title: Interplay of N-Cadherin and matrix metalloproteinase 9 enhances human nasopharyngeal carcinoma cell invasion.
abstract: N-cadherin is a trans-membrane adhesion molecule associated with advanced carcinoma progression and poor prognosis. The effect of N-cadherin on matrix metalloproteinase 9 (MMP-9) regulation is implicated in human nasopharyngeal carcinoma (NPC) cell invasion.
  
  
  
  Exposure of NPC cells to phorbol-12-myristate-13-acetate (PMA) or macrophage conditioned media (CM) upregulated MMP-9 and N-cadherin cleavage, which resulted in NPC cell invasion. MMP-9 cleaved the extracellular domain of N-cadherin, which was further cleaved by γ-secretase with PMA or macrophage-CM treatment. The extracellular cleavage of N-cadherin was inhibited with treatment with an MMP inhibitor and MMP-9 siRNA, whereas the intracellular cleavage of N-cadherin was inhibited by treatment with a γ-secretase inhibitor (γI), which resulted in enhanced accumulation of N-cadherin C-terminal fragment (CTF1, ~40 kDa). CTF2/N-cad (CTF2), a product of the γ-secretase cleavage of N-cadherin, was released and translocated into the nuclear compartment in PMA-treated cells. Moreover, CTF2 enhanced the effect of PMA-mediated MMP-9 gene expression as assessed by treatment with γI or overexpression with exogenous CTF2. Additionally, siRNA silencing of N-cadherin decreased PMA-mediated MMP-9 expression and cell invasion. The outside-in signaling effect of MMP-9 in macrophage CM- or PMA-treated cell cultures significantly enhanced NPC cell invasion via N-cadherin cleavage.
  
  
  
  Extracellular and intracellular cleavage of N-cadherin might be involved in elevated MMP-9 expression enhancing tumor cell invasion. Furthermore, N-cadherin-affected tumor progression might be via enhanced MMP-9 signaling in a cross-talk regulatory mechanism. N-cadherin might contribute to the invasive characteristics of carcinoma cells by upregulating MMP-9, thereby leading to increased aggressive metastasis.
authors.affiliation: Department of Physical Medicine and Rehabilitation, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.|Department of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Chin
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Shiang-Fu
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Graduate Institute of Rehabilitation Science, Chang Gung University, Taoyuan, Taiwan.|Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jong-Shyan
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Department of Physiology, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Wing-Keung
authors.initials: WK
authors.lastname: Chu
authors.affiliation: Department of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ju-En
authors.initials: JE
authors.lastname: Nien
authors.affiliation: Department of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Wei-Shan
authors.initials: WS
authors.lastname: Chen
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan. chowse@mail.cgu.edu.tw.|Department of Nature Science, Center for General Studies, Chang Gung University, Taoyuan, Taiwan. chowse@mail.cgu.edu.tw.
authors.forename: Shu-Er
authors.initials: SE
authors.lastname: Chow
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D015398:Signal Transduction
chemical_list: D015820:Cadherins; D016328:NF-kappa B; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9
keywords: Invasion; MMP-9; Metastasis; N-Cadherin; PMA