Cystatin B is a progression marker of human epithelial ovarian tumors mediated by the TGF-β signaling pathway

Abstract

Advanced ovarian cancer is a devastating disease. Gaining biomarkers of early detection during ovarian tumorigenesis may lead to earlier diagnosis and better therapeutic strategies. Cystatin B (CSTB) functions as an inhibitor to suppress intracellular cysteine proteases and has been implicated in several types of cancers. The present study explored the expression of CSTB in human ovarian tumors, to investigate CSTB expression associated with clinicopathological features, and to examine the effect of transforming growth factor-β (TGF-β), which plays a key role in ovarian tumorigenesis, on CSTB expression in ovarian cancer cells. The ovarian tissue samples from 33 patients were retrieved. The expression of CSTB in ovarian tissue was examined by immunohistochemistry. We found that CSTB was overexpressed in human ovarian surface epithelial tumors, including serous, mucinous and clear cell tumors. The immunoreactive staining of CSTB was strong in borderline and malignant tumors, weak in benign tumors, and negative in normal tissue counterparts, but was not correlated with the clinicopathological features of patients with ovarian tumors, such as age, histological types, tumor size, lymph node metastasis and clinical stages. The CSTB at mRNA and protein levels in two types of epithelial ovarian cancer cells, OVCAR-3 and SK-OV-3, was decreased after TGF-β1 treatment detected by quantitative PCR and western blot analysis, respectively. The inhibitory effect of TGF-β1 on CSTB expression was abolished in the presence of SB-431542, a TGF-β type I receptor kinase inhibitor. Our data suggest that CSTB is tumor tissue-specific and overexpressed in ovarian borderline and malignant tumors. The increased CSTB expression in ovarian tissue represents tumor progression and is dysregulated by the TGF-β signaling pathway. CSTB may become a novel diagnostic intracellular biomarker for the early detection of ovarian cancer.