title: Matrix metalloproteinase 12 is induced by heterogeneous nuclear ribonucleoprotein K and promotes migration and invasion in nasopharyngeal carcinoma.
abstract: BACKGROUND
  Overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a DNA/RNA binding protein, is associated with metastasis in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying hnRNP K-mediated metastasis is unclear. The aim of the present study was to determine the role of matrix metalloproteinase (MMP) in hnRNP K-mediated metastasis in NPC.
  
  
  METHODS
  We studied hnRNP K-regulated MMPs by analyzing the expression profiles of MMP family genes in NPC tissues and hnRNP K-knockdown NPC cells using Affymetrix microarray analysis and quantitative RT-PCR. The association of hnRNP K and MMP12 expression in 82 clinically proven NPC cases was determined by immunohistochemical analysis. The hnRNP K-mediated MMP12 regulation was determined by zymography and Western blot, as well as by promoter, DNA pull-down and chromatin immunoprecipitation (ChIP) assays. The functional role of MMP12 in cell migration and invasion was demonstrated by MMP12-knockdown and the treatment of MMP12-specific inhibitor, PF-356231.
  
  
  RESULTS
  MMP12 was overexpressed in NPC tissues, and this high level of expression was significantly correlated with high-level expression of hnRNP K (P = 0.026). The levels of mRNA, protein and enzyme activity of MMP12 were reduced in hnRNP K-knockdown NPC cells. HnRNP K interacting with the region spanning -42 to -33 bp of the transcription start site triggered transcriptional activation of the MMP12 promoter. Furthermore, inhibiting MMP12 by MMP12 knockdown and MMP12-specific inhibitor, PF-356231, significantly reduced the migration and invasion of NPC cells.
  
  
  CONCLUSIONS
  Overexpression of MMP12 was significantly correlated with hnRNP K in NPC tissues. HnRNP K can induce MMP12 expression and enzyme activity through activating MMP12 promoter, which promotes cell migration and invasion in NPC cells. In vitro experiments suggest that NPC metastasis with high MMP12 expression may be treated with PF-356231. HnRNP K and MMP12 may be potential therapeutic markers for NPC, but additional validation studies are warranted.
authors.forename: I-Che
authors.initials: IC
authors.lastname: Chung
authors.forename: Lih-Chyang
authors.initials: LC
authors.lastname: Chen
authors.forename: An-Ko
authors.initials: AK
authors.lastname: Chung
authors.forename: Mei
authors.initials: M
authors.lastname: Chao
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Huang
authors.forename: Chuen
authors.initials: C
authors.lastname: Hsueh
authors.forename: Ngan-Ming
authors.initials: NM
authors.lastname: Tsang
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Chang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, 259 Wen-Hwa Ist Road, Taoyuan, Kwei-shan 333, Taiwan. paili@mail.cgu.edu.tw.
authors.forename: Hsin-Pai
authors.initials: HP
authors.lastname: Li
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004790:Enzyme Induction; D005260:Female; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D012189:Retrospective Studies; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D055815:Young Adult
chemical_list: D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D012261:Ribonucleoproteins; C072074:HNRNPK protein, human; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12