MiR-200c and HuR in ovarian cancer

Abstract

BackgroundMicroRNAs in solid malignancies can behave as predictors of either good or poor outcome. This is the case with members of the miR-200 family, which are the primary regulators of the epithelial to mesenchymal transition and have been reported to act as both oncogenes and tumor suppressors. This study assessed the role of miR-200c as regulator of class III β-tubulin (TUBB3), a factor associated with drug-resistance and poor prognosis in ovarian cancer.MethodsExpression of miR-200c was assessed in a panel of ovarian cancer cell lines with inherent or acquired drug-resistance. Stable overexpression of miR-200c was obtained in A2780 and Hey cell lines. Crosslinking-coupled affinity purification method and ribonucleic-immunoprecipitation assay were used to characterise the complexes between miR-200c, HuR and 3′UTR region of TUBB3 mRNA. Nanofluidic technology and immunohistochemistry were used to analyze the expression of HuR, TUBB3 and miR-200c in 220 ovarian cancer patients.ResultsIn a panel of ovarian adenocarcinoma cell lines, we observed a direct correlation between miR-200c expression and chemoresistance. In A2780 cells miR-200c targeted TUBB3 3′UTR, while a positive correlation was observed between miR-200c and TUBB3 expression in most of the other cell lines. Through the analysis of 3′UTR-associated complexes, we found that the miR-200c can increase the association of the RNA binding protein HuR with TUBB3 mRNA, whereas HuR binding enhanced TUBB3 mRNA translation. Most importantly, in our analysis on 220 ovarian cancer patients we observed that overexpression of miR-200c correlated with poor or good outcome depending on the cellular localization of HuR.ConclusionThis study suggests a model for the combined regulatory activity of miR-200c and HuR on TUBB3 expression in ovarian cancer. When HuR is nuclear, high expression of miR-200c inhibits TUBB3 expression and results in a good prognosis, whereas when HuR occurs in cytoplasm, the same miRNA enhances TUBB3 expression and produces a poor outcome. These findings reveal the usefulness of multidimensional analysis in the investigation of the prognostic role of miRNA expression.

RNA-binding protein HuR and the members of the miR-200 family play an unconventional role in the regulation of c-Jun mRNA

“…Most of the evidence comes from the work of Vasudevan and colleagues at the end of the past decade indicating a convincing direct relationship between the presence of specific miRNAs and the expression of a definite set of proteins. These noncanonical, positive effects of microRNAs seem to be delimited by a series of conditions, the most important being the growth condition (Vasudevan et al 2007) and the stress status of the cells (Prislei et al 2013). …”

Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer

“…Further studies are required in order to investigate and elucidate the complex mechanisms underlying the interaction between HuR expression levels and the response of patients to chemotherapy. Although numerous previous studies have reported that the expression of HuR in the cytoplasm has important roles in tumor aggressiveness, prognosis and the modulation of chemosensitivity-associated factors (6,8,28,31,32). It remains to be elucidated whether this is also true of nuclear HuR expression.…”

“…These findings were concordant with the results of previous studies of other types of cancer (11,14). By contrast, it has also been suggested that increased HuR expression levels are associated with decreased sensitivity to CDDP in ovarian cancer (31). As aforementioned, CDDP is the principal agent in first-line chemotherapy (21,30).…”

“…Therefore, HuR is able to mediate and suppress the anticancer effects of GEM. Furthermore, in addition to GEM, high HuR expression levels may regulate the response to paclitaxel via regulation of chemoresistance-associated factors including microRNA (31,32). A previous in vitro study demonstrated that cytoplasmic HuR expression was associated with the efficacy of various anticancer agents (33-35); however, it has also been revealed that HuR is able to mediate chemoresistance in numerous types of cancer (36,37).…”

“…It remains to be elucidated whether this is also true of nuclear HuR expression. Nuclear HuR expression was demonstrated to inhibit the chemoresistance-associated protein, tubulin beta class 3 (TUBB3), resulting in a improved prognosis, whereas the expression of cytoplasmic HuR enhanced TUBB3 expression and was associated with an improved treatment outcome in patients with ovarian cancer (31). Furthermore, the association between HuR expression levels and chemoresistance depends on the presence of certain binding partners, including acidic leucine-rich nuclear phosphoprotein 32 family member A (38,39).…”