Abstract
Members of the heat shock protein 70 (HSP70) family play an important role in assisting protein folding, preventing protein aggregation and transport of proteins across membranes under physiological conditions. Following environmental (i.e., irradiation, chemotherapy), physiological (i.e., cell growth, differentiation), and pathophysiological (i.e., inflammation, tumorigenesis) stress, the synthesis of heat shock proteins (HSPs) is highly up-regulated, whereas protein synthesis in general is reduced. In contrast to normal cells, many tumor entities including hepatocellular carcinoma (HCC) overexpress HSP70, the major-stress-inducible member of the HSP70 family, present it on their cell surface and secrete it into the extracellular milieu. Herein, the prognostic relevance of serum HSP70 levels in patients with chronic hepatitis (CH; n = 50), liver cirrhosis (LC; n = 46), and HCC (n = 47) was analyzed. Similar to other tumor entities, HSP70 is also present on the surface of primary HCC cells. The staining intensity of intracellular HSP70 in HCC tissue is stronger compared to control and cirrhotic liver sections. HSP70 serum levels in all HCC patients were significantly higher compared to a control group without liver disease (n = 40). No significant age- and gender-related differences in HSP70 serum levels were observed in male and female healthy human volunteers (n = 86). Patients with CH (n = 50) revealed significantly higher HSP70 serum levels compared to the control group, however, these values were significantly lower than those of HCC patients (n = 47). Furthermore, a subgroup of patients with LC who subsequently developed HCC (LC-HCC, n = 13) revealed higher HSP70 serum levels than patients with LC (n = 46, p = 0.05). These data indicate that serum HSP70 levels are consecutively increased in patients with CH, LC and liver carcinomas and thus might have a prognostic value.
Highlights
The incidence of hepatocellular carcinoma (HCC) is increasing dramatically in the Western societies in the last years and HCC is the third leading cause of cancer-related deaths [1]
We aim to evaluate the prognostic significance of the major stressinducible heat shock protein 70 (HSP70) in the serum of patients as a potential biomarker to distinguish patients with chronic inflammation and liver cirrhosis (LC) from patients with HCC
Since the availability of tumor biopsy material is limited during the course of disease, we addressed the question whether serum HSP70 levels could reflect the HSP70 membrane status of the tumor cells in HCC patients
Summary
The incidence of hepatocellular carcinoma (HCC) is increasing dramatically in the Western societies in the last years and HCC is the third leading cause of cancer-related deaths [1]. Tobacco, vinyl chloride, and aflatoxin-B1 toxin can initiate HCC in humans. Apart from toxins, HCC can arise from a dysregulated expression of small non-coding microRNAs (i.e., miR-122), diabetes, non-alcoholic fatty liver disease, hemochromatosis, liver cirrhosis (LC), and chronic hepatitis (CH) B/C viral infections. The production of pro-inflammatory cytokines and chemokines, which induces a chronic inflammation in the liver are discussed to increase the risk for a malignant transformation [2,3,4]. These data indicate that a multitude of different parameters including toxins, diseases, and the microenvironment of the host can play a role in the development of HCC [5]
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