MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene
Open accessAbstract
MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively control expression of target genes in animals and plants. The microRNA-21 gene (mir-21) has been identified as the only miRNA commonly overexpressed in solid tumors of the lung, breast, stomach, prostate, colon, brain, head and neck, esophagus and pancreas. We initiated a screen to identify miR-21 target genes using a reporter assay and identified a potential miR-21 target in the 3'-UTR of the programmed cell death 4 (PDCD4) gene. We cloned the full-length 3'-UTR of human PDCD4 downstream of a reporter and found that mir-21 downregulated, whereas a modified antisense RNA to miR-21 upregulated reporter activity. Moreover, deletion of the putative miR-21-binding site (miRNA regulatory element, MRE) from the 3'-UTR of PDCD4, or mutations in the MRE abolished the ability of miR-21 to inhibit reporter activity, indicating that this MRE is a critical regulatory region. Western blotting showed that Pdcd4 protein levels were reduced by miR-21 in human and mouse cells, whereas quantitative real-time PCR revealed little difference at the mRNA level, suggesting translational regulation. Finally, overexpression of mir-21 in MCF-7 human breast cancer cells and mouse epidermal JB6 cells promoted soft agar colony formation by downregulating Pdcd4 protein levels. The demonstration that miR-21 promotes cell transformation supports the concept that mir-21 functions as an oncogene by a mechanism that involves translational repression of the tumor suppressor Pdcd4.
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Inhibition of miR-21 via different strategies elevated apoptotic cell death, sensitivity to chemotherapy/radiotherapy, and diminished tumor progression.
“Inhibition of miR-21 via different strategies elevated apoptotic cell death, sensitivity to chemotherapy/radiotherapy, and diminished tumor progression (24–28).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [28]
miR-21 silencing has demonstrated effective results both in vitro and in vivo.
“In addition, miR-21 silencing has demonstrated effective results both in vitro and in vivo (24–28).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [28]
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- Authors
- Lu, Z., Liu, M., Stribinskis, V, Klinge, C. M., Ramos, K. S., Colburn, N. H., & Li, Y.
- Affiliations
- University of Louisville (US)
- Chinese Academy of Sciences (CN)
- Frederick National Laboratory for Cancer Research (US)
- Venue
- Oncogene
- Published
- 2008-03-31
- Volume
- 27
- Issue
- 31
- Pages
- 4373-4379
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC11968769
- OpenAlex
- W2075258024
- Cited by
- 711
- References
- 5
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 17 · 2023: 18 · 2022: 28 · 2021: 19 · 2020: 28 · 2019: 24 · 2018: 35 · 2017: 30 · 2016: 47 · 2015: 59 · 2014: 63 · 2013: 53 · 2012: 54
- FWCI
- 24.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R21CA124811)
- National Institute of Environmental Health Sciences (P30ES014443)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- miR-21, PDCD4, miRNA target identification, 3' untranslated region, protein synthesis inhibition, tumor suppressor, cell transformation, breast cancer, soft agar colony formation
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Humans, Phenotype, RNA, Tissue Distribution, Protein Biosynthesis, Gene Expression Regulation, Neoplastic, Oligonucleotides, Antisense, RNA-Binding Proteins, 3' Untranslated Regions, MicroRNAs, Cell Line, Tumor, Apoptosis Regulatory Proteins, Mice
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