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Long non-coding RNA profile in mantle cell lymphoma identifies a functional lncRNA ROR1-AS1 associated with EZH2/PRC2 complex.

ABSTRACT: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by rapid disease progression. The needs for new therapeutic strategies for MCL patients call for further understanding on the molecular mechanisms of pathogenesis of MCL. Recently, long noncoding RNAs (lncRNAs) have been recognized as key regulators of gene expression and disease development, however, the role of lncRNAs in non-Hodgkin lymphoma and specifically in MCL is still unknown. Next generation RNA-sequencing was carried out on MCL patient samples along with normal controls and data was analyzed. As a result, several novel lncRNAs were found significantly overexpressed in the MCL samples with lncRNA ROR1-AS1 the most significant one. We cloned the ROR1-AS1 lncRNA in expression vector and ectopically transfected in MCL cell lines. Results showed that overexpression of ROR1-AS1 lncRNA promoted growth of MCL cells while decreased sensitivity to the treatment with drugs ibrutinib and dexamethasone. ROR-AS1 overexpression also decreased the mRNA expression of P16 (P = 0.21), and SOX11 (p = 0.017), without much effect on P53, ATM and P14 mRNA. RNA-immunoprecipitation assays demonstrated high affinity binding of lncRNA ROR1-AS1 with EZH2 and SUZ12 proteins of the polycomb repressive complex-2 (PRC2). Suppressing EZH2 activity with pharmacological inhibitor GSK343 abolished binding of ROR1-AS1 with EZH2. Taken together, this study identified a functional lncRNA ROR-AS1 involved with regulation of gene transcription via associating with PRC2 complex, and may serve as a novel biomarker in MCL patients.

SUBMITTER: Hu G

PROVIDER: S-EPMC5655192 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Long non-coding RNA profile in mantle cell lymphoma identifies a functional lncRNA ROR1-AS1 associated with EZH2/PRC2 complex.

Hu Guangzhen G Gupta Shiv K SK Troska Tammy P TP Nair Asha A Gupta Mamta M

Oncotarget 20170517 46

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by rapid disease progression. The needs for new therapeutic strategies for MCL patients call for further understanding on the molecular mechanisms of pathogenesis of MCL. Recently, long noncoding RNAs (lncRNAs) have been recognized as key regulators of gene expression and disease development, however, the role of lncRNAs in non-Hodgkin lymphoma and specifically in MCL is still unknown. Next generation RNA-sequencing was ca ...[more]

PMID: 29113297

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Project description:Hepatocellular carcinoma (HCC) is a common disease of the digestive system with no curative treatments. Long noncoding RNA tyrosine protein kinase transmembrane receptor 1 antisense RNA 1 (lncRNA ROR1‑AS1) is an lncRNA whose functions have been predicted in human diseases; however, its important role in cancer has been probed only in mantle cell lymphoma, not in HCC. Therefore, the present study aimed to elucidate the prognostic significance of lncRNA ROR1‑AS1 in HCC. The Cancer Genome Atlas Liver Hepatocellular Carcinoma was used to analyze the expression of ROR1‑AS1 in liver cancer. χ2 tests were performed to evaluate associations between clinical characteristics and ROR1‑AS1 expression. The role of ROR1‑AS1 in HCC prognosis was assessed using Kaplan‑Meier curves and proportional hazards model (Cox) analysis. Gene set enrichment analysis was performed by using a Gene Expression Omnibus dataset. At the same time, Multi Experiment Matrix was used to predict genes that may be co‑expressed with ROR1‑AS1. The Database for Annotation, Visualization and Integrated Discovery and KO‑Based Annotation System were used to analyze the most closely associated cytological behaviors and pathways in HCC. Then, the genes in the three databases were integrated to screen mRNAs, microRNAs and lncRNAs that had co‑expression relationships with ROR1‑AS1. Cytoscape, Search Tool for the Retrieval of Interacting Genes/Proteins and Molecular Evolutionary Genetics Analysis were used to map potential regulatory networks and developmental relationships associated with ROR1‑AS1. Finally, 12 genes most closely associated with ROR1‑AS1 were identified, and their relationship was described using a Circos plot. The results showed that ROR1‑AS1 was upregulated in HCC, and its expression was related to clinical stage, T stage and N stage. Furthermore, Kaplan‑Meier curves and Cox analysis indicated that high expression of ROR1‑AS1 was associated with poor prognosis, and that ROR1‑AS1 was an independent risk factor for HCC. Co‑expression data suggested that there may be a large regulatory network of 45 genes with indirect associations with ROR1‑AS1, a small regulatory network of 15 genes with direct or indirect regulatory relationships, and a special regulatory network containing 12 genes directly associated with ROR1‑AS1. The present findings indicated that high expression of ROR1‑AS1 suggests poor prognosis in patients with HCC.

Project description:Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.

Dataset Information

Long non-coding RNA profile in mantle cell lymphoma identifies a functional lncRNA ROR1-AS1 associated with EZH2/PRC2 complex.

Publications

Long non-coding RNA profile in mantle cell lymphoma identifies a functional lncRNA ROR1-AS1 associated with EZH2/PRC2 complex.

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