Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182

Abstract

Abstract. Altered expression of cullin-5 (CUL5), a member of the cullin-RING E3 ubiquitin ligase family, has been implicated in a number of types of cancers including breast, cervical and hepatocellular cancers. In the present study, we found that CUL5 expression was significantly decreased in both endometrioid and serous endometrial adenocarcinomas with the more aggressive serous type displaying a higher reduction (-4.3-fold) than the less aggressive endometrioid type (-2.9-fold). Overexpression of CUL5 mRNA and protein in Ishikawa H endometrial cancer cells resulted in decreased cell proliferation and in a reduction in CUL5-RING E3 ligase downstream clients JAK2 and FAS-L. Finally, we demonstrated for the first time that CUL5 is a direct target of miR-182 that we previously showed to be significantly overexpressed in endometrial adenocarcinomas and we provided evidence that increased miR-182 expression is, at least in part, a result of demethylation of its upstream promoter. These data suggest a cascade in which miR-182 expression is epigenetically increased leading to decreased CUL5 expression and increased cellular proliferation. The final step in the cascade may be operating through a decrease in ubiquitination of pro-growth CUL5 ubiquitin ligase clients. This cascade offers a series of potential interventional steps involving epigenetic modification, miRNA and/or gene targeting and ubiquitination.

Proteomic Analysis of Human Serum from Patients with Chronic Kidney Disease

“…High antigen KI-67 and CUL5 expression levels in tissues are associated with cancers [44,[52][53][54][55][56]. We observed increased serum concentrations of these proteins in patients with CKD in this study.…”

miR-652 Promotes Tumor Proliferation and Metastasis by Targeting RORA in Endometrial Cancer

“…In this study, we revealed 56 dysregulated miRNAs through which endometrial cancer tissues can be distinguished from benign endometrium. Some of these miRNAs have been reported in endometrial cancer before, such as miR-200a (14), miR-182 (37), and miR-183 (38). These data suggest that miRNAs play important roles in tumorigenesis.…”

“…miRNAs express aberrantly in cancers and have a profound effect on many processes that are usually disrupted during malignant transformation, such as cell proliferation, apoptosis, stress responses, maintenance of stem cell potency, and metabolism (36). Recent advances have suggested that dysregulation of miRNAs is a common event in endometrial cancer (37). In this study, we revealed 56 dysregulated miRNAs through which endometrial cancer tissues can be distinguished from benign endometrium.…”

Recent findings on epigenetic gene abnormalities involved in uterine cancer

“…CUL5 was significantly downregulated in serous endometrial adenocarcinoma with a poor prognosis, compared with its level in endometrial carcinoma with a good prognosis (58). The action of CUL5 involves non-coding RNAs (ncRNAs), which are RNAs that do not include genetic information for protein synthesis.…”

“…Two highly-conserved miR-182-binding regions are present in the 3'-UTR of CUL5, and CUL5 targets miR-182 in endometrial cancer. CUL5 downregulation causes miR-182 upregulation and progression of endometrial cancer (58). Zhou et al demonstrated that miR-30c overexpression inhibited metastasis-associated gene-1 (MTA1) (59).…”