Transcriptome-wide characterization of the endogenous miR-34A-p53 tumor suppressor network

Samuel, Nardin; Wilson, Gavin; Said, Badr Id; Pan, Anna; Deblois, Geneviève; Fischer, Nicholas W.; Alexandrova, Roumiana; Casallo, Guillermo; Paton, Tara; Lupien, Mathieu; Gariépy, Jean; Merico, Daniele; Hudson, Thomas J.; Malkin, David

doi:10.18632/oncotarget.10417

Cited by 9 publications

(10 citation statements)

References 22 publications

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“…Previous studies have demonstrated that miR-34a is a direct downstream target of p53, which is a tumor suppressor whose transcriptional targets regulate cell cycle, cell senescence, DNA repair, apoptosis and other biological behaviors [34, 35]. The p53-miR-34a network plays a crucial role in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

Liu

Ren

Chen

2017

Cell Physiol Biochem

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Background: MiR-34a is identified as a tumor suppressor gene and involved in acute myeloid leukemia (AML) development. However, the regulatory mechanism of miR-34a in AML is unclear. Methods: The expression of miR-34a and HMGB1 in HL-60, THP-1 and HS-5 cells were detected by qRT-PCR and western blot. Lipofectamine 2000 was used to transfect with miR-34a mimics, miR-34a inhibitor, si-HMGB1, pcDNA 3.1-HMGB1, and corresponding controls. The apoptosis and autophagy of transfected AML cells were assessed by flow cytometry and western blot, respectively. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-34a. The effects of miR-34a mimics or si-HMGB1 on chemotherapy-induced autophagy were further explored in HL-60 cells treated with all-trans retinoic acid (ATRA) along with lysosomal protease inhibitors E64d and pepstatin A. Results: MiR-34a was lower expressed and HMGB1 mRNA and proteins were both higher expressed in HL-60 and THP-1 cells compared with that in HS-5 cells. Higher expression levels of MiR-34 and lower expression levels of HMGB1 both significantly promoted apoptosis and inhibited autophagy in HL-60 and THP-1 cells. Dual luciferase reporter system confirmed that HMGB1 was a potential target of miR-34a. Moreover, overexpression of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by higher expression level of miR-34a. Higher expression level of miR-34a and lower expression level of HMGB1 both inhibited chemotherapy-induced autophagy by stimulating the LC3 conversion. Conclusion: MiR-34a promoted cell apoptosis and inhibited autophagy by targeting HMGB1. Therefore, miR-34a may be a potential promising molecular target for AML therapy.

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Section: Discussionmentioning

confidence: 99%

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

Liu

Ren

Chen

2017

Cell Physiol Biochem

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“…In addition to the p21 and BAX, p53 also is reported to activate the transcription of miR-34a, a potent tumor-suppressive miR, which gains much attention in recent cancer researches [20, 31]. This triggers our interest to investigate the effect of JP-1 on miR-34a transcription.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…MiR-34a is the first identified and well-studied miR in the p53 regulatory network [20, 31]. Owing to its established role in cancer, synthetic miR-34a mimics are currently in Phase I clinical trials for lung and a variety of types of cancers (NCT01829971) [31]. However, effective delivery of miR-34a mimics to solid tumors is limited by factors, including reticuloendothelial system clearance and nuclease degradation [18].…”

Section: Discussionmentioning

confidence: 99%

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Activation of p53/miR‐34a Tumor Suppressor Axis by Chinese Herbal Formula JP‐1 in A549 Lung Adenocarcinoma Cells

Yao

Chow

Lin

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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Lung cancer is the leading cause of cancer death worldwide; the most common pathologic type is lung adenocarcinoma (LADC). In spite of the recent progress in targeted therapy, most LADC patients eventually expired due to the inevitable recurrence and drug resistance. New complementary agent with evidence-based molecular mechanism is urgently needed. MiR-34a is an important p53 downstream tumor suppressor, which regulates apoptosis, cell-cycle, EMT (epithelial mesenchymal transition), and so forth. Its expression is deficient in many types of cancers including LADC. Here, we show that a Chinese herbal formula JP-1 activates p53/miR-34a axis in A549 human LADC cells (p53 wild-type). Treatment with JP-1 induces p53 and its downstream p21 and BAX proteins as well as the miR-34a, resulting in growth inhibition, colony formation reduction, migration repression, and apoptosis induction. Accordingly, the decreases of miR-34a downstream targets such as CDK6, SIRT1, c-Myc, survivin, Snail, and AXL were observed. Moreover, JP-1 activates AMPKα and reduces mTOR activity, implying its inhibitory effect on the energy-sensitive protein synthesis and cell proliferation signaling. Our results show that JP-1 activates p53/miR-34a tumor suppressor axis and decreases proteins related to proliferation, apoptosis resistance, and metastasis, suggesting its potential as a complementary medicine for LADC treatment.

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“…A component of TP53 tumor suppressor network, mir-34a represents another tumor suppressor gene that regulates cell proliferation by targeting cyclin D1 (CCDC1), cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) proteins or Wnt/β-catenin signaling pathway in laryngeal [50], breast [51] colon and cervical cancers [52].…”

Section: Mirnas Can Function As Oncogenes or Tumor Suppressor Genesmentioning

confidence: 99%

The Role of miRNAs in Diagnosis, Prognosis and Treatment Prediction in Cervical Cancer

Bălăcescu¹,

Bălăcescu²,

Baldasici³

et al. 2017

Colposcopy and Cervical Pathology

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Cervical cancer represents one of the major problems of health women worldwide, especially in the developing countries. If discovered in its earliest stages, cervical cancer is successfully treatable; however, due to lack of proper implementation of screening programs, the majority of cervical cancer patients are diagnosed in advanced stages, which dramatically influence their outcome. Almost a half of these patients will suffer recurrence or metastasis in the following 2 years after therapy. If there are no immediate prospects in terms of developing new or more effective therapies, identifying new tools for early diagnosis, prognosis and treatment prediction remains a big challenge for cervical cancer. miRNAs have been validated to be key players in cell physiology, alterations in miRNA expression being associated with cancer progression and response to therapy. Cervical cancer studies have showed that alterations of miRNA expression can be identified in tumor tissues, exfoliated cervical cells and patients serum and that their transcription pattern is regulated by the present HPV genotype. Furthermore, miRNAs have been associated with patients response to therapy, therefore suggesting their potential to be used as biomarkers for cervical cancer diagnosis, prognosis and treatment response.

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Transcriptome-wide characterization of the endogenous miR-34A-p53 tumor suppressor network

Cited by 9 publications

References 22 publications

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

Activation of p53/miR‐34a Tumor Suppressor Axis by Chinese Herbal Formula JP‐1 in A549 Lung Adenocarcinoma Cells

The Role of miRNAs in Diagnosis, Prognosis and Treatment Prediction in Cervical Cancer

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