Identification and functional annotation of differentially expressed long noncoding RNAs in retinoblastoma

Abstract

Retinoblastoma (RB), the most common intraocular malignancy, typically occurs in pediatric patients under the age of 6 years. The present study aimed to explore the long noncoding RNA (lncRNA) expression profile in RB and identify novel lncRNA biomarkers to facilitate the investigation of molecular mechanisms of RB and improve clinical therapy. Raw microarray data for the comparison of gene expression between three RB and three adjacent normal tissue samples were downloaded from Gene Expression Omnibus (dataset no. GSE111168). After identification of differentially expressed lncRNAs (DELs) and differentially expressed mRNAs (DEMs) in RB, functional enrichment analyses and a DEL-DEM weighted correlation network analysis were performed. A total of 3,915 DELs (1,774 upregulated and 2,141 downregulated) and 3,715 DEMs (1,492 upregulated and 2,223 downregulated) were identified in RB. The DEL-targeted DEMs were highly enriched by genes involved in hexose transport, muscle tissue morphogenesis, the stereocilium membrane, endothelin B receptor binding and γ-filamin/ABP-L, α-actinin and telethonin binding protein of the Z-disc binding. Furthermore, associations of the DELs and DEMs with several pathways were determined, including PI3K/AKT, Hippo and cancer signaling, as well as extracellular matrix-receptor interaction pathways. Coexpression network analysis revealed that the top three DELs, lnc-DAZ1-161, lnc-HDAC7-21 and lnc-OR52A1-55, formed coexpression modules with 181, 156 and 210 DEMs, respectively. In addition, the top three DEMs, namely EIF1AY, GSTM1 and NLRP11, formed coexpression modules with 33, 50 and 41 DELs, respectively. Validation using reverse transcription-quantitative PCR indicated that the expression of representative lncRNAs (lnc-DAZ1-161 and lnc-HDAC7-21) in RB cells in vitro was consistent with that in RB tissues in the database, while the expression of lnc-OR52A1-55 was not consistent with the database. These results suggested that the aberrant lncRNA expression profile in RB is related to the differential regulation of numerous physiological and pathological processes. The lncRNA and mRNA profiles in RB identified may provide novel targets for the investigation of its molecular mechanisms and thus lead to improvements in clinical therapy for RB.

Identifying Treatment Resistance Related Pathways by Analyzing Serum Extracellular Vesicles of Patients With Resistant Versus Regressed Retinoblastoma

“…Previous microarray and bioinformatics analysis on RB tumor specimens revealed that the above enriched terms were associated with RB tumor occurrence, development, and chemo-resistance by regulating cell growth, cell survival, and proliferation. 22 , 29 , 30 Several studies have demonstrated that the neuroactive ligand–receptor interaction pathway is linked to a poor prognosis in various cancers, and breast cancer patients with low expression of cannabinoid receptor 1 (CNR1, part of this pathway) may benefit from chemotherapy. 31 Bioinformatics analysis of gene expression data of RB tumor tissues compared to normal retina revealed that the aberrantly expressed protein coding genes and target genes for DE lncRNAs are enriched for neuroactive ligand–receptor interaction.…”

“… 31 Bioinformatics analysis of gene expression data of RB tumor tissues compared to normal retina revealed that the aberrantly expressed protein coding genes and target genes for DE lncRNAs are enriched for neuroactive ligand–receptor interaction. 29 , 30 Moreover, this is one of the 50 pathways significantly enriched for DEGs between chemoresistance Y79 versus parental Y79 cells. 32 MicroRNAs in cancer were enriched only for DE genes of TR-RB.…”

The Hippo signalling pathway and its impact on eye diseases

“…Therefore, it is necessary to identify new RB-specific biomarkers, elucidate their molecular mechanisms and develop improved RB-targeted therapeutic strategies. 114 RB is caused by the biallelic deletion of the tumour suppressor gene RB transcriptional co-repressor 1 (RB1) in 98% of cases, whereas 2% of cases have normal RB1 levels in tumours initiated by amplification of the MYCN oncogene. 115 An increasing number of studies have shown that the Hippo pathway is important in RB.…”

“…115 An increasing number of studies have shown that the Hippo pathway is important in RB. 114,116 Reduced LATS2 levels can strongly inhibit the induction of cellular senescence by RB protein. 117 TAZ is highly expressed in RB tissues, and TAZ downregulation can inhibit retinoblastoma cell proliferation and block cell cycle progression.…”

“…An increasing number of studies have shown that the Hippo pathway is important in RB 114,116 . Reduced LATS2 levels can strongly inhibit the induction of cellular senescence by RB protein 117 .…”