1. Targeting PADI2 as a potential therapeutic strategy against metastasis in oral cancer via suppressing EMT-mediated migration and invasion and CCL3/5-induced angiogenesis.
- Author
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Hung SK, Yu CC, Lin HY, Chiou WY, Lee MS, Lin RI, and Lu MC
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Xenograft Model Antitumor Assays, Neoplasm Invasiveness, Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell metabolism, Mice, Nude, Chemokine CCL20 metabolism, Chemokine CCL20 genetics, Squamous Cell Carcinoma of Head and Neck pathology, Squamous Cell Carcinoma of Head and Neck metabolism, Lung Neoplasms secondary, Lung Neoplasms pathology, Lung Neoplasms metabolism, Mice, Inbred BALB C, Angiogenesis, Epithelial-Mesenchymal Transition, Mouth Neoplasms pathology, Mouth Neoplasms metabolism, Cell Movement, Neovascularization, Pathologic pathology, Neovascularization, Pathologic metabolism, Protein-Arginine Deiminase Type 2 metabolism, Cell Proliferation
- Abstract
Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy, with metastasis being the leading cause of death in patients. Unfortunately, therapeutic options for metastatic OSCC remain limited. Peptidylarginine deiminases (PADI) are implicated in various tumorigenesis and metastasis processes across multiple cancers. However, the role of PADI2, a type of PADI, in OSCC is not well understood. This study aimed to explore the impact of PADI2 on epithelial-mesenchymal transition (EMT), angiogenesis, and OSCC metastasis. The effect of PADI2 on EMT was evaluated using cell lines by Western blot analysis with shRNA targeting PADI2. In addition, the selective PADI2 inhibitor AFM32a was used to assess the effect of PADI2 on cancer metastasis and angiogenesis in animal models. Our findings indicated that PADI2 expression correlated with EMT changes, and PADI2 knockdown reversed these changes, reducing cell proliferation, cell migration, and invasion. PADI2 inhibition also diminished tube formation in HUVECs and decreased secretion of angiogenesis-related chemokines CCL3, CCL5 and CCL20. In a mouse model, AFM32a markedly reduced lung metastasis and production of CCL3 and CCL5. Our in vitro and in vivo studies suggested inhibiting PADI2 could prevent OSCC metastasis by impeding EMT and angiogenesis via AKT/mTOR signaling pathway. These results highlight PADI2 as a potential therapeutic target for combating OSCC metastasis., Competing Interests: Declarations. Ethical approval: Animal protocols obeyed the instructions of the Institutional Animal Care and Use Committee of Dalin Tzu Chi Hospital (IACUC no.112001). Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
- Published
- 2024
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