title: OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway.
abstract: BACKGROUND
  MicroRNA-196 (miR-196), which is highly up-regulated in oral cancer cells, has been reported to be aberrantly expressed in several cancers; however, the significance of miR-196 in oral cancer has not yet been addressed.
  
  
  METHODS
  Cellular functions in response to miR-196 modulation were examined, including cell growth, migration, invasion and radio/chemosensitivity. Algorithm-based studies were used to identify the regulatory target of miR-196. The miR-196 target gene and downstream molecular mechanisms were confirmed by RT-qPCR, western blot, luciferase reporter and confocal microscopy analyses. miR-196 expression was determined in paired cancer and adjacent normal tissues from oral cancer patients.
  
  
  RESULTS
  Both miR-196a and miR-196b were highly over-expressed in the cancer tissue and correlated with lymph node metastasis (P = 0.001 and P = 0.006, respectively). Functionally, miR-196 actively promoted cell migration and invasion without affecting cell growth. Mechanistically, miR-196 performed it's their function by inhibiting NME4 expression and further activating p-JNK, suppressing TIMP1, and augmenting MMP1/9.
  
  
  CONCLUSIONS
  miR-196 contributes to oral cancer by promoting cell migration and invasion. Clinically, miR-196a/b was significantly over-expressed in the cancer tissues and correlated with lymph node metastasis. Thus, our findings provide new knowledge of the underlying mechanism of cancer metastasis. miR-196 may serve as a promising marker for better oral cancer management.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Lu
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Chang
authors.forename: Chun-Ta
authors.initials: CT
authors.lastname: Liao
authors.forename: Chung-Jan
authors.initials: CJ
authors.lastname: Kang
authors.forename: Shiang-Fu
authors.initials: SF
authors.lastname: Huang
authors.forename: I-How
authors.initials: IH
authors.lastname: Chen
authors.forename: Chi-Che
authors.initials: CC
authors.lastname: Huang
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Huang
authors.forename: Wen-Ho
authors.initials: WH
authors.lastname: Chen
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: Tsai
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Wang
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.forename: Guo-Rung
authors.initials: GR
authors.lastname: You
authors.forename: Chang-Hsu
authors.initials: CH
authors.lastname: Chiang
authors.affiliation: Department of Medical Biotechnology, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Taoyuan, 333, Taiwan. annjoycheng@gap.cgu.edu.tw.
authors.forename: Ann-Joy
authors.initials: AJ
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D061107:Nucleoside Diphosphate Kinase D / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
chemical_list: C542543:MIRN196 microRNA, human; D035683:MicroRNAs; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D048031:JNK Mitogen-Activated Protein Kinases; C517946:NME4 protein, human; D061107:Nucleoside Diphosphate Kinase D; D020782:Matrix Metalloproteinases