title: The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic significance.
abstract: BACKGROUND
  A role for autophagy, a conserved cellular response to stress, has recently been demonstrated in human cancers. Aberrant expression of Beclin-1, an important autophagic gene, has been reported in various human cancers. In the present study, we investigated the significance and relationship between Beclin-1 expression and cell proliferation, apoptosis, microvessel density (MVD) and clinical pathological changes or prognosis in human hepatocellular carcinoma (HCC).
  
  
  METHODS
  A total of 103 primary HCC patients were involved in the study. Expression of Beclin-1, PCNA, NET-1, Bcl-2, Bax, Survivin in cancer cells and CD34 in stromal microvessels were evaluated immunohistochemically in tissue microarrays comprising 103 cases of HCC and 57 matched adjacent nontumor liver tissues. Correlations between clinicopathological characteristics and survival of HCC patients were explored.
  
  
  RESULTS
  The positive rate of Beclin-1 was significantly lower in HCC tissues than adjacent tissues (72.8 vs. 89.5%, χ2 = 6.085, P = 0.015). In HCC, Beclin-1 expression was negatively correlated with cirrhosis background (r = -0.216, P = 0.029), Edmondson grade (r = -0.249, P = 0.011), vascular invasion (r = -0.246, P = 0.012), PCNA (r = -0.242, P = 0.014), NET-1 (r = -0.245, P = 0.013), anti-apoptosis protein Bcl-2 (r = -0.245, P = 0.013) and MVD (r = -0.292, P = 0.003), and positively correlated with pro-apoptosis protein Bax (r = 0.242, P = 0.014).Significant differences in the 5-year survival rates were seen among patients with Beclin-1 strong positive (++) (59.1%, 13/22), moderate positive (+) (28.3%, 15/53) and weak negative expression (-) (14.6%, 7/28) (P = 0.043). Significant differences were detected between Beclin-1 (++) and either Beclin-1 (+) (P = 0.036) or Beclin-1 (-) groups (P = 0.008), but no significant difference between Beclin-1 (+) and Beclin-1 (-) groups (P = 0.281) was observed.Survival rates were positively related to high Beclin-1 co-expressed with low PCNA, NET-1, or Bcl-2, lower MVD, and high Bax. Univariate and multivariate Cox regression analysis revealed that Beclin-1 expression was an independent indicator for overall survival in HCC patients (P < 0.05).
  
  
  CONCLUSIONS
  The pathogenesis and progression of HCC are associated with reduced autophagy. The expression of Beclin-1 and Bax in HCC tissues may provide a synergistic effect towards inhibiting HCC proliferation, infiltration, metastasis and angiogenesis. Beclin-1 expression may be a valuable prognostic marker of HCC.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Qiu
authors.forename: Gui-Lan
authors.initials: GL
authors.lastname: Wang
authors.affiliation: Department of Pathological Anatomy, Nantong University, Qixiu road 19#, Nantong, Jiangsu Province, China 226001. chenli_ntbl@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Yu-Yin
authors.initials: YY
authors.lastname: Xu
authors.forename: Song
authors.initials: S
authors.lastname: He
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Cao
authors.forename: Jing
authors.initials: J
authors.lastname: Qin
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Zhou
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zhang
authors.forename: Qun
authors.initials: Q
authors.lastname: E
mesh_terms: D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000032:analysis*; D001343:Autophagy; D000071186:Beclin-1; D014408:Biomarkers, Tumor / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000032:analysis; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000032:analysis*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D015513:Oncogene Proteins / Q000032:analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012189:Retrospective Studies; D000077022:Survivin; D046888:Tissue Array Analysis; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C491997:BECN1 protein, human; C107489:BIRC5 protein, human; D000071186:Beclin-1; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; C099763:NET1 protein, human; D015513:Oncogene Proteins; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D051028:bcl-2-Associated X Protein