Identification of a chrXq27.3 microRNA cluster associated with early relapse in advanced stage ovarian cancer patients

Abstract

A major challenge in advanced-stage epithelial ovarian cancer (EOC) is prediction of chemoresistant relapse. Our aim was to identify a microRNA (miRNA) signature associated with early relapse in advanced-stage EOC patients. miRNA expression was assessed by microarray profiling in training (n = 55) and test (n = 30) sets selected on the basis of time to relapse (TTR), followed by internal quantitative reverse transcriptase-PCR validation on a set of 45 consecutive cases unselected for clinical response and external in silico validation on publicly available datasets. Thirty-two differentially expressed miRNAs in early vs. late relapsing patients were identified in the training set. In the test set, 8 of these, belonging to a cluster located on chrXq27.3, were down-modulated in early relapsing patients. Hierarchical clustering of the internal validation set according to chrXq27.3 miRNA expression associated low miRNA expression with shorter TTR (log-rank P=0.00074, HR 2.44). The cluster was an independent prognostic factor in both internal and external validation sets. Forced expression of chrXq27.3-cluster selected miRNAs in human EOC cellular models was associated to reduction of cell proliferation and increased sensitivity to cisplatin. The role of down-modulation of the chrXq27.3 miRNA cluster in early relapse of advanced-stage EOC patients and its association to a reduced sensitivity to chemotherapeutic treatments warrant further investigation.

Found in transcription: FOXO1 upregulates miRNAs on chromosome X

“…Since most of those proteins are produced in an inactive form and require activation by additional stimuli, the identified miRNAs might fine-tune the responsiveness of cells to a variety of growth- and survival-promoting signals. The role of the miRNAs as PI3K-sensitive brakes on tumor progression is consistent with the observed correlations between these miRNAs and the clinical features of human cancers 7 . Intriguingly, the miRNAs are also predicted to target FOXO1 and FOXO3, suggesting the existence of a negative feedback in regulation of these proteins.…”

Copy Number Gain of hsa-miR-569 at 3q26.2 Leads to Loss of TP53INP1 and Aggressiveness of Epithelial Cancers

“…Importantly, TP53INP1 mRNA expression was markedly reduced in ovarian cancer samples that have high miR569 levels (Figure 7D). Furthermore, reduced TP53INP1 expression was observed in invasive ovarian cancers compared to low malignant potential tumors (Figure S6A) and miR569 levels were increased in late compared to early stage ovarian cancers (Bagnoli et al, 2011) (Figure S6B). …”

Increased Sensitivity to Chemotherapy Induced by CpG-ODN Treatment Is Mediated by microRNA Modulation

“…The time to relapse (TTR) and overall survival (OS) with respect to each miRNA on two public datasets (GSE25204 and GSE27290) [21]; [22] were analyzed. Patients were stratified according to miRNA expression below (low expression) or above (high expression) the median expression value.…”

“…Two publicly available datasets GSE27290 [20] and GSE25204 [21] reporting miRNA expression and clinical annotated data were downloaded from the Gene Expression Omnibus (GEO) database. The former dataset consists of 62 diagnosed patients with stage III or IV serous ovarian cancer profiled on a pre-commercial version of miRNA chips (GPL7341) designed on miRBase 9.1.…”