Downregulation of microRNA‑25‑3p inhibits the proliferation and promotes the apoptosis of multiple myeloma cells via targeting the PTEN/PI3K/AKT signaling pathway

Zi, Youmei; Zhang, Yingzi; Wu, Yanwei; Zhang, Lina; Yang, Ru; Huang, Yan

doi:10.3892/ijmm.2020.4841

Cited by 17 publications

(13 citation statements)

References 37 publications

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“…Knockdown of miR-551b caused increased TTP, led to less Cyclin D1 and E2F1 level, resulting decreased myeloma proliferation and enhanced Dex sensitivity. MiR-25 has been characterized with onco-miR functions with multiple validated target genes [32][33][34][35][36]. We demonstrated miR-25 mediates Dex resistance in myeloma via targeting ULK1 and p27.…”

Section: Discussionmentioning

confidence: 90%

“…MiR-25 has been characterized with onco-miR functions with multiple validated targets including Unc-51 Like Autophagy Activating Kinase 1 (ULK1) and Cyclin-dependent kinase inhibitor 1B CDKN1B(p27) [32][33][34][35][36]. Knockdown of miR-25 signi cantly increased ULK1 levels.…”

Section: Sumoylation Inhibition Enhances Dex Sensitivity In MM Through Regulating Mir-551b and Mir-25mentioning

confidence: 99%

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SUMOylation Inhibition Enhances Dexamethasone Sensitivity in Multiple Myeloma

Liu

Aldana-Masangkay

et al. 2021

Preprint

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BackgroundMultiple myeloma (MM) is an incurable plasma cell malignancy. Although Dexamethasone (Dex) is the most widely used therapeutic drug in MM treatment, patients develop Dex resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms driving Dex resistance and develop new reagents to address this problem. We propose SUMOylation as a potential mechanism regulating Dex resistance and SUMOylation inhibition can enhance Dex sensitivity in MM.MethodsUsing MM cell lines and primary MM samples from relapsing MM patients, we evaluated the effects of knockdown of SUMO E1 (SAE2) or using TAK-981, a novel and specific SUMO E1 inhibitor, on Dex sensitivity. Xenograft mouse models were generated to determine the in vivo anti-MM effects of TAK-981 as a single agent and in combination with Dex. miRNA-seq, RNA-seq and GSEA analysis were utilized for evaluating key factors mediating Dex resistance. Chromatin immunoprecipitation (ChIP) assay was performed to determine the binding occupancy of c-Myc on promoter region of miRs. ResultsWe observed a significant negative correlation between SUMO E1 (SAE2) expression and Dex sensitivity in primary MM samples. Knockdown of SAE2 or using TAK-981 significantly enhances myeloma sensitivity to Dex in MM cell lines. Moreover, the enhanced anti-MM activity by TAK-981 and Dex combination has been validated using primary relapsing MM patient samples and xenograft mouse models. SUMOylation inhibition increased glucocorticoid receptor (GR) expression via downregulation miR-130b. Using RNA and microRNA sequencing, we identified miR-551b and miR-25 as important miRs mediating Dex resistance in MM. Overexpression of miR-551b and miR-25 caused resistance to Dex, however, knockdown of miR-551b and miR-25 significantly enhanced Dex sensitivity in MM. SAE2 knockdown or TAK-981 treatment downregulated the expression of miR-551b and miR-25, leading to induction of miR targets ZFP36, ULK1 and p27, resulting in apoptosis and autophagy. We demonstrated c-Myc as a major transcriptional activator of miR-130b, miR-551b and miR-25 and SUMOylation inhibition downregulates these miRs level by decreasing c-Myc level. ConclusionOur study proves SUMOylation plays a crucial role in Dex resistance in MM and SUMOylation inhibition appears to be an attractive strategy to advance to the clinic for MM patients.

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Section: Discussionmentioning

confidence: 90%

Section: Sumoylation Inhibition Enhances Dex Sensitivity In MM Through Regulating Mir-551b and Mir-25mentioning

confidence: 99%

SUMOylation Inhibition Enhances Dexamethasone Sensitivity in Multiple Myeloma

Liu

Aldana-Masangkay

et al. 2021

Preprint

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“…Another interesting regulator in TRAIL apoptosis is miR-25, as it has been implicated to block TRAIL death receptor (DR) 4, thereby blocking induced apoptosis. Additionally, predictive analysis has also confirmed Bim and Mcl-1 as targets for miR-25 [ 86 , 87 ]. In the case of DR4, bioinformatic analysis has determined direct targeting of the 3´UTR of DR4 by miR-25 [ 86 ].…”

Section: Regulation Mechanismmentioning

confidence: 99%

“…Additionally, predictive analysis has also confirmed Bim and Mcl-1 as targets for miR-25 [ 86 , 87 ]. In the case of DR4, bioinformatic analysis has determined direct targeting of the 3´UTR of DR4 by miR-25 [ 86 ]. Moreover, DR4 can also be repressed by Hedgehog signaling Gl3, thereby serving as an antagonist to TRAIL-induced apoptosis [ 88 ].…”

Section: Regulation Mechanismmentioning

confidence: 99%

“…Meanwhile, miR-25-3p (part of the miR-25 cluster) has been shown to promote malignant phenotypes by also regulating the PTEN/Akt pathway and the promotion of the epithelial–mesenchymal transition similarly, as does miR-92a in non-small-cell lung cancer cells (NSCLC) and miR-129-5p in retinoblastomas by targeting PAX6 [ 93 , 94 , 95 ]. In addition, Wan et al showed that miR-25-3p can induce Vimentin and Snail and suppress E-cadherin, which enhances invasiveness [ 86 , 96 ].…”

Section: Regulation Mechanismmentioning

confidence: 99%

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Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

Quiroz-Reyes,

Delgado-Gonzalez,

Islas

et al. 2021

Pharmaceutics

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.

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