BackgroundAberrant expression of heparanase (Hpa) is associated with apoor prognosis in ovarian and cervical cancer patients. Inhibitors of Hpa can prevent the growth and metastasis of malignant tumor cells, and suramin may be such a compound that has strong anti-proliferative effects on several kinds of cancer cells. We have therefore tested whether the growth inhibiting effect of suramin on ovarian and cervical cancer cells is due to downregulation of Hpa expression.ResultsSuramin at 300–600 μg/ml significantly inhibited HO-8910 PM and HeLa cell growth at 24 h, in both a time-dependent and dose-dependent manner, with an IC50 of 320 μg/ml and 475 μg/ml, respectively. Suramin at 300 μg/ml significantly decreased the expression of Hpa mRNA (P < 0.005) and protein (P < 0.005) in both HO-8910 PM and HeLa cells at 48 h.ConclusionsThe inhibitory effect of suramin on Hpa enzyme may be due to downregulating of its expression in cancer cells. These findings confirm the importance of Hpa in tumor growth and the potential clinical application of Hpa inhibitors in the treatment of ovarian and cervical cancer.
Heparanase (HPA) is an enzyme that plays an important role in cancer metastasis and angiogenesis and is a potential target for molecular treatment of tumors. We previously found that abnormally high HPA expression in cervical cancer tissues is associated with poor survival and increased lymph node metastasis. The present study was conducted to assess the utility of inhibiting HPA enzyme activity in cervical cancer treatment. Two series of 13 novel HPA inhibitors were synthesized and optimized. All tested inhibitors reduced HPA enzyme activity (IC50 values ranged from 4.47 μM to 47.19 μM) and inhibited the growth of HeLa cells (IC50 values ranged from 48.16 μM to 96.64 μM). The No. 16 inhibitor inhibited the migration and growth of HeLa and Siha cells in a dose- and time-dependent manner, and increased cell apoptosis and cell cycle G0/G1 and G2/M phase arrest, while decreasing the S phase cell population. More importantly, No. 16 sensitized cervical cancer cells to low concentrations of nedaplatin, decreased HPA, c-Myc and h-TERT levels, and increased p53 levels in HeLa and Siha cells. These results suggest that this HPA inhibitor reduced proliferation and HPA expression in cervical cancer cells by restoring p53 activity and downregulating h-TERT and c-Myc expression.
Abstract. The aim of this study was to explore the expression of heparanase (HPA) in metastatic lymph nodes (LNs) of cervical cancer and to evaluate HPA as a marker of micro-metastasis of LNs. Immunohistochemistry was performed to detect the expression of HPA in 53 cases with metastasis of LNs (group A) and 49 cases without (group B). Scoring was determined based on the intensity of immuno staining and the size of the staining area. Three points or higher score was considered as positive. Among all cases, the positive rate of HPA was 76.5% in primary lesions and 84.9% in both primary lesions and metastatic LNs in group A. In group B, the rates were 67.3% in primary lesions and 8.2% in metastatic LNs. The expression of HPA in group A was significantly higher than that in group B (P<0.05). Compared with stage IA-IB and well-differentiated and non-metastatic LNs, the LNs of stage IIA and moderately/poorly differentiated and metastatic LNs expressed higher HPA (P<0.05). The overall 5-year survival rate was 73.3% and the median overall survival time (MOS) was 49.0 months. The MOS of the two groups was 36.0 and 58.5 months, respectively (P=0.023); the MOS of patients with positive HPA expression was distinctly lower than that of negative patients (P=0.040). Clinical staging, degree of differentiation, lymph node metastasis and expression of HPA notably affected patient prognosis; lymph node metastasis and expression of HPA were independent risk factors affecting patient prognosis (P<0.05). Our study demonstrated that high-level expression of HPA in cervical cancer was involved in LN metastasis, further impacting on patients' long-term survival. The clinical value of HPA requires further in-depth study.
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