High levels of KAP1 expression are associated with aggressive clinical features in ovarian cancer

Abstract

KAP1 is an universal corepressor for Kruppel-associated box zinc finger proteins in both normal and tumor cells. In this study, the biological function and clinical significance of KAP1 expression in ovarian cancer were investigated. Immunohistological staining of KAP1 was evaluated in 111 patients with ovarian epithelial cancer, 15 with ovarian borderline tumor, and 20 normal ovarian tissue. The correlations of KAP1 expression with clinicopathological features were studied. Kaplan-Meier analysis and Cox proportional hazard modeling were used to assess overall survival to analyze the effect of KAP1 expression on the prognosis of ovarian cancer. The positive rates of KAP1 were significantly higher in ovarian epithelial cancer (55.7%) and borderline tumor (20.0%) than in normal ovarian tissue (5.0%) (all p < 0.01). KAP1 expression correlated significantly with clinical stage (χ2 = 14.57, p < 0.0001), pathological grade (χ2 = 6.06, p = 0.048) and metastases (χ2 =10.38, p = 0.001). Patients with high KAP 1 levels showed poor survival (p < 0.0001). Multivariate analysis showed that KAP1 high expression was an independent predictor for ovarian cancer patients (hazard ratio = 0.463; 95% confidence interval = 0.230-0.9318, p = 0.031). Functionally, depletion of KAP1 by siRNA inhibited ovarian cancer cell proliferation, cell migration. KAP1 expression correlated with aggressive clinical features in ovarian cancer. High KAP1 expression was a prognostic factor of ovarian cancer.

Figure 1

Expression of KAP1 in human non-tumor ovarian tissues and ovarian cancer. (A) in normal ovarian tissue; (B) in borderline tumor; (C) in ovarian cancer; (D) KAP1 expression levels in normal ovarian, borderline tumor and ovarian cancer tissues; (E) the expression level of KAP1 in non-tumor cells was lower than tumor cells in one sample and (F) western blot showed the expression level of KAP1 in cancer tissues was higher than normal ovarian tissues. (IHC, 400×). (** p < 0.01; *** p < 0.001).

Figure 2

KAP1 expression levels in different histological types (A1, serous carcinomas, A2 endometrioid carcinomas, A3 mucinous carcinomas and A4 clear cell adenocarcinomas); (B) Significant differences in KAP1 expression levels between serous, endometrioid carcinoma or clear cell adenocarcinoma and mucinous carcinoma. (* p < 0.05).

Figure 3

KAP1 expression levels in different pathological grade (A) grade 1; (B) grade 2; (C) grade 3; (D) Significant differences in KAP1 expression levels between grade 1 and grade 3 and (E) KAP1 expression levels in groups of different metastasis status. (** p < 0.01).

Figure 4

The prognostic effects of KAP1 expression levels in ovarian cancer patients. (A) Patients with high KAP 1 expression showed significantly shorter overall survival than those with low KAP 1 expression (p < 0.001) and (B) Patients with stage I–II disease showed significantly longer overall survival than those with stage III–IV disease (p < 0.001).

Figure 5

Downregulated expression of KAP1 inhibits cell growth and migration in SKOV3 cells. (A) western blot indicates KAP1 interference efficiency; (B) MTT assay at 0, 24, 48, 72 and 96 h after transfection; (C) representative images of two-dimensional culture of cells; (D) representative images of soft agar colony formation assay of cells (100×); (E) photographs representing the cells migrated into the wounded area, and histogram showing the relative migration distance of cells in the wound-healing assay (200×) and (F) transwell migration assay (100×). (* p < 0.05; ** p < 0.01; *** p < 0.001).

Figure 6

Downregulated expression of KAP1 inhibits cell growth and migration in A2780 cells. (A) western blot indicates the KAP1 interference efficiency; (B) MTT assay at 0, 24, 48, 72 and 96 h after transfection; (C) representative images of two-dimensional culture of cells; (D) representative images of soft agar colony formation assay of cells (100×); (E) photographs represent cells migrated into the wounded area, and histogram shows the relative migration distance of cells in the wound-healing assay (200×) and (F) transwell migration assay (100×). (* p < 0.05; ** p < 0.01; *** p < 0.001).