DNA-PKcs Mediates An Epithelial-Mesenchymal Transition Process Promoting Cutaneous Squamous Cell Carcinoma Invasion And Metastasis By Targeting The TGF-β1/Smad Signaling Pathway

• Main Authors: Zhang J, Jiang H, Xu D, Wu WJ, Chen HD, He L
• Format: Article
• Language: English
• Published: Dove Medical Press 2019-11-01
• Series: OncoTargets and Therapy
• Subjects: cutaneous squamous cell carcinoma; dna-dependent protein kinase catalytic subunit; epithelial-mesenchymal transition; transforming growth factor-β1; e-cadherin.
• Online Access: https://www.dovepress.com/dna-pkcs-mediates-an-epithelial-mesenchymal-transition-process-promoti-peer-reviewed-article-OTT

Juan Zhang,1,* Hui Jiang,1,* Dan Xu,1,* Wen-Juan Wu,1 Hong-Duo Chen,2 Li He1 1Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology & Venereology of Yunnan Province, Kunming, People’s Republic of China; 2Department of Dermatology, The First Hospital of China Medical University, Shenyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li HeDepartment of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology & Venereology of Yunnan Province, 295 Xi Chang Road, Kunming 650032, People’s Republic of ChinaEmail [e-mail] Hong-Duo ChenDepartment of Dermatology, The First Hospital of China Medical University, 155 North Nanjing Street, Shenyang 110001, People’s Republic of ChinaTel [phone]Email [e-mail]: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has attracted extensive attention in various types of malignant tumors. However, the role of DNA-PKcs in cutaneous squamous cell carcinoma (cSCC) development has not been elucidated. In this study, we investigated the role of DNA-PKcs in cSCC and the molecular mechanisms of TGF-β1-induced cSCC progression mediated by DNA-PKcs.Methods: We performed bioinformatic analysis and RT-PCR to examine the DNA-PKcs expression level in cSCC. Then, we downregulated DNA-PKcs using a DNA-PK-specific inhibitor or small interfering RNA (siRNA) to explore the effects of DNA-PKcs on SCL-1 cell migration and invasion. To further investigate the mechanism by which DNA-PKcs promotes cSCC progression, TGF-β1 and the TGF-β receptor (TGF-βR) I/II dual inhibitor LY2109761 were used to examine whether DNA-PKcs participates in TGF-β1/Smad signaling.Results: DNA-PKcs expression was upregulated in cSCC. DNA-PK inhibition or expression knockdown resulted in inhibited migration and invasion and altered epithelial-mesenchymal transition (EMT) marker expression patterns in SCL-1 cells. Importantly, TGF-β1 mediated EMT induction in cSCC cells, and DNA-PKcs was identified as a TGF-β1-responsive gene. TGF-β1 promoted DNA-PKcs transcription, and DNA-PKcs enhanced the TGF-β1-induced EMT program involved in cSCC invasion and metastasis by phosphorylating Smad3.Conclusion: This study is the first to show that DNA-PKcs mediates EMT to promote cSCC aggressiveness by targeting the TGF-β1/Smad signaling pathway, which provides insight into how DNA-PKcs impacts cSCC progression and identifies a new therapeutic target.Keywords: cutaneous squamous cell carcinoma, DNA-dependent protein kinase catalytic subunit, epithelial-mesenchymal transition, transforming growth factor-β1, E-cadherin