Loss of Both USP10 and p14ARF Protein Expression Is an Independent Prognostic Biomarker for Poor Prognosis in Patients With Epithelial Ovarian Cancer

Abstract

Background/Aim: The prognostic role of USP10 in epithelial ovarian cancer has been studied in various human cancers. Our aim was to evaluate the clinical and pathological significance of USP10 in epithelial ovarian cancer. Materials and Methods: Immunohistochemical analyses of the expression of USP10 and p14ARF by using tissue microarrays were performed in 336 ovarian tumours and the data were compared with clinicopathological variables. We examined their level of DNA methylation around the putative transcriptional start site in 5' CpG islands in fresh frozen tissues and ovarian cancer cells. Results: Expression of USP10 and p14ARF was significantly lower in cancer tissues than in normal epithelium. Low USP10 expression and a combined USP10/p14ARF low expression were revealed to be independent prognostic factors. A high degree of methylation in USP10 and p14ARF CpG islands was found by methylation specific PCR analysis in cancer than in normal tissues and cells. Conclusion: Decreased expression of USP10 or combined USP10/p14ARF decreased expression is a strong indicator of poor prognosis in patients with ovarian cancer. Epithelial ovarian cancer (EOC) is one of the most common gynaecological cancer. It is one of the most lethal diseases among the top five leading causes of cancer-related death in women (1). Advanced EOC patients exhibit only 40% of 5year survival rate (2). Surgical cytoreduction followed by adjuvant combined chemotherapy is the standard treatment of EOC patients. Despite the improvement in treatment modalities, most women with EOC experience relapse and eventually die from the disease. One of the major limitations to successful treatment is development of acquired resistance against the chemotherapeutic agent. Consequently, understanding the molecular mechanisms of EOC and the availability of predictive biomarkers for chemosensitivity of EOC would lead to the development of more specific prognostic markers to improve patient survival. Ubiquitination and de-ubiquitination are important posttranslational modifications which regulate activation, localization and degradation of proteins through conjugating or deconjugating ubiquitin from substrate proteins (3). Ubiquitin-specific protease10 (USP10), a member of the ubiquitin-specific protease (USP) family, regulates crucial signalling factors for cellular growth and apoptosis (4, 5). Recently, several studies have reported USP10 as a novel regulator of p53 in cancers (6). It has also been reported that it contributes to tumorigenesis in several types of cancers, such as breast cancer, stomach cancer, and glioblastoma (7-9). p14ARF located in the INK4a/ARF locus at chromosome 9q21 is an alternative reading frame product that encodes p16protein (10). It is a potent tumour suppressor which stabilizes p53 that induces cellular senescence and prevents tumour cell growth. Down-regulation or deletion of p14ARF in various cancers, including breast, lung and gastric, has been reported (11-13). Recently, Ko et al. (14) demonstrated that USP10 and/or p14ARF are...

Revisiting the Concept of Stress in the Prognosis of Solid Tumors: A Role for Stress Granules Proteins?

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