Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma

Int J Med Sci. 2015 Feb 15;12(3):256-63. doi: 10.7150/ijms.10735. eCollection 2015.

Abstract

Background: Heat shock proteins (HSPs) are overexpressed in human hepatocellular carcinoma (HCC) tissue and correlate with aggressiveness and prognosis of HCC.

Methods: Using the GSE14520 microarray expression profile from Gene Expression Omnibus, we compared HSP gene expression between tumour and non-tumour tissues and correlated this with outcomes in HCC patients.

Results: We analysed 220 hepatitis B virus (HBV)-related HCC patients and 25 HSPs in this study. With the exception of HSPA4L, HSPA12A and HSPB8, members of the HSP family, including HSPH1, HSPBP1, HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA4, HSPA5, HSPA8, HSPA9, HSPAA1, HSPAB1, HSPA14, HSPB11, HSPA13, HSP90B1 and HSPBAP1, were all overexpressed in tumour tissues (all P < 0.001). In contrast, HSPB6, HSPB7, HSPA6, HSPB2 and HSPB3 were upregulated in non-tumour tissues (all P < 0.001). Multivariate analysis showed that cirrhosis (HR = 5.282, 95% CI = 1.294-21.555, P = 0.02), Barcelona Clinic liver cancer (BCLC) staging (HR = 2.151, 95% CI = 1.682-2.750, P < 0.001), HSPA12A (HR = 1.042, 95% CI = 1.003-1.082, P = 0.033) and HSP90B1 (HR = 1.001, 95% CI = 1.000-1.001, P = 0.011) were negatively associated with survival of HBV-related HCC patients. Furthermore, advanced BCLC staging (HR = 1.797, 95% CI = 1.439-2.244, P < 0.001) was also associated with earlier recurrence of HCC. The high expression of HSPA4 (HR = 1.002, 95% CI = 1.000-1.004, P = 0.019), HSPA5 (HR = 1.0, 95% CI = 1.0-1.0, P = 0.046) and HSPA6 (HR = 1.008, 95% CI = 1.001-1.015, P = 0.021) was similarly associated with HCC recurrence.

Conclusions: The expression of most HSPs was higher in tumour tissues than in non-tumour tissues. High BCLC staging scores, advanced cirrhosis and the overexpression of HSPA12A and HSP90B1 might be associated with poor survival from HCC, whereas high levels of HSPA4, HSPA5 and HSPA6 might be associated with earlier recurrence of HCC.

Keywords: BCLC stage; HSP70.; HSP90B1; HSPA12A; HSPA4; HSPA5; HSPA6; carcinoma, hepatocellular; cirrhosis; heat shock proteins; recurrence; survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Endoplasmic Reticulum Chaperone BiP
  • Female
  • Gene Expression Regulation, Neoplastic
  • HSP110 Heat-Shock Proteins / biosynthesis*
  • HSP110 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / biosynthesis*
  • HSP70 Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / biosynthesis*
  • Heat-Shock Proteins / genetics
  • Hepatitis B virus / pathogenicity
  • Humans
  • Kaplan-Meier Estimate
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Male
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / genetics
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Treatment Outcome

Substances

  • Endoplasmic Reticulum Chaperone BiP
  • HSP110 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • HSPA12A protein, human
  • HSPA4 protein, human
  • HSPA5 protein, human
  • HSPA6 protein, human
  • Heat-Shock Proteins
  • Membrane Glycoproteins
  • endoplasmin