MiR-7 in Cancer Development

Korać, Petra; Antica, Mariastefania; Matulić, Maja

doi:10.3390/biomedicines9030325

Cited by 45 publications

(25 citation statements)

References 181 publications

(115 reference statements)

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“…Here, we found that miR-7-5p loaded exosomes could combine with Everolimus to induce apoptosis in the mitochondrial pathway and the death receptor pathway through dual targeting the MNK/eIF4E axis and mTOR pathway. The strategy of miR-7-5p loaded exosomes combined with Everolimus was more effective than our previous combination of CGP57380 with Everolimus in NSCLC, which only promoted apoptosis through the mitochondrial pathway [ 10 ]. Enforced levels of exogenous miR-7 in TRAIL-overexpressed MSCs sensitize the treatment of TRAIL to increase apoptosis in the death receptor pathway through targeting XIAP in glioma cells [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Besides, there are changes of the miRNA profiles in A549 cells with Everolimus treatment [ 9 ]. MIR-7 is regarded as a tumor suppressor in NSCLC, which dominantly regulates several basic cellular processes including proliferation, differentiation, apoptosis, migration and expression of stem cell features [ 10 ]. Also miR-7 can decrease EGFR mRNA level [ 11 ] and regulate many genes of the mTOR pathway, like MNK, eIF4E and 70 kDa ribosomal protein S6 kinase (p70S6K) [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer

et al. 2022

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Everolimus is a kind of mammalian target of rapamycin (mTOR) inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). The eIF4E phosphorylation increased by mTOR inhibitors is mainly mediated by MNKs. However, the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposure. Our previous studies have confirmed that tumor suppressor miR-7-5p is decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. In this study, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. We confirmed that Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B-dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but a supplement of extra exosomal miR-7-5p could reverse it. Of note, both low expression of miR-7-5p and elevated MNK1 protein were associated with a poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus by inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and in vivo. The combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy through dual abrogation of MNK/eIF4E and mTOR in NSCLC. In conclusion, Everolimus decreases the intracellular miR-7-5p by releasing of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy by targeting MNK/eIF4E axis and mTOR. Besides, both low levels of miR-7-5p and positive expression of MNK1 act as independent poor prognostic biomarkers for NSCLC. Therefore, restoring miR-7-5p carried by exosome may be a promising novel combined therapeutic strategy with Everolimus for NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer

et al. 2022

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“…miR-7-5p has been previously described as suppressor miRNA across multiple cancer types [ 22 ], including lung, colon, and breast cancer. In particular, miR-7-5p acts as tumor suppressor in signaling pathways with a crucial role in cancer (EGFR/MAPK, PI3K/Akt, Wnt, and others), inhibiting cell survival, proliferation, and migration.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of miR-7-5p and miR-548ar-5p predicts malignancy in indeterminate thyroid nodules negative for BRAF and RAS mutations

et al. 2022

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Purpose The value of molecular markers in refining preoperative risk assessment of indeterminate thyroid nodules is being widely investigated. MicroRNAs (miRNA) are emerging as promising biomarkers for diagnostic and prognostic purposes. The aim of this study is to identify miRNAs specifically deregulated in mutation-negative indeterminate thyroid nodules. Methods Ninety-eight nodules preoperatively diagnosed as TIR 3A or TIR 3B with available histological diagnosis of follicular adenoma (FA), noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP), and follicular variant papillary thyroid carcinoma (FV-PTC) have been retrospectively selected. Mutations in BRAF and RAS genes have been tested in all samples by real-time PCR; miRNAs were purified from cytology slides of 60 samples; expression analysis of 798 miRNAs was measured by the nCounter system. Results Point mutations in BRAF and RAS genes were detected in 32 out of 98 nodules (32.7%), the majority of which in FV-PTCs. Differential expression of miRNA in wild-type nodules highlighted that two miRNAs, namely miR-7-5p and miR-548ar-5p, were downregulated in FV-PTCs compared to FAs. The combined expression of these miRNAs, tested by ROC analysis, showed an area under the curve of 0.79. Sensitivity and negative predictive value were high both in wild-type (93% and 92%, respectively) and in mutated nodules (94% and 85%, respectively). Conclusion The analysis of miR-7-5p and miR-548ar-5p expression in indeterminate thyroid nodules demonstrated a promising value in ruling out malignancy.

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“…For the reasons that numerous reports con rmed miR-7 is a miRNA involved in the regulation of several signaling pathways, and acts as a tumor suppressor in NSCLC [12]. It dominantly regulates several basic cellular processes, which include proliferation, differentiation, apoptosis, migration and expression of stem cell features [13]. It is worth noting that miR-7 was also shown to decrease EGFR mRNA expression [14] and regulate many genes of the mTOR pathway, like MNK, eIF4E and 70 kDa ribosomal protein S6 kinase (p70S6K) [15].…”

Section: Introductionmentioning

confidence: 99%

Exosome-Mediated miR-7-5p Delivery Enhances the Anticancer Effect of Everolimus via Blocking MNK/eIF4E Axis in Non-Small Cell Lung Cancer

Liu

Wang

Ning

et al. 2021

Preprint

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Background Everolimus is a kind of mTOR inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). Typically, eIF4E phosphorylation increased by mTOR inhibitors was mainly mediated by MNKs. But the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposing. Our previous studies have confirmed that tumor suppressor miR-7-5p was decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. Here, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. Methods miR-7-5p level and expression of main markers of MNK/eIF4E axis were evaluated by qRT-PCR, western blot, in situ hybridization, and immunohistochemistry on NSCLC cell lines and human NSCLC samples. Proliferation, migration and invasion of NSCLC cells in culture were explored by Colony formation, CCK-8, Wound healing and Transwell assays. NSCLC cell tumorigenicity was assessed by xenotransplants in nude mice. Targeted binding of miR-7-5p to MNK1 was confirmed by the Dual-luciferase reporter assay. And the isolation and identification of exosomes were investigated by Invitrogen™ Total Exosome RNA Isolation Kit, western blot, transmission electron microscopy and Zetasizer Nano ZS90 instrument. Results Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but supplement of extra exosomal miR-7-5p could reverse it. Of note, both lower expression of miR-7-5p and elevated MNK1 protein were associated with poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus through inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and vivo. Combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy via dual abrogation of MNK/eIF4E and mTOR in NSCLC. Conclusion Everolimus decreases the intracellular miR-7-5p levels through release of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy via targeting MNK/eIF4E axis and mTOR. Therefore, exosome-mediated miR-7-5p delivery combined with Everolimus may be considered as a promising novel combined therapeutic strategy for NSCLC.

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MiR-7 in Cancer Development

Cited by 45 publications

References 181 publications

Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer

Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer

Down-regulation of miR-7-5p and miR-548ar-5p predicts malignancy in indeterminate thyroid nodules negative for BRAF and RAS mutations

Exosome-Mediated miR-7-5p Delivery Enhances the Anticancer Effect of Everolimus via Blocking MNK/eIF4E Axis in Non-Small Cell Lung Cancer

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