A 4-miRNA signature to predict survival in glioblastomas

Abstract

Glioblastomas are among the most lethal cancers; however, recent advances in survival have increased the need for better prognostic markers. microRNAs (miRNAs) hold great prognostic potential being deregulated in glioblastomas and highly stable in stored tissue specimens. Moreover, miRNAs control multiple genes representing an additional level of gene regulation possibly more prognostically powerful than a single gene. The aim of the study was to identify a novel miRNA signature with the ability to separate patients into prognostic subgroups. Samples from 40 glioblastoma patients were included retrospectively; patients were comparable on all clinical aspects except overall survival enabling patients to be categorized as short-term or long-term survivors based on median survival. A miRNome screening was employed, and a prognostic profile was developed using leave-one-out cross-validation. We found that expression patterns of miRNAs; particularly the four miRNAs: hsa-miR-107_st, hsa-miR-548x_st, hsa-miR-3125_st and hsa-miR-331-3p_st could determine short- and long-term survival with a predicted accuracy of 78%. Heatmap dendrograms dichotomized glioblastomas into prognostic subgroups with a significant association to survival in univariate (HR 8.50; 95% CI 3.06–23.62; p<0.001) and multivariate analysis (HR 9.84; 95% CI 2.93–33.06; p<0.001). Similar tendency was seen in The Cancer Genome Atlas (TCGA) using a 2-miRNA signature of miR-107 and miR-331 (miR sum score), which were the only miRNAs available in TCGA. In TCGA, patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors and low miR sum score had the shortest survival. Adjusting for age and MGMT status, low miR sum score was associated with a poorer prognosis (HR 0.66; 95% CI 0.45–0.97; p = 0.033). A Kyoto Encyclopedia of Genes and Genomes analysis predicted the identified miRNAs to regulate genes involved in cell cycle regulation and survival. In conclusion, the biology of miRNAs is complex, but the identified 4-miRNA expression pattern could comprise promising biomarkers in glioblastoma stratifying patients into short- and long-term survivors.

miR-548x and miR-4698 controlled cell proliferation by affecting the PI3K/AKT signaling pathway in Glioblastoma cell lines

“…www.nature.com/scientificreports www.nature.com/scientificreports/ In the present study, we searched for microRNAs that could inhibit the PI3K pathway in glioblastoma cell lines. Although previous studies in TCGA have not reported any expression changes for miR-548x and miR-4698 in glioblastoma 11 , our bioinformatics studies (GSE93850) reveal that the expression of miR-4698 was downregulated (P < 0.05) in the serum of GBM patient compared to the healthy group. Also, another investigation showed (GSE32466, GSE103229, GSE112462) expression of miR-548o-b-a-g-k-d-e downregulated in GBM, but miR-548x and miR-4698 did not show any significant change compared to control.…”

“…They found four miRNAs: miR-548x, miR-331-3p, miR-3125, and miR-107 were capable predicted short-and long-term survival up 78%, and all of these miRNAs were downregulated in GBM. Their investigation showed that low expression of these microRNAs were significantly correlated with short term survival 11 . He et al; in 2017 used next-generation sequencing (NGS) and qRT-PCR to analyze the miRNA expression profile of adenocarcinomas tumor compared adjacent non-tumor tissue.…”

MicroRNA-mRNA Interactions at Low Levels of Compressive Solid Stress Implicate mir-548 in Increased Glioblastoma Cell Motility

“…The high cumulative absolute FC of the mir-548 family suggests that regulation likely occurs via large changes in a small number of target mRNA. Compared to normal brain tissue, the miR548 family is typically downregulated in GBM, suggesting a protective, prognostic role in the healthy brain 32 . Expression also correlates with survival, with mir548d-3p/-5p upregulated in long-term survival patients 33 .…”

“…5F). Downregulation of the miR181 family is associated with glioma progression 31 , whereas the miR548 family is associated with prognosis and survival 32,33 . These results suggest that both families are potential therapeutic targets.…”

Genome‐wide identification of a novel miRNA‐based signature to predict recurrence in patients with gastric cancer

“…In agreement with our findings, similar studies have already been carried out for the identification of prognostic miRNA signatures from the TCGA in other types of cancers, including bladder cancer, glioblastoma, colon cancer, etc. (Gonzalez-Vallinas et al, 2018;Hermansen et al, 2017;Liu et al, 2017a;Wong et al, 2016;Xu et al, 2016;Zhou et al, 2015).…”