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Deep RNA sequencing reveals the dynamic regulation of miRNA, lncRNAs, and mRNAs in osteosarcoma tumorigenesis and pulmonary metastasis.

ABSTRACT: Osteosarcoma (OS) is the most common pediatric malignant bone tumor, and occurrence of pulmonary metastasis generally causes a rapid and fatal outcome. Here we aimed to provide clues for exploring the mechanism of tumorigenesis and pulmonary metastasis for OS by comprehensive analysis of microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA expression in primary OS and OS pulmonary metastasis. In this study, deep sequencing with samples from primary OS (n?=?3), pulmonary metastatic OS (n?=?3), and normal controls (n?=?3) was conducted and differentially expressed miRNAs (DEmiRNAs), lncRNAs (DElncRNAs), and mRNAs (DEmRNAs) between primary OS and normal controls as well as pulmonary metastatic and primary OS were identified. A total of 65 DEmiRNAs, 233 DElncRNAs, and 1405 DEmRNAs were obtained between primary OS and normal controls; 48 DEmiRNAs, 50 DElncRNAs, and 307 DEmRNAs were obtained between pulmonary metastatic and primary OS. Then, the target DEmRNAs and DElncRNAs regulated by the same DEmiRNAs were searched and the OS tumorigenesis-related and OS pulmonary metastasis-related competing endogenous RNA (ceRNA) networks were constructed, respectively. Based on these ceRNA networks and Venn diagram analysis, we obtained 3 DEmiRNAs, 15 DElncRNAs, and 100 DEmRNAs, and eight target pairs including miR-223-5p/(CLSTN2, AC009951.1, LINC01705, AC090673.1), miR-378b/(ALX4, IGSF3, SULF1), and miR-323b-3p/TGFBR3 were involved in both tumorigenesis and pulmonary metastasis of OS. The TGF-? superfamily co-receptor TGFBR3, which is regulated by miR-323b-3p, acts as a tumor suppressor in OS tumorigenesis and acts as a tumor promoter in pulmonary metastatic OS via activation of the epithelial-mesenchymal transition (EMT) program.In conclusion, the OS transcriptome (miRNA, lncRNA, and mRNA) is dynamically regulated. These analyses might provide new clues to uncover the molecular mechanisms and signaling networks that contribute to OS progression, toward patient-tailored and novel-targeted treatments.

SUBMITTER: Xie L

PROVIDER: S-EPMC6039476 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Deep RNA sequencing reveals the dynamic regulation of miRNA, lncRNAs, and mRNAs in osteosarcoma tumorigenesis and pulmonary metastasis.

Xie Lin L Yao Zhihong Z Zhang Ya Y Li Dongqi D Hu Fengdi F Liao Yedan Y Zhou Ling L Zhou Yonghong Y Huang Zeyong Z He Zewei Z Han Lei L Yang Yihao Y Yang Zuozhang Z

Cell death & disease 20180710 7

Osteosarcoma (OS) is the most common pediatric malignant bone tumor, and occurrence of pulmonary metastasis generally causes a rapid and fatal outcome. Here we aimed to provide clues for exploring the mechanism of tumorigenesis and pulmonary metastasis for OS by comprehensive analysis of microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA expression in primary OS and OS pulmonary metastasis. In this study, deep sequencing with samples from primary OS (n = 3), pulmonary metastatic OS (n = 3) ...[more]

PMID: 29991755

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Project description:BackgroundThe effective transmission mode of Neospora caninum, with infection leading to reproductive failure in ruminants, is vertical transmission. The uterus is an important reproductive organ that forms the maternal-fetal interface. Neospora caninum can successfully invade and proliferate in the uterus, but the molecular mechanisms underlying epithelial-pathogen interactions remain unclear. Accumulating evidence suggests that host long noncoding RNAs (lncRNAs) play important roles in cellular molecular regulatory networks, with reports that these RNA molecules are closely related to the pathogenesis of apicomplexan parasites. However, the expression profiles of host lncRNAs during N. caninum infection has not been reported.MethodsRNA sequencing (RNA-seq) analysis was used to investigate the expression profiles of messenger RNAs (mRNAs) and lncRNAs in caprine endometrial epithelial cells (EECs) infected with N. caninum for 24 h (TZ_24h) and 48 h (TZ_48 h), and the potential functions of differentially expressed (DE) lncRNAs were predicted by using Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of their mRNA targets.ResultsRNA-seq analysis identified 1280.15 M clean reads in 12 RNA samples, including six samples infected with N. caninum for 24 h (TZ1_24h-TZ3_24h) and 48 h (TZ1_48h-TZ3_48h), and six corresponding control samples (C1_24h-C3_24h and C1_48h-C3_48h). Within the categories TZ_24h-vs-C_24h, TZ_48h-vs-C_48h and TZ_48h-vs-TZ_24h, there were 934 (665 upregulated and 269 downregulated), 1238 (785 upregulated and 453 downregulated) and 489 (252 upregulated and 237 downregulated) DEmRNAs, respectively. GO enrichment and KEGG analysis revealed that these DEmRNAs were mainly involved in the regulation of host immune response (e.g. TNF signaling pathway, MAPK signaling pathway, transforming growth factor beta signaling pathway, AMPK signaling pathway, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway), signaling molecules and interaction (e.g. cytokine-cytokine receptor interaction, cell adhesion molecules and ECM-receptor interaction). A total of 88 (59 upregulated and 29 downregulated), 129 (80 upregulated and 49 downregulated) and 32 (20 upregulated and 12 downregulated) DElncRNAs were found within the categories TZ_24h-vs-C_24h, TZ_48h-vs-C_48h and TZ_48h-vs-TZ_24h, respectively. Functional prediction indicated that these DElncRNAs would be involved in signal transduction (e.g. MAPK signaling pathway, PPAR signaling pathway, ErbB signaling pathway, calcium signaling pathway), neural transmission (e.g. GABAergic synapse, serotonergic synapse, cholinergic synapse), metabolism processes (e.g. glycosphingolipid biosynthesis-lacto and neolacto series, glycosaminoglycan biosynthesis-heparan sulfate/heparin) and signaling molecules and interaction (e.g. cytokine-cytokine receptor interaction, cell adhesion molecules and ECM-receptor interaction).ConclusionsThis is the first investigation of global gene expression profiles of lncRNAs during N. caninum infection. The results provide valuable information for further studies of the roles of lncRNAs during N. caninum infection.

Project description:Osteosarcoma (OS) is the most frequently occurring primary bone malignancy with a rapid progression and poor survival. In the present study, in order to examine the molecular mechanisms of OS, we analyzed the microarray of GSE28425. GSE28425 was downloaded from Gene Expression Omnibus, which also included the miRNA expression profile, GSE28423, and the mRNA expression profile, GSE28424. Each of the expression profiles included 19 OS cell lines and 4 normal bones. The differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) were screened using the limma package in Bioconductor. The DEGs associated with tumors were screened and annotated. Subsequently, the potential functions of the DEGs were analyzed by Gene Ontology (GO) and pathway enrichment analyses. Furthermore, the protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software. Furthermore, modules of the PPI network were screened using the ClusterOne plugin in Cytoscape. Additionally, the transcription factor (TF)-DEG regulatory network, DE-miRNA-DEG regulatory network and miRNA-function collaborative network were separately constructed to obtain key DEGs and DE-miRNAs. In total, 1,609 DEGs and 149 DE-miRNAs were screened. Upregulated FOS-like antigen 1 (FOSL1) also had the function of an oncogene. MAD2 mitotic arrest deficient-like 1 (MAD2L1; degree, 65) and aurora kinase A (AURKA; degree, 64) had higher degrees in the PPI network of the DEGs. In the TF-DEG regulatory network, the TF, signal transducer and activator of transcription 3 (STAT3) targeted the most DEGs. Moreover, in the DE-miRNA-DEG regulatory network, downregulated miR‑1 targeted many DEGs and estrogen receptor 1 (ESR1) was targeted by several highly expressed miRNAs. Moreover, in the miRNA-function collaborative networks of upregulated miRNAs, miR‑128 targeted myeloid dendritic associated functions. On the whole, our data indicate that MAD2L1, AURKA, STAT3, ESR1, FOSL1, miR‑1 and miR‑128 may play a role in the development and/or progressio of OS.

Dataset Information

Deep RNA sequencing reveals the dynamic regulation of miRNA, lncRNAs, and mRNAs in osteosarcoma tumorigenesis and pulmonary metastasis.

Publications

Deep RNA sequencing reveals the dynamic regulation of miRNA, lncRNAs, and mRNAs in osteosarcoma tumorigenesis and pulmonary metastasis.

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