ArticleBMC cancer2016
Leptin and insulin up-regulate miR-4443 to suppress NCOA1 and TRAF4, and decrease the invasiveness of human colon cancer cells.
Article in BMC cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 2 of them syntheses that pooled it.
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Who cites it
48 citing papers in PubMed, 2 syntheses or guidelines pooled it, 66 citations in OpenAlex.
- Systematic review: The gut microbiota as a link between colorectal cancer and obesity.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2025Pooled it
- Clinical significance of miRNA‑1 and its potential target gene network in lung squamous cell carcinoma.Molecular medicine reports · 2019Pooled it
- Clinical role and mechanism of miR-4443 in coronary heart disease: a prognostic marker and regulator of vascular smooth muscle cell Function.Journal of cardiothoracic surgery · 2026Article
- Discovering Anticancer Effects of Phytochemicals on MicroRNA in the Context of Data Mining.Nutrients · 2025Article
- Dysregulated miRNAs Targeting Adiponectin Signaling in Colorectal Cancer.International journal of molecular sciences · 2025Review
- Unraveling molecular interconnections and identifying potential therapeutic targets of significance in obesity-cancer link.Journal of the National Cancer Center · 2025Review
- Metabolic syndrome in colorectal cancer liver metastasis: metabolic reprogramming and microenvironment crosstalk.Frontiers in immunology · 2025Review
- The multifaceted therapeutic value of targeting steroid receptor coactivator-1 in tumorigenesis.Cell & bioscience · 2024Review
- Childhood obesity, metabolic syndrome, and oxidative stress: microRNAs go on stage.Reviews in endocrine & metabolic disorders · 2023Review
- Upregulated expression of miR-4443 and miR-4488 in drug resistant melanomas promotes migratory and invasive phenotypes through downregulation of intermediate filament nestin.Journal of experimental & clinical cancer research : CR · 2023Article
- Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.Signal transduction and targeted therapy · 2023Review
- Associations between polymorphisms in leptin and leptin receptor genes and colorectal cancer survival.Cancer biology & medicine · 2023Article
- miRNA Expression in Fibroblastic Foci within Idiopathic Pulmonary Fibrosis Lungs Reveals Novel Disease-Relevant Pathways.The American journal of pathology · 2023Article
- Extracellular vesicle-associated microRNA signatures related to lymphovascular invasion in early-stage lung adenocarcinoma.Scientific reports · 2023Article
- Evaluation of Circulating Leptin and Its Receptor (Ob-R) Tissue Expression in Colorectal Cancer, a Report From North of Iran.Iranian journal of pathology · 2023Article
- MicroRNAs as Quality Assessment Tool in Stored Packed Red Blood Cell in Blood Banks.Journal of blood medicine · 2023Review
- miR-4443 promotes radiation resistance of esophageal squamous cell carcinoma via targeting PTPRJ.Journal of translational medicine · 2022Article
- miR-4443/MMP2 suppresses the migration and invasion of trophoblasts through the HB-EGF/EGFR pathway in preeclampsia.Cell cycle (Georgetown, Tex.) · 2022Article
- Aberrant expression of microRNA-4443 (miR-4443) in human diseases.Bioengineered · 2022Review
- Nuclear receptor coactivator SRC-1 promotes colorectal cancer progression through enhancing GLI2-mediated Hedgehog signaling.Oncogene · 2022Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundObesity is a risk factor for colorectal cancer (CRC). Normal and tumor cells respond to metabolic hormones, such as leptin and insulin. Thus, obesity-associated resistance to these hormones likely leads to changes in gene expression and behavior of tumor cells. However, the mechanisms affected by leptin and insulin signaling in CRC cells remain mostly unknown.
methodsWe hypothesized that microRNAs (miRNAs) are involved in the regulation of tumorigenesis-related gene expression in CRC cells by leptin and insulin. To test this hypothesis, miRNA levels in the CRC-derived cell lines HCT-116, HT-29 and DLD-1 were profiled, following leptin and insulin treatment. Candidate miRNAs were validated by RT-qPCR. Predicted miRNA targets with known roles in cancer, were validated by immunoblots and reporter assays in HCT-116 cells. Transfection of HCT-116 cells with candidate miRNA mimic was used to test in vitro effects on proliferation and invasion.
resultsOf ~800 miRNAs profiled, miR-4443 was consistently up-regulated by leptin and insulin in HCT-116 and HT-29, but not in DLD-1, which lacked normal leptin receptor expression. Dose response experiments showed that leptin at 100 ng/ml consistently up-regulated miR-4443 in HCT-116 cells, concomitantly with a significant decrease in cell invasion ability. Transfection with miR-4443 mimic decreased invasion and proliferation of HCT-116 cells. Moreover, leptin and miR-4443 transfection significantly down-regulated endogenous NCOA1 and TRAF4, both predicted targets of miR-4443 with known roles in cancer metastasis. miR-4443 was found to directly regulate TRAF4 and NCOA1, as validated by a reporter assay. The up-regulation of miR-4443 by leptin or insulin was attenuated by the inhibition of MEK1/2.
conclusionsOur findings suggest that miR-4443 acts in a tumor-suppressive manner by down-regulating TRAF4 and NCOA1 downstream of MEK-C/EBP-mediated leptin and insulin signaling, and that insulin and/or leptin resistance (e.g. in obesity) may suppress this pathway and increase the risk of metastatic CRC.
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