular proliferative, migratory, and invasive abilities, and VEGF, VEGF-C, pERK, Rho-A, and Rho-C expression was inhibited. Following inhibition of either Rho or pERK, VEGF expression was down-regulated.


CONCLUSIONS
PRL-3 induces microvascular and lymphatic vessel formation by facilitating VEGF and VEGF-C expression in lung cancer tissues, thus promoting distant and lymph node metastasis of lung cancer. PRL-3 up-regulates pERK and Rho expression and activity, facilitating VEGF expression, and accelerating angiogenesis and distant metastasis. How to regulate VEGF-C expression needs to be further studied.
Ming
Jian
J
Department of Pathology, College of Basic Medical Sciences, China Medical University and First Affiliated Hospital of China Medical University, Shenyang, China.
Liu
Nan
N
Gu
Yumei
Y
Qiu
Xueshan
X
Wang
En-Hua
EH
D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042583:Lymphangiogenesis / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D048049:Extracellular Signal-Regulated MAP Kinases; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein