Differential expression of HSP90 isoforms and their correlations with clinicopathologic factors in patients with colorectal cancer

Abstract

Heat shock protein 90 (HSP90), a molecular chaperone, plays critical roles in cellular protection against various stressful stimuli and in the regulation of cellular growth and apoptosis. HSP90 has four human isoforms; HSP90α, HSP90β, glucose related protein 94 (GRP94), and tumor necrosis factor (TNF) receptor-associated protein 1 (TRAP1). We evaluated the differential expression of these HSP90 isoforms in colorectal cancer (CRC) and correlated their expression levels with clinicopathological factors and patient survival rates. We performed immunohistochemical staining for HSP90α, HSP90β, GRP94, and TRAP1 in 129 CRC tumor samples and found that HSP90α expression was significantly associated with advanced pT stage (P = 0.011) and shorter recurrence-free survival (RFS) (P = 0.010), whereas GRP94 expression was correlated with low grade (P = 0.029) and better RFS (P < 0.001). HSP90β and TRAP1 had no prognostic impact, although HSP90β expression was positively correlated with tumor size (P = 0.008). Based on our results, HSP90α and GRP94 are potential prognostic biomarkers of CRC. In addition, the differences in expression and functional activities among four HSP90 isoforms imply that isoform selectivity should be seriously considered when HSP90 inhibitors are studied or adopted for the treatment of CRC.

Keywords: Colorectal cancer; GRP94; HSP90; TRAP1; immunohistochemistry; prognosis.

Figure 1

Immunohistochemical staining of HSP90 isoforms in colorectal cancers. Low (A) and high (B) expression of HSP90α, low (C) and high (D) expression of HSP90β, low (E) and high (F) expression of GRP94, and low (G) and high (H) expression of TRAP1.

Figure 2

Survival analysis using the Kaplan-Meier method: Recurrence-free survival (RFS) according to the expression levels of HSP90α in all patients (A) and in patients younger than 70 years old (B). RFS according to the expression levels of GRP94 (C) and the combined expression levels of HSP90α and GRP94 (D) in all patients.