Krüppel-like factor 17 inhibits urokinase plasminogen activator gene expression to suppress cell invasion through the Src/p38/MAPK signaling pathway in human lung adenocarcinoma
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Xing-Dong Cai1,*, Li Che1,*, Jia-Xin Lin1,*, Shuai Huang2, Jiong Li3, Xiao-Yan Liu1, Xing-Fei Pan4, Qin-Qin Wang1, Li Chen1, Ming-Juan Lin1, Zhi-Hong Huang1, Hong-Ming Ma1, Yi Wu1, Sheng-Ming Liu1, Yan-Bin Zhou5
1Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
2Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
3Department of Anatomy, The Medical College of Jinan University, Guangzhou 510630, China
4Department of Infectious Disease, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
5Department of Pulmonary Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
*These authors contributed equally to this work
Yan-Bin Zhou, email: [email protected]
Sheng-Ming Liu, email: [email protected]
Xing-Dong Cai, email: [email protected]
Keywords: Krüppel-like-factor 17(KLF17), urokinase plasminogen activator (uPA), invasion, lung adenocarcinoma, signal pathway
Received: December 29, 2016 Accepted: March 30, 2017 Published: April 10, 2017
Krüppel-like factor 17 (KLF17) has been reported to be involved in invasion and metastasis suppression in lung cancer, but the molecular mechanisms underlying the anti-invasion and anti-metastasis roles of KLF17 in lung cancer are not fully illustrated. Here, we showed that KLF17 inhibited the invasion of A549 and H322 cells; the anti-invasion effect of KLF17 was associated with the suppression of urokinase plasminogen activator (uPA/PLAU) expression. KLF17 can bind with the promoter of uPA and inhibit its expression. Enforced expression of uPA abrogated the anti-invasion effect of KLF17 in A549 and H322 cells. In addition, immunohistochemistry staining showed that the protein expression of KLF17 was negatively correlated with that of uPA in archived samples from patients with lymph node metastasis of lung adenocarcinoma (rho = −0.62, P = 0.01). The mutually exclusive expression of KLF17 with uPA could predict lymph node metastasis for lung adenocarcinoma (AUC = 0.758, P = 0.005). Enforced expression of KLF17 inhibited the expression of phosphorylated Src and phosphorylated p38/MAPK in A549 and H322 cells. The invasiveness of the cells were suppressed by treating with sb203580 (p38/MAPK inhibitor) or HY-13805 (PP2, Src inhibitor). furthermore, p38/MAPK inhibition could block the KLF17-induced reduction of p-p38/MAPK and uPA, and Src inhibition enhanced the KLF17-induced suppression of p-Src and uPA in A549 and H322 cells. In conclusion, our study indicated that KLF17 suppressed the uPA-mediated invasion of lung adenocarcinoma. The Src and p38/MAPK signaling pathways were suggested as mediators of KLF17-induced uPA inhibition, thus providing evidence that KLF17 might be a potential anti-invasion candidate for lung adenocarcinoma.
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