Hsp60 exerts a tumor suppressor function by inducing cell differentiation and inhibiting invasion in hepatocellular carcinoma

Abstract

Heat shock protein 60 (Hsp60), a typical mitochondrial chaperone, is associated with progression of various cancers. However, its expression and significance in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, the mRNA and protein expression of Hsp60 in HCC tissues were detected by quantitative RT-PCR (n=24), western blot (n=7), and immunohistochemical staining (n=295), respectively. The correlation between Hsp60 expression and clinicopathological characteristics of HCC patient was also analyzed. Meanwhile, the influence of Hsp60 on malignant phenotype of HCC cells was further investigated. We found that expression of Hsp60 was significantly downregulated in HCC tissues compared to peritumor tissues. Hsp60 expression was significantly correlated with serum alpha -foetoprotein (AFP) level and tumor differentiation grade. Moreover, high Hsp60 expression cancer/ pericancer (C/P) ratio was associated with a better overall survival rate (P=0.035, n=295). The prognostic implication of Hsp60 in HCC was further confirmed in another cohort of 107 HCC patients (P=0.027). Up-regulation of Hsp60 remarkably induced the cell differentiation and inhibited the invasive potential of HCC in vitro and in vivo. Intriguingly, the down-regulation of Hsp60 significantly impaired mitochondrial biogenesis. Although more data are required to clarify the underling mechanism responsible for function of Hsp60, our results suggested that the effect of Hsp60 on differentiation and invasion of HCC cells might be associated with mitochondrial biogenesis. Collectively, our findings indicated that Hsp60 exerted a tumor suppressor function, and might serve as a potential therapeutic target in the treatment of HCC.

Targeting HSP60 by subcutaneous injections of jetPEI/HSP60‐shRNA destabilizes cytoplasmic survivin and inhibits hepatocellular carcinoma growth

“…In this study, we found HSP60‐silencing in HCC cells led to inhibition of cell proliferation and promotion of cell apoptosis in vitro and in vivo. The findings were inconsistent with a previous study reporting no effects on cell proliferation and apoptosis of HCC cells with HSP60‐silencing in 2016 . The discrepancies might be due to different cell lines used or efficiencies of transfection systems.…”

“…However, a study in 2016 indicated significant under‐expression of HSP60 in HCCs. This study suggested that HSP60 functioned as a tumor suppressor in HCC due to its ability to induce cell differentiation and to inhibit cell invasion and migration, while no effect was found on cell proliferation and apoptosis . Given the reported conflicting roles of HSP60 in HCC, we aim to clarify this issue by more precise analysis of HSP60 expression levels in the cancerous and adjacent non‐cancerous liver tissues of HCCs.…”

Heat shock protein 60 and chromatin assembly factor-1 mRNA levels in hepatitis C virus-related hepatocellular carcinoma and clinical significance

“…They reported that HSP60 exerted a tumor suppressor function and that its overexpression induced HCC cell differentiation with good prognosis. 8 A previous study by Lim et al reported non-significant HSP60 difference between tumor and non-tumor HBV-related HCC specimens by immunohistochemistry and dot-immunoblotting. 38 The present study showed a highly significant expressed CAF-1 mRNA levels (urine and blood) in HCC cases compared to cirrhosis and controls (p<0.001).…”

“…42 On the other hand, Zhang et al reported that HSP60 expression was significantly correlated with serum AFP and its high expression in cancer compared to pericancer tissue was associated with better overall survival. 8 Moreover, Lim et al found that HSP60 had no relation with histopathological grading and not affecting the survival in HBV-related HCC. 38 In agreement with our study; Xu et al observed a significant positive correlation between CAF-1 expression and both tumor number and size but 40 In the present study, HSP60 mRNA in urine at cutoff 258354 RU had 85%, sensitivity and 66% specificity for HCC diagnosis, a result agreed with Abdalla and Haj-Ahmad, who found 83% sensitivity and 43% specificity for HSP60 in urine for diagnosis of HCC.…”

“…However, its expression and significance in HCC are still largely obscure. 8 Chromatin assembly factor-1 (CAF-1) is a highly conserved heterotrimeric histone chaperone consists of p48, p60 and p150 protein subunits and plays a critical role in DNA replication and repair, though regulation of chromatin assembly (deposition of histones H3 and H4, required for S-phase progression of the cell cycle, on newly synthesized DNA).…”