title: Asparagine synthetase is an independent predictor of surgical survival and a potential therapeutic target in hepatocellular carcinoma.
abstract: BACKGROUND
  Asparagine synthetase (ASNS) is associated with drug resistance in leukaemia, and the function of this enzyme in the context of hepatocellular carcinoma (HCC) is not clear. In this study, the relationship between ASNS expression and clinical outcomes after surgical resection was investigated, and the therapeutic value of ASNS was also evaluated.
  
  
  METHODS
  The expression of ASNS was evaluated in HCC samples by real-time PCR and immunohistochemistry assays. The correlation between ASNS expression and clinicopathological features was investigated. Potential clinicopathological prognostic factors were examined by univariate and multivariate survival analysis. Asparagine synthetase was overexpressed and knocked down in HCC cell lines to assess the influence of the enzyme on cell proliferation, migration and tumourigenicity. L-asparaginase was used to treat HCC cells with high or low levels of ASNS in vitro and in vivo to examine the therapeutic efficacy.
  
  
  RESULTS
  The expression of ASNS was higher in HCC tumour tissues and was closely correlated with the serum AFP level, tumour size, microscopic vascular invasion, tumour encapsulation, TNM stage and BCLC stage. Patients with low ASNS expression levels had a poor prognosis with respect to overall survival (OS). The multivariate survival analysis indicated that ASNS is an independent prognostic factor for OS. Furthermore, functional studies demonstrated that ASNS significantly inhibits the proliferation, migration and tumourigenicity of HCC cells. The knockdown of ASNS markedly increased sensitivity to L-asparaginase, indicating that cells with different ASNS protein levels have different sensitivities to L-asparaginase.
  
  
  CONCLUSIONS
  The expression of ASNS is an independent factor affecting the survival of HCC patients, and low ASNS expression in HCC was correlated with worse surgical outcomes. The ASNS may be a promising therapeutic target for the treatment of HCC.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, Shanghai 200438, People's Republic of China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.forename: L-W
authors.initials: LW
authors.lastname: Dong
authors.forename: Y-X
authors.initials: YX
authors.lastname: Tan
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: Y-F
authors.initials: YF
authors.lastname: Pan
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.forename: M-H
authors.initials: MH
authors.lastname: Li
authors.forename: Z-W
authors.initials: ZW
authors.lastname: Ding
authors.forename: L-J
authors.initials: LJ
authors.lastname: Liu
authors.forename: T-Y
authors.initials: TY
authors.lastname: Jiang
authors.forename: J-H
authors.initials: JH
authors.lastname: Yang
authors.forename: H-Y
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D001215:Asparaginase / Q000494:pharmacology; D001217:Aspartate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000401:mortality / Q000601:surgery; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000401:mortality / Q000601:surgery; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D013534:Survival; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D000509:alpha-Fetoproteins; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase