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Downregulated plasma miR-92a levels have clinical impact on multiple myeloma and related disorders.

ABSTRACT: Recent studies have demonstrated that one-third of known microRNAs (miRNAs) are stably detectable in plasma. Therefore, we assessed plasma miRNAs to investigate the dynamics of oncomir 17-92a, which is highly expressed in multiple myeloma (MM) patients. The plasma miR-92a level in symptomatic MM patients was significantly downregulated compared with normal subjects (P<0.0001), regardless of immunoglobulin subtypes or disease stage at diagnosis. In contrast, miR-92a levels in peripheral blood CD8(+) or CD4(+) cells from MM patients were lower than those of normal subjects, and the miR-92a levels of the cells tended to correlate with plasma miR-92a levels. The plasma miR-92a level in the complete remission group became normalized, whereas the partial response (PR) and very good PR groups did not reach the normal range. In smoldering MM, the plasma miR-92a level did not show a significant difference compared with normal subjects. Our findings suggest that measurement of the plasma miR-92a level in MM patients could be useful for initiation of chemotherapy and monitoring disease status, and the level may represent, in part, the T-cell immunity status of these patients.

SUBMITTER: Yoshizawa S

PROVIDER: S-EPMC3270255 | biostudies-other | 2012 Jan

REPOSITORIES: biostudies-other

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Downregulated plasma miR-92a levels have clinical impact on multiple myeloma and related disorders.

Yoshizawa S S Ohyashiki J H JH Ohyashiki M M Umezu T T Suzuki K K Inagaki A A Iida S S Ohyashiki K K

Blood cancer journal 20120120 1

Recent studies have demonstrated that one-third of known microRNAs (miRNAs) are stably detectable in plasma. Therefore, we assessed plasma miRNAs to investigate the dynamics of oncomir 17-92a, which is highly expressed in multiple myeloma (MM) patients. The plasma miR-92a level in symptomatic MM patients was significantly downregulated compared with normal subjects (P<0.0001), regardless of immunoglobulin subtypes or disease stage at diagnosis. In contrast, miR-92a levels in peripheral blood CD8 ...[more]

PMID: 22829237

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Project description:BACKGROUND: Plasma microRNA (miRNA) has become a promising biomarker for detecting cancer; however, it remains uncertain whether miRNA expression levels in plasma reflect those in tumor cells. Our aim was to determine the biological relevance of miR-92a, which has been implicated as an oncomiR in both plasma and leukemia cells in patients with acute leukemia and to evaluate whether it could be a novel biomarker for monitoring these patients. RESULTS: We quantified the expression level of miR-92a in both cells and plasma by reverse transcription polymerase chain reaction in 91 patients with acute leukemia. We also determined miR-92a expression levels in peripheral blood mononuclear cells (PBMNC) from normal controls. We compared miR-92a expression in plasma with its expression in leukemia cells. Synthetic anti-miR-92a inhibitor was transfected into Raji and OM9;22 cells, and apoptosis was assessed. For in vivo assessment, 6-week-old female nude mice were injected with U937 cells, and miR-92a expression in plasma and tumors was measured. The level of miR-92a expression in fresh leukemia cells was highly variable compared with PBMNC, but significantly lower compared with CD34-positive cells obtained from healthy volunteers. We also noticed that miR-92a was preferentially expressed in acute lymphoblastic leukemia (ALL) cells in comparison with acute myeloid leukemia (AML) cells. More specifically, cellular miR-92a expression was significantly increased in a subset of ALL cells, and ALL patients with overexpressed miR-92a had poor prognoses. The anti-miR-92a inhibitor-treated Raji and OM9;22 cells revealed an increase of apoptotic cells. Notably, the cell to plasma ratio of miR-92a expression was significantly higher in both AML and ALL cells compared with PBMNC from healthy volunteers. In tumor-bearing mice, the plasma miR-92a level was significantly decreased in accordance with tumor growth, while tumor tissue was strongly positive for miR-92a. CONCLUSIONS: The miR-92a expression in leukemia cells could be a prognostic factor in ALL patients. The inverse correlation of miR-92a expression between cells and plasma and the cell to plasma ratio may be important to understanding the clinical and biological relevance of miR-92a in acute leukemia.

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.

Project description:It was recently discovered that brain cells release extracellular vesicles (EV) which can pass from brain into blood. These findings raise the possibility that brain-derived EV's present in blood can be used to monitor disease processes occurring in the cerebrum. Since the levels of certain micro-RNAs (miRNAs) have been reported to be altered in Alzheimer's disease (AD) brain, we sought to assess miRNA dysregulation in AD brain tissue and to determine if these changes were reflected in neural EVs isolated from blood of subjects with AD. To this end, we employed high-content miRNA arrays to search for differences in miRNAs in RNA pools from brain tissue of AD (n = 5), high pathological control (HPC) (n = 5), or cognitively intact pathology-free controls (n = 5). Twelve miRNAs were altered by >1.5-fold in AD compared to controls, and six of these were also changed compared to HPCs. Analysis of hits in brain extracts from 11 AD, 7 HPCs and 9 controls revealed a similar fold difference in these six miRNAs, with three showing statistically significant group differences and one with a strong trend toward group differences. Thereafter, we focused on the four miRNAs that showed group differences and measured their content in neurally derived blood EVs isolated from 63 subjects: 16 patients with early stage dementia and a CSF Aβ42+ tau profile consistent with AD, 16 individuals with mild cognitive impairment (MCI) and an AD CSF profile, and 31 cognitively intact controls with normal CSF Aβ42+ tau levels. ROC analysis indicated that measurement of miR-132-3p in neurally-derived plasma EVs showed good sensitivity and specificity to diagnose AD, but did not effectively separate individuals with AD-MCI from controls. Moreover, when we measured the levels of a related miRNA, miR-212, we found that this miRNA was also decreased in neural EVs from AD patients compared to controls. Our results suggest that measurement of miR-132 and miR-212 in neural EVs should be further investigated as a diagnostic aid for AD and as a potential theragnostic.

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Downregulated plasma miR-92a levels have clinical impact on multiple myeloma and related disorders.

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Downregulated plasma miR-92a levels have clinical impact on multiple myeloma and related disorders.

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