title: Blocking TNF-α inhibits angiogenesis and growth of IFIT2-depleted metastatic oral squamous cell carcinoma cells.
abstract: Our previous study demonstrated that the depletion of interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) promoted metastasis and was associated with a poor prognosis in patients with oral squamous cell carcinoma (OSCC). Our current study explores the major downstream signaling involved in IFIT2 depletion-induced OSCC metastasis. To this end, we used two cell lines (designated sh-control-xeno and sh-IFIT2-xeno) derived from human OSCC xenografts expressing sh-control and sh-IFIT2, respectively, and one metastatic OSCC subline (sh-IFIT2-meta) from an IFIT2-depleted metastatic tumor. We found that the sh-IFIT2-meta cells proliferated more slowly than the sh-control-xeno cells but exhibited higher migration and chemoresistance. Using microarray technology and Ingenuity Pathway Analysis, we found that TNF-α was one of the major downstream targets in IFIT2-depleted OSCC cells. Quantitative real-time PCR, western blotting, and ELISA results confirmed that TNF-α was upregulated in the sh-IFIT2-meta cells. Blocking TNF-α abolished the angiogenic activity induced by the sh-IFIT2-meta cells. Furthermore, the human-specific TNF-α antibody golimumab significantly inhibited in vivo angiogenesis, tumor growth and metastasis of sh-IFIT2-meta cells. These results demonstrate that IFIT2 depletion results in TNF-α upregulation, leading to angiogenesis and metastasis of OSCC cells.
authors.affiliation: Department of Pharmacology, Tzu Chi University, Hualien, Taiwan. Electronic address: kuochu@gms.tcu.edu.tw.
authors.forename: Kuo-Chu
authors.initials: KC
authors.lastname: Lai
authors.affiliation: Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Chung-Ji
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Institute of Pharmacology and Toxicology, Department of Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Tsung-Jen
authors.initials: TJ
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ai-Chung
authors.initials: AC
authors.lastname: Mar
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hsiu-Hua
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chi-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan.
authors.forename: Zi-Xuan
authors.initials: ZX
authors.lastname: Hong
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Te-Chang
authors.initials: TC
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009362:Neoplasm Metastasis; D011506:Proteins / Q000502:physiology*; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C484289:IFIT2 protein, human; D011506:Proteins; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: Angiogenesis; Golimumab; IFIT2; OSCC; TNF-α