Heat Shock Proteins 27, 70, and 110: Expression and Prognostic Significance in Colorectal Cancer

Heat shock proteins (HSPs) are evolutionarily conserved chaperones occurring in virtually all living organisms playing a key role in the maintenance of cellular homeostasis. They are constitutively expressed to prevent and repair protein damage following various physiological and environmental stressors. HSPs are overexpressed in various types of cancers to provide cytoprotective function, and they have been described to influence prognosis and response to therapy. Moreover, they have been used as a tumor marker in blood serum biochemistry and they represent a potentially promising therapeutic target. To clarify prognostic significance of two canonical HSPs (27 and 70) and less known HSP110 (previously known as HSP105) in colorectal carcinoma (CRC), we retrospectively performed HSP immunohistochemistry on tissue microarrays from formalin-fixed paraffin-embedded tumor tissue from 297 patients with known follow-up. Survival analysis (univariate Kaplan–Meier analysis with the log-rank test and multivariate Cox regression) revealed significantly shorter overall survival (OS, mean 5.54 vs. 7.07, p = 0.033) and borderline insignificantly shorter cancer specific survival (CSS, mean 6.3 vs. 7.87 years, p = 0.066) in patients with HSP70+ tumors. In the case of HSP27+ tumors, there was an insignificantly shorter OS (mean 6.36 vs. 7.13 years, p = 0.2) and CSS (mean 7.17 vs. 7.95 years, p = 0.2). HSP110 showed no significant impact on survival. Using Pearson’s chi-squared test, there was a significant association of HSP27 and HSP70 expression with advanced cancer stage. HSP27+ tumors were more frequently mismatch-repair proficient and vice versa (p = 0.014), and they occurred more often in female patients and vice versa (p = 0.015). There was an enrichment of left sided tumors with HSP110+ compared to the right sided (p = 0.022). In multivariate Cox regression adjusted on the UICC stage, grade and right/left side; both HSPs 27 and 70 were not independent survival predictors (p = 0.616 & p = 0.586). In multivariate analysis, only advanced UICC stage (p = 0) and right sided localization (p = 0.04) were independent predictors of worse CSS. In conclusion, from all three HSPs examined in our study, only HSP70 expression worsened CRC prognosis, although stage-dependent. The contribution of this article may be seen as a large survival analysis of HSPs 27 and 70 and the largest analysis of HSP110 described in CRC.

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Expression of heat shock proteins in classical Hodgkin lymphoma: correlation with apoptotic pathways and prognostic significance

Histopathology ◽

10.1111/j.1365-2559.2011.03803.x ◽

2011 ◽

Vol 58 (7) ◽

pp. 1072-1080 ◽

Cited By ~ 9

Author(s):

Almudena Santón ◽

Mónica García-Cosío ◽

Eva Cristóbal ◽

Alejandro Pascual ◽

Alfonso Muriel ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Hodgkin Lymphoma ◽

Prognostic Significance ◽

Classical Hodgkin Lymphoma ◽

Apoptotic Pathways ◽

Shock Proteins

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Expression of heat shock proteins in medulloblastoma

Journal of Neurosurgery Pediatrics ◽

10.3171/2013.7.peds1376 ◽

2013 ◽

Vol 12 (5) ◽

pp. 452-457 ◽

Cited By ~ 19

Author(s):

George A. Alexiou ◽

George Vartholomatos ◽

Kalliopi Stefanaki ◽

Amalia Patereli ◽

Lefkothea Dova ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Significant Positive Correlation ◽

Large Cell ◽

Hsp70 Expression ◽

Ki 67 ◽

Positive Correlation ◽

Wide Range ◽

Shock Proteins ◽

Multiplex Bead

Object Medulloblastoma (MB) is the most common malignant brain tumor in children. Heat shock proteins (HSPs) comprise a superfamily of proteins that serve as molecular chaperones and are overexpressed in a wide range of human cancers. The purpose of the present study was to investigate the expression of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt by multiplex bead array assay of MBs. The results of HSP and Akt expression were correlated with MB subtype; immunohistochemical expression of Ki-67 index, bcl-2, and p53; and patients' prognosis. Methods The authors retrospectively evaluated 25 children with MB who underwent surgery. Immunohistochemical analysis of Ki-67, p53, and bcl-2 expression was performed in all cases. By using multiplex bead array assay, a simultaneous detection of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt was performed. Results Medulloblastoma with extensive nodularity had significantly lower HSP27 (pSer15) expression (p = 0.039) but significantly higher HSP60 expression (p = 0.021) than classic MB. Large-cell MB had significantly higher HSP70 expression (p = 0.028) than classic MB. No significant difference was found between HSP27 (pSer82), HSP40, HSP90-α, Akt, or phospho-Akt expression and MB subtype. Large-cell MBs had significantly higher Ki-67 index compared with classic MBs (p = 0.033). When analyzing all MBs, there was a significant negative correlation between HSP27 (pSer15) and Ki-67 index (r = −0.475, p = 0.016); a significant positive correlation between HSP70 expression and Ki-67 index (r = 0.407, p = 0.043); and a significant positive correlation between HSP70 expression and bcl-2 index (r = 0.491, p = 0.023). Patients with large-cell MB had a worse survival than those with classic MB, but the difference did not reach statistical significance (p = 0.076). Conclusions A substantial expression of several HSPs in MB was observed. Given that HSPs represent an attractive strategy for anticancer therapy, further studies, involving larger series of patients, are obviously necessary to clarify the relationship of HSPs with tumor aggressiveness and prognosis.

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The repeated bout effect and heat shock proteins: intramuscular HSP27 and HSP70 expression following two bouts of eccentric exercise in humans

Acta Physiologica Scandinavica ◽

10.1046/j.1365-201x.2002.00922.x ◽

2002 ◽

Vol 174 (1) ◽

pp. 47-56 ◽

Cited By ~ 76

Author(s):

H. S. Thompson ◽

P. M. Clarkson ◽

S. P. Scordilis

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Eccentric Exercise ◽

Hsp70 Expression ◽

Repeated Bout Effect ◽

Shock Proteins ◽

Exercise In Humans ◽

Repeated Bout

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Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus

Cancer ◽

10.1002/(sici)1097-0142(19990415)85:8<1649::aid-cncr2>3.0.co;2-v ◽

1999 ◽

Vol 85 (8) ◽

pp. 1649-1657 ◽

Cited By ~ 63

Author(s):

Kensyu Kawanishi ◽

Hitoshi Shiozaki ◽

Yuichiro Doki ◽

Isao Sakita ◽

Masatoshi Inoue ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Heat Shock ◽

Heat Shock Proteins ◽

Cell Carcinoma ◽

Squamous Cell ◽

Prognostic Significance ◽

Carcinoma Of The Esophagus ◽

Shock Proteins

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Prognostic and Functional Significant of Heat Shock Proteins (HSPs) in Breast Cancer Unveiled by Multi-Omics Approaches

Biology ◽

10.3390/biology10030247 ◽

2021 ◽

Vol 10 (3) ◽

pp. 247

Author(s):

Miriam Buttacavoli ◽

Gianluca Di Cara ◽

Cesare D’Amico ◽

Fabiana Geraci ◽

Ida Pucci-Minafra ◽

...

Keyword(s):

Breast Cancer ◽

Heat Shock ◽

Heat Shock Proteins ◽

Cancer Progression ◽

Prognostic Significance ◽

Molecular Size ◽

Good Prognosis ◽

Mesenchymal Transition ◽

Wide Range ◽

Shock Proteins

Heat shock proteins (HSPs) are a well-characterized molecular chaperones protein family, classified into six major families, according to their molecular size. A wide range of tumors have been shown to express atypical levels of one or more HSPs, suggesting that they could be used as biomarkers. However, the collective role and the possible coordination of HSP members, as well as the prognostic significance and the functional implications of their deregulated expression in breast cancer (BC) are poorly investigated. Here, we used a systematic multi-omics approach to assess the HSPs expression, the prognostic value, and the underlying mechanisms of tumorigenesis in BC. By using data mining, we showed that several HSPs were deregulated in BC and significantly correlated with a poor or good prognosis. Functional network analysis of HSPs co-expressed genes and miRNAs highlighted their regulatory effects on several biological pathways involved in cancer progression. In particular, these pathways concerned cell cycle and DNA replication for the HSPs co-expressed genes, and miRNAs up-regulated in poor prognosis and Epithelial to Mesenchymal Transition (ETM), as well as receptors-mediated signaling for the HSPs co-expressed genes up-regulated in good prognosis. Furthermore, the proteomic expression of HSPs in a large sample-set of breast cancer tissues revealed much more complexity in their roles in BC and showed that their expression is quite variable among patients and confined into different cellular compartments. In conclusion, integrative analysis of multi-omics data revealed the distinct impact of several HSPs members in BC progression and indicate that collectively they could be useful as biomarkers and therapeutic targets for BC management.

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Protective effect of Zingiber zerumbet Smith extract on thermotolerance

Bioactive Compounds in Health and Disease ◽

10.31989/bchd.v4i1.777 ◽

2021 ◽

Vol 4 (1) ◽

pp. 1

Author(s):

Yasuhito Shirai ◽

Hisakazu Kobayashi ◽

Shuji Ueda ◽

Yun Sang Soon ◽

Akiho Kushiya ◽

...

Keyword(s):

Heat Treatment ◽

Growth Rate ◽

Heat Stress ◽

Heat Shock ◽

Heat Shock Proteins ◽

Hsp70 Expression ◽

Heat Shock Treatment ◽

Zingiber Zerumbet ◽

Murine Liver ◽

Shock Proteins

Background: Global warming causes severe heat conditions. Heat stress contributes to higher morbidity of heatstroke in human and mortality in livestock. To protect them from heat stress, thermotolerance mechanisms were widely studied, and some studies suggest relationship between heat shock proteins (HSPs) and thermotolerance. HSPs were not induced by only heat shock but also some stimulations including bioactive compounds from plants. Zingiber zerumbet is a perennial herb found in many tropical countries, including Thailand. The rhizome of Zingiber zerumbet contains zerumbone that is a bioactive compound to induce HSPs expression in animal cells.Objective: To prevent higher morbidity of heatstroke in human and mortality in livestock by the heat stress, we investigated the effect of zerumbone, the extract of Zingiber zerumbet Smith, on thermotolerance, using a cell line and mice.Methods: The murine liver hepatoma cell line, Hepa1c1c7 cells, were incubated in medium supplemented with extract from rhizome of Zingiber zerumbet Simith containing zerumbone, and then the expression of heat shock proteins (HSP) 40, 70 and 90 were investigated by western blotting. Furthermore, we established the evaluation system of thermotolerance using mice, and studied the effect of the extract on the growth rate of mice under the heat shock treatment. Briefly, 4 weeks old C57BL6 mice were fed that with the extract (or vehicle) for a week before the first heat shock treatment (38 °C for an hour). Before and after five days heat treatment, body weights were measured. The protein expressions of heat shock proteins in liver were measured by western blotting using HSPs antibodies.Results: The extract of Zingiber zerumbet rhizome, equivalent to 50 μM zerumbone, significantly increased the expression of heat shock proteins (HSP40, HSP70, HSP90). The growth rate of the mice under the heat treatment were lower than control. The feeding with the extract containing 25 ppm zerumbone have significantly attenuated the decline of the growth rate led by the heat treatment, whereas there was little effect on mouse growth rate grown under normal conditions. The protein expression of HSP70 in the liver of zerumbone-fed mice was upregulated compared with control mice, equivalent to heat treatment without zerumbone. On the other hand, both treatments of zerumbone and heat resulted in highest HSP70 expression among four groups.Conclusion: Our study demonstrated that oral administration of the extract of Zingiber zerumbet Smith led to the attenuation of decline of growth rate induced by heat treatment. HSP70 expression in murine liver was enhanced by either feeding the extract or heat treatment. More interestingly, HSP70 expression was further enhanced by both treatments of zerumbone and heat. These results suggested that zerumbone may contribute to thermotolerance via, at least, HSP70 expression.Keywords: Zingiber zerumbet, thermotolerance, heat shock protein

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Modulation of thermal induction of hsp70 expression by Ku autoantigen or its individual subunits.

Molecular and Cellular Biology ◽

10.1128/mcb.16.7.3799 ◽

1996 ◽

Vol 16 (7) ◽

pp. 3799-3806 ◽

Cited By ~ 29

Author(s):

S H Yang ◽

A Nussenzweig ◽

L Li ◽

D Kim ◽

H Ouyang ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Cell Lines ◽

Heat Shock Response ◽

Hsp70 Expression ◽

Shock Response ◽

Ku Protein ◽

Shock Proteins ◽

Ku Autoantigen ◽

Thermal Induction

Previously, we proposed a dual control mechanism for the regulation of the heat shock response in mammalian cells: a positive control mediated by the heat shock transcription factor HSF1 and a negative control mediated by the constitutive heat shock element-binding factor (CHBF). To study the physiological role of CHBF in the regulation of heat shock response, we purified CHBF to apparent homogeneity and showed it to be identical to the Ku autoantigen, a heterodimer consisting of 70-kDa (Ku-70) and 86-kDa (Ku-80) polypeptides. To study further the functional significance of Ku/CHBF in the cellular response to heat shock, we established rodent cell lines that stably and constitutively overexpressed one or both subunits of the human Ku protein, and examined the thermal induction of hsp70 and other heat shock proteins in these Ku-overexpressing ing cells. We show that expression of the human Ku-70 and Ku-80 subunits jointly or of the Ku-70 subunit alone specifically inhibits heat-induced hsp70 expression. Conversely, expression of human Ku-80 alone does not have this effect. Thermal induction of other heat shock proteins in all of the Ku-overexpressing cell lines appears not to be significantly affected, nor is the state of phosphorylation or the DNA-binding ability of HSF1 affected. These findings support a model in which hsp70 expression is controlled by a second regulatory factor in addition to the positive activation of HSF1. The Ku protein, specifically the Ku-70 subunit, is involved in the regulation of hsp70 gene expression.

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