HSPA1A, HSPA1L and TRAP1 heat shock genes may be associated with prognosis in ovarian epithelial cancer

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with the presence of chemoresistance contributing to the poor prognosis. Heat Shock Proteins (HSPs) genes are activated in response to pathophysiological stress and serve a role in a variety of stages in carcinogenesis, acting primarily as anti-apoptotic agents and in chemotherapy resistance in a variety of tumor types. The current study evaluated the HSP gene expression profile in women with ovarian cancer (OC) and their correlation with clinical and pathological aspects of patients with OC. A total of 51 patients included in the current study were divided into four groups: Primary Epithelial Ovarian Cancer (EOC; n=14), metastatic EOC (n=11), ovarian serous cystadenoma (n=7) and no evidence of ovarian malignancy or control groups (n=19). RNA extraction and reverse transcription-quantitative (RT-q) PCR was then performed on the samples obtained. RT-qPCR was performed to compare TNF receptor associated protein 1 (TRAP1), heat shock protein family (HSP) HSPB1, HSPD1, HSPA1A and HSPA1L expression in primary and metastatic EOCs. TRAP1, HSPB1, HSPD1, HSPA1A and HSPA1L gene expression did not differ among groups. HSPA1A, HSPA1L and TRAP1 were revealed to be underexpressed in the primary and metastatic EOC groups, with HSPA1L exhibiting the lowest expression. TRAP1 expression was higher in tumors at stages I/II compared with those at stages III/IV. No correlation was exhibited between HSP expression and age, menarche, menopause, parity, period after menopause initiation, cytoreduction, CA-125 or overall and disease-free survival. HSPA1A was negatively correlated with the risk of mortality from OC. The results indicated that the downregulation of HSPA1A, HSPA1L and TRAP1 could be associated with the clinical prognostic features of women with EOC.

Keywords: gene expression; heat shock proteins; ovarian cancer; prognosis; resistance to chemotherapy.

Figure 1.

The association between TRAP1, HSPD1, HSPB1, HSPA1L and HSPA1A expression in ovarian tumors. The values represent TRAP1, HSPD1, HSPB1, HSPA1L and HSPA1A expression. The horizontal line indicates the median expression ratio, and the box plots demonstrate the interquartile range (25–75%). The 10 to 90th percentile ranges are also presented. The differences between groups were evaluated using a Man-Whitney U test and a Wilcoxon test. TRAP1, TNF receptor associated protein 1; HSP, heat shock protein family.

Figure 2.

Comparison of the expression of the TRAP1, HSPD1, HSP1, HSPA1 and HSPA1A genes in patients diagnosed with primary and metastatic EOC compared with patients with normal ovaries. Patients with normal ovary were considered as a control group (value of the expression equals 1, logarithm equals 0). The confidence intervals (red stems) of the genes intersecting the dashed line do not differ from each other. Intervals with confidence below the dashed line (less than 0) indicate that the gene is underexpressed. TRAP1, TNF receptor associated protein 1; HSP, heat shock protein family; EOC, epithelial ovarian carcinoma.

Figure 3.

Kaplan-Meier analysis of overall survival among women with primary and metastatic EOC according to their TRAP1, HSPD1, HSPB1, HSPA1L and HSPA1A gene expression. TRAP1, TNF receptor associated protein 1; HSP, heat shock protein family; EOC, epithelial ovarian carcinoma.

Figure 4.

Kaplan-Meier analysis of disease-free survival among women with primary and metastatic EOC according to their TRAP1, HSPD1, HSPB1, HSPA1L and HSPA1A gene expression. TRAP1, TNF receptor associated protein 1; HSP, heat shock protein family; EOC, epithelial ovarian carcinoma.

Figure 5.

Gene functional and Network pathway analysis of TRAP1, HSPD1, HSPB1, HSPA1L and HSPA1A. The Gene functional and Network pathway analysis evaluated in silico by STRING database. The circles colors indicate the HSP functions in network. Chaperone mediated protein folding, negative regulated of oxidative stress-induced intrinsic apoptotic signaling pathway (green), MAPK signaling pathway (yellow), and spliceossoma (purple). TRAP1, TNF receptor associated protein 1; HSP, heat shock protein family.