title: Tumor necrosis factor-α induces epithelial-mesenchymal transition of renal cell carcinoma cells via a nuclear factor kappa B-independent mechanism.
abstract: Chronic low dose of tumor necrosis factor-α (TNF-α) stimulation promotes tumorigenesis by facilitating tumor proliferation and metastasis. The plasma levels of TNF-α are increased in patients with renal cell carcinoma (RCC). Furthermore, high-grade clear cell RCC cell lines secrete more TNF-α than low-grade ones, and allow low-grade cell lines' gain of invasive ability. However, the molecular mechanism of TNF-α in mediating progression of RCC cells remains unclear. In the present study, TNF-α induced epithelial-mesenchymal transition (EMT) of RCC cells by repressing E-cadherin, promoting invasiveness and activating matrix metalloproteinase (MMP) 9 activity. RCC cells underwent promoted growth in vivo following stimulation with TNF-α. In addition, TNF-α induced phosphorylation of extracellular signal-regulated kinase, nuclear factor kappa B (NF-κB) and Akt in a time-dependent manner, and increased nuclear translocation and promoter activity of NF-κB. To investigate the role of NF-κB activation in TNF-α-induced EMT of RCC, we employed chemical inhibitors (NF-κB activation inhibitor and Bay 11-7082) and transfected dominant-negative (pCMV-IκBαM) and overexpressive (pFLAG-p65) vectors of NF-κB. While overexpression of NF-κB p65 alone could induce E-cadherin loss in RCC, EMT phenotypes and MMP9 expressions induced by TNF-α were not reversed by the inhibitors of NF-κB activation. These results suggest that the TNF-α signaling pathway is involved in the tumorigenesis of RCC. However, NF-κB activation is not crucial for invasion and EMT enhanced by TNF-α in RCC cells.
authors.affiliation: Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
authors.forename: Sheng-Tang
authors.initials: ST
authors.lastname: Wu
authors.forename: Guang-Huan
authors.initials: GH
authors.lastname: Sun
authors.forename: Chih-Ying
authors.initials: CY
authors.lastname: Hsu
authors.forename: Chang-Shuo
authors.initials: CS
authors.lastname: Huang
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Wu
authors.forename: Hsiao-Hsien
authors.initials: HH
authors.lastname: Wang
authors.forename: Kuang-Hui
authors.initials: KH
authors.lastname: Sun
mesh_terms: D000354:Africa, Western; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000139:chemically induced*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D009570:Nitriles; D012334:RNA, Neoplasm; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9