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Whole transcriptome analysis reveals correlation of long noncoding RNA ZEB1-AS1 with invasive profile in melanoma.

ABSTRACT: Melanoma is the deadliest form of skin cancer, and little is known about the impact of deregulated expression of long noncoding RNAs (lncRNAs) in the progression of this cancer. In this study, we explored RNA-Seq data to search for lncRNAs associated with melanoma progression. We found distinct lncRNA gene expression patterns across melanocytes, primary and metastatic melanoma cells. Also, we observed upregulation of the lncRNA ZEB1-AS1 (ZEB1 antisense RNA 1) in melanoma cell lines. Data analysis from The Cancer Genome Atlas (TCGA) confirmed higher ZEB1-AS1 expression in metastatic melanoma and its association with hotspot mutations in BRAF (B-Raf proto-oncogene, serine/threonine kinase) gene and RAS family genes. In addition, a positive correlation between ZEB1-AS1 and ZEB1 (zinc finger E-box binding homeobox 1) gene expression was verified in primary and metastatic melanomas. Using gene expression signatures indicative of invasive or proliferative phenotypes, we found an association between ZEB1-AS1 upregulation and a transcriptional profile for invasiveness. Enrichment analysis of correlated genes demonstrated cancer genes and pathways associated with ZEB1-AS1. We suggest that the lncRNA ZEB1-AS1 could function by activating ZEB1 gene expression, thereby influencing invasiveness and phenotype switching in melanoma, an epithelial-to-mesenchymal transition (EMT)-like process, which the ZEB1 gene has an essential role.

SUBMITTER: Siena ADD

PROVIDER: S-EPMC6683136 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Whole transcriptome analysis reveals correlation of long noncoding RNA ZEB1-AS1 with invasive profile in melanoma.

Siena Ádamo Davi Diógenes ÁDD Plaça Jéssica Rodrigues JR Araújo Luiza Ferreira LF de Barros Isabela Ichihara II Peronni Kamila K Molfetta Greice G de Biagi Carlos Alberto Oliveira CAO Espreafico Enilza Maria EM Sousa Josane Freitas JF Silva Wilson Araújo WA

Scientific reports 20190805 1

Melanoma is the deadliest form of skin cancer, and little is known about the impact of deregulated expression of long noncoding RNAs (lncRNAs) in the progression of this cancer. In this study, we explored RNA-Seq data to search for lncRNAs associated with melanoma progression. We found distinct lncRNA gene expression patterns across melanocytes, primary and metastatic melanoma cells. Also, we observed upregulation of the lncRNA ZEB1-AS1 (ZEB1 antisense RNA 1) in melanoma cell lines. Data analysi ...[more]

PMID: 31383874

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Project description:OBJECTIVES:The long-noncoding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes in glioblastoma (GBM) tissues. However, the expression pattern and biological function of lncRNAs remain largely unknown. Here, for the first time, the effects of lncRNA lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) on GBM progression both in vitro and in vivo are investigated. MATERIALS AND METHODS:Expression profiles of LEF1-AS1 in GBM specimens were investigated by bioinformatics analyses. LEF1-AS1 expression in GBM tissues was detected using a quantitative polymerase chain reaction. LEF1-AS1 expression was inhibited by transfecting the LEF1-AS1-specific small interfering RNAs (siRNAs) and stable cell lines established were inhibited by transfecting si-LEF1-AS1 viruses. The Cell Counting Kit-8, ethynyl deoxyuridine, and colony formation assay were used to examine proliferation function. The flow cytometry detected cell-cycle change and apoptosis. Migration effects were detected by a Transwell assay. The tumor xenografts and immunohistochemistry were performed to evaluate tumor growth in vivo. RESULTS:In this study, LEF1-AS1 expression was found significantly upregulated in GBM specimens compared with normal tissues. The 5-year overall survival in GBM patients from The Cancer Genome Atlas with high expression of LEF1-AS1 was inferior to that with low expression. It was confirmed that expression of LEF1-AS1 was higher in GBM tissues than normal ones. Knockdown of LEF1-AS1 significantly inhibited the malignancy of GBM cells, including proliferation and invasion, and promoted cell apoptosis. The result of Western blot assays indicated that knockdown of LEF1-AS1-mediated tumor suppression in GBM cells may be via the reduction of ERK and Akt/mTOR signaling activities. Finally, the in vivo experiment also demonstrated that knockdown LEF1-AS1 inhibited the growth-promoting effect of LEF1-AS1 of U87 cells. CONCLUSION:Our result indicated that lncRNA LEF1-AS1 acts as an oncogene in GBM and may be a pivotal target for this disease.

Project description:The incidence of malignant melanoma continues to increase each year with poor prognosis for survival in many relapse cases. To reverse this trend, whole body response measures are needed to discover collaborative paths to primary and secondary malignancy. Several species of fish provide excellent melanoma models because fish and human melanocytes both appear in the epidermis, and fish and human pigment cell tumors share conserved gene expression signatures. For the first time, we have examined the whole body transcriptome response to invasive melanoma as a prelude to using transcriptome profiling to screen for drugs in a medaka (Oryzias latipes) model. We generated RNA-seq data from whole body RNA isolates for controls and melanoma fish. After testing for differential expression, 396 genes had significantly different expression (adjusted p-value <0.02) in the whole body transcriptome between melanoma and control fish; 379 of these genes were matched to human orthologs with 233 having annotated human gene symbols and 14 matched genes that contain putative deleterious variants in human melanoma at varying levels of recurrence. A detailed canonical pathway evaluation for significant enrichment showed the top scoring pathway to be antigen presentation but also included the expected melanocyte development and pigmentation signaling pathway. Results revealed a profound down-regulation of genes involved in the immune response, especially the innate immune system. We hypothesize that the developing melanoma actively suppresses the immune system responses of the body in reacting to the invasive malignancy, and that this mal-adaptive response contributes to disease progression, a result that suggests our whole-body transcriptomic approach merits further use. In these findings, we also observed novel genes not yet identified in human melanoma expression studies and uncovered known and new candidate drug targets for further testing in this malignant melanoma medaka model.

Dataset Information

Whole transcriptome analysis reveals correlation of long noncoding RNA ZEB1-AS1 with invasive profile in melanoma.

Publications

Whole transcriptome analysis reveals correlation of long noncoding RNA ZEB1-AS1 with invasive profile in melanoma.

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