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. 2016 Mar 16:9:1559-69.
doi: 10.2147/OTT.S100050. eCollection 2016.

Ubiquitin-specific protease 7 expression is a prognostic factor in epithelial ovarian cancer and correlates with lymph node metastasis

Ming Ma  1 , Nina Yu  2
Affiliations

Ubiquitin-specific protease 7 expression is a prognostic factor in epithelial ovarian cancer and correlates with lymph node metastasis

Ming Ma et al. Onco _targets Ther. .

Abstract

Objective: Ubiquitin-specific protease 7 (USP7) is a common _target of herpesviruses and is important in the DNA damage response, which is also upregulated in several cancers, including prostate, colon, liver, and lung cancers. However, less is known about its expression in ovarian cancer tissues. The role of USP7 in epithelial ovarian cancer (EOC) has not yet been investigated.

Materials and methods: We recruited 141 patients from Linyi People's Hospital between June 1999 and June 2013, all pathologically diagnosed with primary EOC. Their clinical data were collected, and the expression of USP7 in the tumor tissues was determined using immunohistochemistry. The correlations between USP7 expression and the clinicopathological variables of patients with EOC were assessed using Spearman's rank correlation test. Kaplan-Meier analysis and Cox regression analysis were used to identify the prognosis value of USP7. The function of USP7 in the EOC cells was also detected in vitro.

Results: Among the 141 cases, USP7 expression was high in 59 EOC samples (41.8%), and was significantly correlated with lymphatic invasion; USP7 can act as independent prognostic indicator for the overall survival (OS) of EOC, and its high expression was associated with poor OS rate. The RNA inteference and overexpression assays indicated that USP7 can positively regulate the ovarian cell vitality and invasion process.

Conclusion: Patients with EOC expressing high level of USP7 have worse OS compared with those with low USP7 expression. USP7 may be involved in the proliferation and invasion of EOC cells, and USP7 expression can serve as an independent predictor of EOC.

Keywords: USP7; epithelial ovarian cancer; invasion; lymph node metastasis; prognosis.

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Figures

Figure 1
Figure 1
Representative figures of lower (A and B) and higher (C and D) USP7 immunohistochemistry staining in clinical samples of EOC (scale bar: 100 μm). Abbreviations: USP7, ubiquitin-specific protease 7; EOC, epithelial ovarian cancer.
Figure 2
Figure 2
Correlation between clinicopathologic parameters, USP7 expression, and prognosis in validation cohort. Notes: Survival curve of the total patients was estimated (A). Survival analysis suggests that older age (B), advanced FIGO stage (C), higher pathological grade (E), positive lymph node metastasis (F), and high USP7 expression level (H) were significantly associated with poorer prognosis, while histology types (D) and CA-125 level (G) showed no statistically significant association. Abbreviations: USP7, ubiquitin-specific protease 7; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph node; CA, cancer antigen.
Figure 3
Figure 3
USP7 expression in different ovarian cell lines. Notes: USP7 showed different expression patterns among ovarian benign cell line Hs832 and malignant cell lines OVCAR3 and SKOV3 (A and B). The expression level of USP7 was detected using immunoblotting after 48 hours after transfection with USP7 siRNA in OVCAR3 cells (C and D) and overexpression of USP7 in SKOV3 cells (E and F). *Statistically significant. Abbreviations: USP7, ubiquitin-specific protease 7; ncRNA, negative control siRNA; siUSP7, siRNA of USP7; si, small interfering.
Figure 4
Figure 4
USP7 could increase the viability of malignant ovarian cell lines. Notes: Cell viability was detected by the PrestoBlue Cell Viability Reagent at different time points. The siRNA-transfected OVCAR3 cells showed decreased cell viability compared with blank control and the ncRNA-OVCAR3 (A and B), while the overexpression of UPS7 can significantly increase the cell viability (C and D). *Statistically significant. Abbreviations: USP7, ubiquitin-specific protease 7; ncRNA, negative control siRNA; siUSP7, siRNA of USP7; si, small interfering.
Figure 5
Figure 5
USP7 could promote the invasion of malignant ovarian cells. Notes: Invasion of OVCAR3 and SKOV3 cells was detected by transwell method after the USP7 was knocked down or overexpressed. Knockdown of USP7 could reduce the invasion of the OVCAR3 cells to ~25% (A), and the overexpression of USP7 in SKOV3 cells could significantly promote the invasion ability by ~50% compared with control cells (B). The statistical significance was calculated by Student’s t-test (comparing the tested group and control group at the same time, such as the siUSP7 vs ncRNA, and the vector vs USP7 overexpression). *Statistically significant. Abbreviations: USP7, ubiquitin-specific protease 7; ncRNA, negative control siRNA; siUSP7, siRNA of USP7; si, small interfering.
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