MiR-34a suppresses HNSCC growth through modulating cell cycle arrest and senescence

Wang, Y; Chen, J; Chen, X; Jiang, Feng-Jie; Sun, Yanan; Pan, Yifan; Zhang, W; Zhang, J

doi:10.4149/neo_2017_408

Cited by 24 publications

(18 citation statements)

References 44 publications

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“…AXL also activates the PI3K/AKT cascade . AKT activation leads to cyclin D1 upregulation through inhibition of GSK3β . Cyclin D1 then stimulates cell cycle entry and proliferation .…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL

et al. 2019

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Background: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next‐generation sequencing‐based whole miRNome sequencing and quantitative polymerase chain reaction‐based validation analysis. In this study, we examined the mechanism of action of miR‐139‐5p, one of the downregulated miRNAs identified in the panel. Methods: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR‐139 (dichotomized around the median) using the Kaplan‐Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR‐139 to confirm its targets as well as examine pathways through which miR‐139 may function using cell‐based assays. Results: Low miR‐139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR‐139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR‐139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR‐139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33‐0.82). Overexpression of miR‐139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR‐139 based on multiple miRNA‐binding sites in 3′‐untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR‐139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR‐139 treatment, which was reversed by the addition of miR‐139 antagomir. Examination of the molecular mechanism of growth inhibition by miR‐139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21. Conclusions: miR‐139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.

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“…AXL also activates the PI3K/AKT cascade . AKT activation leads to cyclin D1 upregulation through inhibition of GSK3β . Cyclin D1 then stimulates cell cycle entry and proliferation .…”

Section: Discussionmentioning

confidence: 99%

“…67 Similarly, AXL was found as one of the targets of miR-34a downregulated in head and neck squamous cell carcinoma (HNSCC) that has also been shown to lead cell cycle arrest. 68 Thus, miR-139 may induce G2/M cell cycle arrest by targeted degradation of IGF1R, and/or AXL.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL

et al. 2019

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“… 9 , 10 The transcription of miR-34a was adjusted by p53. 11 – 13 miR-34a was found to inhibit malignant growth of cancer by repressing genes involved in various oncogenic signaling pathways, such as targeting the silent mating type information regulation 2 homologue 1 ( SIRT1 ) gene to enhance p53-mediated cell apoptosis, 14 – 16 repressing CD44 to inhibit the self-renewal of cancer stem cells. 17 Low expression of miR-34 endows cancer cells with high capabilities of proliferation, metastasis, stemness maintenance, apoptosis inhibition, and chemoresistance.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous overexpression of miR-126 and miR-34a induces a superior antitumor efficacy in pancreatic adenocarcinoma

Feng

Mao

Liu

et al. 2017

OTT

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BackgroundPancreatic adenocarcinoma (PAC) is one of the most fatal cancers due to its high degree of malignancy, increasing incidence, high mortality, and unsatisfactory treatment efficacy. Evidence has suggested that numerous microRNAs (miRNAs), including miR-126 and miR-34a, have potent tumor-suppressing effects on PAC, implicating a possible application of miRNA in tumor therapy. However, the therapeutic effect of a single miRNA on pancreatic cancer is limited.MethodsWe simultaneously delivered miR-126 and miR-34a into PAC cells by a carcinoembryonic antigen promoter-driven oncolytic adenovirus (AdCEAp-miR126/34a), and examined the antitumor efficacy of the therapeutic system in in vitro and in vivo experiments.ResultsIn vitro cytological experiments found that the expression levels of miR-126 and miR-34a were specifically increased in the AdCEAp-miR126/34a-infected PAC cells, and the antitumor efficacy was enhanced in aspects of cancer cell viability, migration, invasion, and apoptosis, by synergistically combining the antitumor effects of overexpressed miR-126 and miR-34a and the oncolytic effect of viral replication specifically in PAC cells. The expression levels of miR-126 target genes (vascular endothelial growth factor-A and SOX2) and miR-34a target genes (cyclin D1, E2F1, and Bcl-2) were markedly decreased in the PAC cells after being infected with AdCEAp-miR126/34a. Notable suppression of the therapeutic system on tumor growth was also proven in established PAC xenograft tumor models in nude mice, which demonstrated that the combination of miR-126 and miR-34a exerts more effective antitumor outcomes than a single miRNA.ConclusionThe therapeutic system co-expressing miR-126 and miR-34a mediated by oncolytic adenovirus is a promising system for PAC target therapy.

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“…Changes to miRNA expression in OSCC have been shown to drive transcriptional dysregulation for genes critical in tumorigenesis 18 , 19 , 42 , 43 . However, the molecular interplay between miRNA and mRNA has not been comprehensively profiled.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-transcription factor network analysis reveals miRNAs cooperatively suppress RORA in oral squamous cell carcinoma

Zheng

Wu²,

Liao³

et al. 2018

Oncogenesis

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Oral squamous cell carcinoma (OSCC) represents over 90% of oral cancer incidence, while its mechanisms of tumorigenesis remain poorly characterized. In this study, we applied RNA-seq and microRNA-seq methodologies in four pairs of cancer and adjacent normal tissues to profile the contribution of miRNAs to tumorigenesis-altered functional pathways by constructing a comprehensive miRNA-mediated mRNA regulatory network. There were 213 differentially expressed (DE) miRNAs and 2172 DE mRNAs with the involvement of negative miRNA-mRNA interactions identified by at least two pairs of cancerous tissues. GO analysis revealed that the upregulated microRNAs significantly contributed to a global down-regulation of a number of transcription factors (TFs) in OSCC. Among the negative regulatory networks between the selected miRNAs (133) and TFs (167), circadian rhythm genes (RORA, RORB, RORC, and CLOCK) simultaneously regulated by multiple microRNAs were of particular interest. For instance, RORA transcript was predicted to be targeted by 25 co-upregulated miRNAs, of which, miR-503-5p, miR-450b-5p, miR-27a-3p, miR-181a-5p and miR-183-5p were further validated to directly target RORA, resulting in a stronger effect on RORA suppression together. In addition, we showed that the mRNA and protein expression levels of RORα were significantly decreased in most OSCC samples, associated with advanced clinical stage and poor prognosis. RORα significantly suppressed the proliferation of OSCC cells in vitro and in vivo. Attenuated RORα decreased p53 protein expression and suppressed p53 phosphorylation activity. Altogether, our results strongly suggest the importance of the role of miRNAs in regulating the activity of circadian rhythm-related TFs network during OSCC tumorigenesis, and provide further clues to understand the clinical link between circadian rhythm and cancer therapy.

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MiR-34a suppresses HNSCC growth through modulating cell cycle arrest and senescence

Cited by 24 publications

References 44 publications

MicroRNA‐139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL

MicroRNA‐139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL

Simultaneous overexpression of miR-126 and miR-34a induces a superior antitumor efficacy in pancreatic adenocarcinoma

MicroRNA-transcription factor network analysis reveals miRNAs cooperatively suppress RORA in oral squamous cell carcinoma

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