MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma

Du, Juan; Liu, Shuyan; He, Jié; Liu, Xi; Qu, Ying; Yan, Wenqing; Fan, Jianling; Li, Rong; Xi, Hao; Fu, Weijun; Zhang, Chunyang; Yang, Jing; Hou, Jian

doi:10.18632/oncotarget.3802

Cited by 87 publications

(86 citation statements)

References 33 publications

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“…These results suggest that miR451a plays an important regulatory role in pathogenesis and drug-resistance in the progression of CML. Other studies demonstrated that the down-regulated expression of miR-451a was closely related to the pathogenesis of various hematological malignancies involved in multiple myeloma [33,34], acute myeloid leukemia [35,36], acute lymphoblastic leukemia [37,38], myelodysplastic syndrome [39] and polycythemia vera [40]. In addition, miR-451a was required for erythroid homeostasis [41].…”

Section: Oncotarget S474 Wwwimpactjournalscom/oncotargetmentioning

confidence: 99%

WITHDRAWN: Expression profiles and biological implications of plasma miRNAs associated with chronic myeloid leukemia phases

Zhang¹,

Jiang²,

Han³

et al. 2018

Oncotarget

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ABSTRACTmicroRNAs play important regulatory roles in hematologic malignancies, and dysregulation of circulating miRNAs serves as diagnostic, prognostic and predictive biomarkers in many diseases. The correlation of plasma miRNA profiles with the progression of chronic myeloid leukemia (CML) has not been investigated. We have applied microarrays to identify differentially expressed miRNAs, followed by qRT-PCR to validate candidate miRNAs from four sample pools including chronic phase (CP), accelerated phase(AP), blast crisis(BC) and healthy control. Clustering analyses revealed varying phase-specific patterns of plasma miRNA expression during CML progression. Different phases of CML showed differential expression profiles between sample pools during the progression. The functional annotation tool, DAVID, found that putative targets of dysregulated miRNAs in different phases of diease are involved in several important signaling pathways. Gradually decreased expression levels of miR-451a were validated in CML patients from the CP to AP and BC; when CML patients achieved major molecular response (MMR), miR-451a expression was increased and restored to normal range. These data provide an important resource for studies on CML progression and allow a better understanding of the fundamental differences in plasma miRNA expression profiles among the different phases of CML.

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Section: Oncotarget S474 Wwwimpactjournalscom/oncotargetmentioning

confidence: 99%

WITHDRAWN: Expression profiles and biological implications of plasma miRNAs associated with chronic myeloid leukemia phases

Zhang¹,

Jiang²,

Han³

et al. 2018

Oncotarget

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“…As a novel anti-myeloma agent, suppressor of miR-451 increased the effectiveness of myeloma treatment by reducing MDR1 mRNA expression, decreasing clonogenicity, and inducing apoptosis [19]. In this study, we found that the apoptotic proportion of CSCs was evidently decreased in cells transfected with miR-19b.…”

Section: Discussionmentioning

confidence: 52%

“…Differential expression of TSC1 is also involved in the onset of MM and is associated with significant upregulation of miR-19b [18][19][20]. In this study, we performed in silico analysis and found miR-19b practically targeted TSC1.…”

Section: Introductionmentioning

confidence: 85%

Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells by Regulating the TSC1/mTOR Signaling Pathway in Multiple Myeloma

Wang¹,

Liang²,

Yu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: MiR-19b has been reported to be involved in several malignancies, but its role in multiple myeloma (MM) is still unknown. The objective of this study was to explore the biological mechanism of miR-19b in the progression of MM. Methods: First, we performed real-time polymerase chain reaction (PCR) and Western blot to study the expression of miR-19b, tuberous sclerosis 1 (TSC1), and caspase-3 in different groups. MTT assay was performed to explore the effect of miR-19b on survival and apoptosis of cancer stem cells (CSCs). Computation analysis and luciferase assay were utilized to confirm the interaction between miR-19b and TSC1. Results: A total of 38 participants comprising 20 subjects with MM and 18 healthy subjects as normal controls were enrolled in our study. Real-time PCR showed dramatic upregulation of miR-19b, but TSC1 was evidently suppressed in the MM group. MiR-19b overexpression substantially promoted clonogenicity and cell viability, and further inhibited apoptosis of CSCs in vitro. Furthermore, miR-19b overexpression downregulated the expression of caspase-3, which induced apoptosis. Using in silico analysis, we identified that TSC1 might be a direct downstream target of miR-19b, and this was further confirmed by luciferase assay showing that miR-19b apparently reduced the luciferase activity of wild-type TSC1 3´-UTR, but not that of mutant TSC1 3´-UTR. There was also evident decrease in TSC1 mRNA and protein in CSCs following introduction of miR-19b. Interestingly, reintroduction of TSC1 abolished the miR-19b-induced proliferation promotion and apoptosis inhibition in CSCs. Conclusion: These findings collectively suggest that miR-19b promotes cell survival and suppresses apoptosis of MM CSCs via targeting TSC1 directly, indicating that miR-19b may serve as a potential and novel therapeutic target of MM based on miRNA expression.

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“…PI3K/Akt/mTOR pathway is activated and play a critical role in MMSCs. Du et al [90] found that PI3K/Akt/mTOR signal transduction proteins CAB39, TSC1, P - S6 and P - P70S6K expression levels were significantly higher in SP cells of MM than that in MP cells of MM. Moreover, the mTOR specific inhibitor rapamycin can dramatically decrease the proportion of SP cells of MM.…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Multiple myeloma cancer stem cells

et al. 2016

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Multiple myeloma (MM) remains incurable despite much progress that has been made in the treatment of the disease. MM cancer stem cell (MMSC), a rare subpopulation of MM cells with the capacity for self-renewal and drug resistance, is considered to lead to disease relapse. Several markers such as side population (SP) and ALDH1+ have been used to identify MMSCs. However, ideally and more precisely, the identification of the MMSCs should rely on MMSCs phenotype. Unfortunately the MMSC phenotype has not been properly defined yet. Drug resistance is the most important property of MMSCs and contributes to disease relapse, but the mechanisms of drug resistance have not been fully understood. The major signaling pathways involved in the regulation of self-renewal and differentiation of MMSCs include Hedgehog (Hh), Wingless (Wnt), Notch and PI3K/Akt/mTOR. However, the precise role of these signaling pathways needs to be clarified. It has been reported that the microRNA profile of MMSCs is remarkably different than that of non-MMSCs. Therefore, the search for targeting MMSCs has also been focused on microRNAs. Complex and mutual interactions between the MMSC and the surrounding bone marrow (BM) microenvironment sustain self-renewal and survival of MMSC. However, the required molecules for the interaction of the MMSC and the surrounding BM microenvironment need to be further identified. In this review, we summarize the current state of knowledge of MMSCs regarding their phenotype, mechanisms of drug resistance, signaling pathways that regulate MMSCs self-renewal and differentiation, abnormal microRNAs expression, and their interactions with the BM microenvironment.

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MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma

Cited by 87 publications

References 33 publications

WITHDRAWN: Expression profiles and biological implications of plasma miRNAs associated with chronic myeloid leukemia phases

WITHDRAWN: Expression profiles and biological implications of plasma miRNAs associated with chronic myeloid leukemia phases

Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells by Regulating the TSC1/mTOR Signaling Pathway in Multiple Myeloma

Multiple myeloma cancer stem cells

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