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Epigenetic regulation of miR-21 in colorectal cancer: ITGB4 as a novel miR-21 target and a three-gene network (miR-21-ITGΒ4-PDCD4) as predictor of metastatic tumor potential
Open accessAbstract
Previous studies have uncovered several transcription factors that determine biological alterations in tumor cells to execute the invasion-metastasis cascade, including the epithelial-mesenchymal transition (EMT). We sought to investigate the role of miR-21 in colorectal cancer regulation. For this purpose, miR-21 expression was quantified in a panel of colorectal cancer cell lines and clinical specimens. High expression was found in cell lines with EMT properties and in the vast majority of human tumor specimens. We demonstrate in a cell-specific manner the occupancy of MIR-21 gene promoter by AP-1 and ETS1 transcription factors and, for the first time, the pattern of histone posttranslational modifications necessary for miR-21 overexpression. We also show that Integrin-β4 (ITGβ4), exclusively expressed in polarized epithelial cells, is a novel miR-21 target gene and plays a role in the regulation of EMT, since it is remarkably de-repressed after transient miR-21 silencing and downregulated after miR-21 overexpression. miR-21-dependent change of ITGβ4 expression significantly affects cell migration properties of colon cancer cells. Finally, in a subgroup of tumor specimens, ROC curve analysis performed on quantitative PCR data sets for miR-21, ITGβ4, and PDCD4 shows that the combination of high miR-21 with low ITGβ4 and PDCD4 expression is able to predict presence of metastasis. In conclusion, miR-21 is a key player in oncogenic EMT, its overexpression is controlled by the cooperation of genetic and epigenetic alterations, and its levels, along with ITGβ4 and PDCD4 expression, could be exploited as a prognostic tool for CRC metastasis.
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“miRNAs play a key role in the progression of malignant tumors, they are considered potential anti-tumor therapeutic targets24, 25.”
From miR-21-5p Inhibits the Proliferation, Migration, and Invasion of Glioma by Targeting S100A10 (2023) · cites this paper as [25]
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Cites
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Racicot, R. (2016) · Scholarworks (University of Massachusetts Amherst) · doi:10.7275/8409161
Luk, I. Y. (2017) · Minerva Access (University of Melbourne)
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“Epigenetic regulation of MIR21 transcription has been demonstrated in other malignancies [44], and changes in Drosha/Dicer processing, Argonaute loading, or strand-specific turnover could alter the balance between the 5p and 3p products of the same precursor [37,40,41].”
Programmed cell death protein 4 (PDCD4): a pleiotropic regulator in cardiovascular diseases
Zheng, M., & Jiang, X. (2026) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-026-01237-4
“In CVD, the most pertinent epigenetic observations are those that alter the MIR21/miR-21-PDCD4 axis or RNA modification in ischemic injury [ 33–36].”
Metadata
- Authors
- Ferraro, A., Kontos, C. K., Boni, T., Bantounas, I., Siakouli, D., Kosmidou, V., Vlassi, M., Spyridakis, Y., Tsipras, I., Zografos, G., & Pintzas, A.
- Affiliations
- National Hellenic Research Foundation (GR)
- General Hospital of Athens G. Genimatas (GR)
- Corresponding author
- Pintzas, Alexander
- ORCID
- Venue
- Epigenetics
- Publisher
- Informa UK Limited
- Published
- 2013-10-22
- Volume
- 9
- Issue
- 1
- Pages
- 129-141
- ISSN
- 1559-2294 (ISSN-L)
- 1559-2308
- PMC
- PMC3928175
- OpenAlex
- W2090786568
- Cited by
- 111
- References
- 66
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 14 · 2020: 6 · 2019: 11 · 2018: 19 · 2017: 10 · 2016: 9 · 2015: 11 · 2014: 4
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epigenetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- National Hellenic Research Foundation Helios Repository (National Hellenic Research Foundation) (submittedVersion)
- Funders
- General Secretariat for Research and Technology
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- miR-21, colorectal cancer, epithelial-mesenchymal transition, ITGB4, PDCD4, histone modifications, AP-1 transcription factor, Ets-1 transcription factor, cell migration, metastasis prediction, prognostic factors, microRNA overexpression
- MeSH terms
- Histones, Humans, Neoplasm Metastasis, Protein Processing, Post-Translational, Biomarkers, Tumor, Colorectal Neoplasms, RNA-Binding Proteins, Transcription Factor AP-1, MicroRNAs, Integrin beta4, Epigenesis, Genetic, Cell Line, Tumor, Proto-Oncogene Protein c-ets-1, Apoptosis Regulatory Proteins, Gene Regulatory Networks, Epithelial-Mesenchymal Transition
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