MiR-138 indirectly regulates the MDR1 promoter by NF-κB/p65 silencing

Requenez-Contreras, J.L.; Lopez-Castillejos, Erika Sicahui; Hernández-Flores, R.; Moreno-Eutímio, Mario Adán; Granados-Riverón, Javier T.; Martínez-Ruiz, Gustavo Ulises; Aquino‐Jarquín, Guillermo

doi:10.1016/j.bbrc.2017.01.168

Cited by 22 publications

(8 citation statements)

References 33 publications

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“…For example, miR-129 and miR-145 inhibit P-gp expression and sensitize human cancer cells to chemotherapy drugs by directly targeting the 3′-UTR of MDR1 (Ikemura et al, 2013; Lu et al, 2017). Additionally, the overexpression of miR-506 and miR-138 have been reported to indirectly downregulate P-gp expression by regulating different signaling pathways (Requenez-Contreras et al, 2017; Zhou et al, 2017). In a previous report, miR-298 ameliorated the chemoresistance of breast cancer cells by downregulating P-gp expression, which was markedly decreased in both HBMEC/PHT and U87-MG/DOX cells in the present study ( Figure 2B ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

et al. 2018

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P-glycoprotein (P-gp), a critical multidrug transporter, recognizes and transports various antiepileptic drugs (AEDs) through the blood-brain barrier (BBB). This may decrease the concentrations of AEDs in brain tissues and cause multidrug resistance (MDR) in patients with refractory epilepsy. Compelling evidence indicates that microRNAs (miRNAs) modulate MDR in various cancers by regulating P-gp expression. Furthermore, a previous study showed that miR-298 mediates MDR in breast cancer cells by downregulating P-gp expression. Based on the therapeutic results obtained from tumor cells, we aimed to determine whether miR-298 reverses MDR to AEDs by regulating P-gp expression in the BBB. We first established different drug-resistant cell lines, including PHT-resistant HBMECs (human brain microvascular endothelial cells) and doxorubicin (DOX)-resistant U87-MG (human malignant glioma) cells, by inducing P-gp overexpression. Quantitative real-time PCR (qRT-PCR) analysis revealed reduced expression of miR-298 in both HBMEC/PHT and U87-MG/DOX cells, and the luciferase reporter assay identified the direct binding of miR-298 to the 3′-untranslated region (3′-UTR) of P-gp. Moreover, ectopic expression of miR-298 downregulated P-gp expression at the mRNA and protein levels, thereby increasing the intracellular accumulation of AEDs in drug-resistant HBMEC/PHT and U87-MG/DOX cells. Thus, our findings suggest that miR-298 reverses MDR to AEDs by inhibiting P-gp expression, suggesting a potential target for overcoming MDR in refractory epilepsy.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

et al. 2018

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“… 32 Recent study revealed that miR-138 directly regulated NFκB/RelA expression through binding to its 3′UTR and further mediated drug efflux pump P-glycoprotein expression to induce chemoresistance. 33 Therefore, molecular mechanisms for NFκB/RelA upregulation in cisplatin-resistant UBC cells is not clear yet.…”

Section: Discussionmentioning

confidence: 99%

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway

Xue

Yang

et al. 2018

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BackgroundCisplatin-based chemotherapy is mainstay treatment in urinary bladder cancer (UBC). However, tumor recurrence frequently occurs with the acquisition of cisplatin resistance. We explored the potential effect of a polyherbal preparation, Zyflamend, on UBC cells resistant to cisplatin treatment.MethodsTo establish a cisplatin-resistant human bladder cancer cell line, T24 cells were cultured in increasing concentrations of cisplatin for more than 10 months. These cells (T24R) were then treated with different concentrations of Zyflamend, and both proliferation and activity of nuclear factor kappaB (NFκB) signaling pathway were examined. To test the synergistic effect between Zyflamend and cisplatin, we treated T24R cells either with Zyflamend or cisplatin alone, or in combination. Apoptotic effect was evaluated by Annexin V/propidium iodide double staining, and the levels of the proteins involved in cell cycle and anti-apoptosis were examined by Western blotting. Finally, mice with palpable xenograft were treated either with cisplatin and Zyflamend alone or in combination for 28 days before they were sacrificed for measuring the sizes and weights of the tumor tissues. In addition, proliferation and apoptosis markers were examined by immunohistochemistry.ResultsComparing to that in the parental T24 cells, NFκB is constitutively active in cisplatin-resistant T24R cells. Zyflamend is capable of inhibiting the growth of T24, T24R, as well as another UBC cell line J82 in a concentration-dependent manner. Mechanistically, Zyflamend suppresses NFκB-mediated cell proliferation, survival, and invasion/angiogenesis and induces apoptosis. In addition, Zyflamend significantly increased the sensitivity of T24R and J82 cells to cisplatin treatment and these findings were confirmed in T24R xenograft model with reduced proliferation index and decreased expression of RelA and its downstream target MMP9.ConclusionZyflamend is capable of counteracting bladder cancer resistance to cisplatin by repressing proliferation and inducing apoptosis through targeting NFκB signaling pathway.

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“…A previous study showed that miR-138 expression is involved in the multidrug resistance of leukemia cells through down-regulation of MDR1 [ 45 ]. However, a following study revealed that miR-138 modulates MDR1 expression indirectly by inhibiting NF-κB/p65, a well known transcriptional factor involved in MDR1 regulation [ 46 ]. Importantly, the multidrug resistance of human leukemia cell line HL-60 was achieved after overexpression of miR-138.…”

Section: Discussionmentioning

confidence: 99%

Fascin promotes migration and invasion and is a prognostic marker for oral squamous cell carcinoma

et al. 2017

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Oral squamous cell carcinoma (OSCC) prognosis is related to clinical stage and histological grade. However, this stratification needs to be refined. We conducted a comparative proteome study in microdissected samples from normal oral mucosa and OSCC to identify biomarkers for malignancy. Fascin and plectin were identified as differently expressed and both are implicated in several malignancies, but the clinical impacts of aberrant fascin and plectin expression in OSCCs remains largely unknown. Immunohistochemistry and real-time quantitative PCR were carried out in ex vivo OSCC samples and cell lines. A loss-of-function strategy using shRNA targeting fascin was employed to investigate in vitro and in vivo the fascin role on oral tumorigenesis. Transfections of microRNA mimics were performed to determine whether the fascin overexpression is regulated by miR-138 and miR-145. We found that fascin and plectin are frequently upregulated in OSCC samples and cell lines, but only fascin overexpression is an independent unfavorable prognostic indicator of disease-specific survival. In combination with advanced T stage, high fascin level is also an independent factor of disease-free survival. Knockdown of fascin in OSCC cells promoted cell adhesion and inhibited migration, invasion and EMT, and forced expression of miR-138 in OSCC cells significantly decreased the expression of fascin. In addition, fascin downregulation leads to reduced filopodia formation and decrease on paxillin expression. The subcutaneous xenograft model showed that tumors formed in the presence of low levels of fascin were significantly smaller compared to those formed with high fascin levels. Collectively, our findings suggest that fascin expression correlates with disease progression and may serve as a prognostic marker and therapeutic target for patients with OSCC.

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MiR-138 indirectly regulates the MDR1 promoter by NF-κB/p65 silencing

Cited by 22 publications

References 33 publications

MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway

Fascin promotes migration and invasion and is a prognostic marker for oral squamous cell carcinoma

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MiR-138 indirectly regulates the MDR1 promoter by NF-κB/p65 silencing

Cited by 22 publications

References 33 publications

MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells&nbsp;to cisplatin through inhibiting NF&kappa;B signaling pathway

Fascin promotes migration and invasion and is a prognostic marker for oral squamous cell carcinoma

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Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway