Dataset Information

Epigenetic silencing of long non-coding RNA BM742401 in multiple myeloma: impact on prognosis and myeloma dissemination.

ABSTRACT: Background:Long non-coding RNA (lncRNA) BM742401 is a tumor suppressor in gastric cancer and chronic lymphocytic leukemia. As the promoter and coding region of BM742401 are fully embedded in a CpG island, we hypothesized that BM742401 is a tumor suppressor lncRNA epigenetically silenced by promoter DNA methylation in multiple myeloma. Methods:Methylation-specific PCR and quantitative bisulfite pyrosequencing were performed to detect the methylation of BM742401 in normal plasma cells, myeloma cell lines and primary myeloma samples. The expression of BM742401 was measured by qRT-PCR. The function of BM742401 in multiple myeloma cells was analyzed by lentivirus transduction followed by migration assay. Results:BM742401 methylation was detected in 10 (66.7%) myeloma cell lines but not normal plasma cells, and inversely correlated with expression of BM742401. In primary samples, BM742401 methylation was detected in 3 (12.5%) monoclonal gammopathy of undetermined significance, 9 (15.8%) myeloma at diagnosis and 8 (17.0%) myeloma at relapse/progression. Moreover, BM742401 methylation at diagnosis was associated with inferior overall survival (median OS: 25 vs. 39 months; P?=?0.0496). In myeloma cell line JJN-3, stable overexpression of BM742401 by lentivirus transduction resulted in reduced cell migration (P?=?0.0001) but not impacting cell death or proliferation. Conclusions:This is the first report of tumor-specific methylation-mediated silencing of BM742401 in myeloma, which is likely an early event in myelomagenesis with adverse impact on overall survival. Moreover, BM742401 is a tumor suppressor lncRNA by inhibiting myeloma cell migration, hence implicated in myeloma plasma cell homing, metastasis and disease progression.

SUBMITTER: Li Z

PROVIDER: S-EPMC7446116 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Epigenetic silencing of long non-coding RNA <i>BM742401</i> in multiple myeloma: impact on prognosis and myeloma dissemination.

Li Zhenhai Z Kumar Shaji S Jin Dong-Yan DY Calin George A GA Chng Wee-Joo WJ Siu Kam-Leung KL Poon Ming-Wai MW Chim Chor Sang CS

Cancer cell international 20200825

<h4>Background</h4>Long non-coding RNA (lncRNA) <i>BM742401</i> is a tumor suppressor in gastric cancer and chronic lymphocytic leukemia. As the promoter and coding region of <i>BM742401</i> are fully embedded in a CpG island, we hypothesized that <i>BM742401</i> is a tumor suppressor lncRNA epigenetically silenced by promoter DNA methylation in multiple myeloma.<h4>Methods</h4>Methylation-specific PCR and quantitative bisulfite pyrosequencing were performed to detect the methylation of <i>BM742 ...[more]

PMID: 32855620

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Project description:BackgroundmiR-340-5p, localized to 5q35, is a tumor suppressor miRNA implicated in multiple cancers. As a CpG island is present at the putative promoter region of its host gene, RNF130, we hypothesized that the intronic miR-340-5p is a tumor suppressor miRNA epigenetically silenced by promoter DNA methylation of its host gene in multiple myeloma.ResultsBy pyrosequencing-confirmed methylation-specific PCR, RNF130/miR-340 was methylated in 8/15 (53.3%) myeloma cell lines but not normal plasma cells. Methylation correlated inversely with the expression of both miR-340-5p and RNF130. In completely methylated WL-2 and RPMI-8226R cells, 5-AzadC treatment led to demethylation and re-expression of miR-340-5p. In primary samples, RNF130/miR-340 methylation was detected in 4 (22.2%) monoclonal gammopathy of undetermined significance, 15 (23.8%) diagnostic myeloma, and 7 (23.3%) relapsed myeloma. RNF130/miR-340 methylation at diagnosis was associated with inferior overall survival (median 27 vs. 68 months; P = 3.944E-5). In WL-2 cells, overexpression of miR-340-5p resulted in reduced cellular proliferation [MTS, P = 0.002; verified in KMS-12-PE (P = 0.002) and RPMI-8226R (P = 2.623E-05) cells], increased cell death (trypan blue, P = 0.005), and enhanced apoptosis by annexin V-PI staining. Moreover, by qRT-PCR, overexpression of miR-340-5p led to repression of both known targets (CCND1 and NRAS) and bioinformatically predicted targets in MAPK signaling (MEKK1, MEKK2, and MEKKK3) and apoptosis (MDM4 and XIAP), hence downregulation of phospho-ERK1/2 and XIAP by Western blot. Furthermore, by qRT-PCR, in CD138-sorted primary samples (n = 37), miR-340-5p and XIAP were inversely correlated (P = 0.002). By luciferase assay, XIAP was confirmed as a direct target of miR-340-5p via targeting of the distal but not proximal seed region binding site.ConclusionsCollectively, tumor-specific methylation-mediated silencing of miR-340-5p is likely an early event in myelomagenesis with adverse survival impact, via targeting multiple oncogenes in MAPK signaling and apoptosis, thereby a tumor suppressive miRNA in myeloma.

Dataset Information

Epigenetic silencing of long non-coding RNA BM742401 in multiple myeloma: impact on prognosis and myeloma dissemination.

Publications

Epigenetic silencing of long non-coding RNA <i>BM742401</i> in multiple myeloma: impact on prognosis and myeloma dissemination.

Similar Datasets

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