Catalytically defective receptor protein tyrosine kinase PTK7 enhances invasive phenotype by inducing MMP-9 through activation of AP-1 and NF-κB in esophageal squamous cell carcinoma cells

// Won-Sik Shin 1 , Yuri Hong 1 , Hae Won Lee 2 , Seung-Taek Lee 1 1 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea 2 Department of Thoracic Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea Correspondence to: Seung-Taek Lee, email: stlee@yonsei.ac.kr Keywords: PTK7, MMP-9, NF-κB, AP-1, esophageal squamous cell carcinoma (ESCC) Received: June 04, 2016      Accepted: September 21, 2016      Published: September 28, 2016 ABSTRACT Protein tyrosine kinase 7 (PTK7), a member of the catalytically defective receptor protein tyrosine kinase family, is upregulated in various cancers including esophageal squamous cell carcinoma (ESCC). Here, we have explored the molecular mechanism of PTK7-dependent invasiveness in ESCC cells. PTK7 knockdown reduced gelatin degradation and MMP-9 secretion in cultures of ESCC TE-10 cells, and showed reduced levels of MMP9 mRNA using real-time RT-PCR and luciferase reporter assays. PTK7 knockdown decreased not only phosphorylation of NF-κB, IκB, ERK, and JNK, but also nuclear localization of NF-κB and AP-1 consisting of c-Fos and c-Jun. Activation of AP-1 and NF-κB requires PTK7-mediated activation of tyrosine kinases, including Src. In addition, NF-κB activation by PTK7 involves the PI3K/Akt signaling pathway. PTK7-mediated upregulation of MMP9 was also observed in other ESCC cell lines and in three-dimensional cultures of TE-10 cells. Moreover, MMP-9 expression positively correlated with PTK7 expression in ESCC tumor tissue. These findings demonstrate that PTK7 upregulates MMP9 through activation of AP-1 and NF-κB and, thus increases invasive properties of ESCC cells.