Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers
Open accessAbstract
BACKGROUND: The rates of oropharyngeal cancers such as tonsil cancers are increasing. The tumour suppressor protein Programmed Cell Death Protein 4 (PDCD4) has been implicated in the development of various human cancers and small RNAs such as microRNAs (miRNAs) can regulate its expression. However the exact regulation of PDCD4 by multiple miRNAs in oropharyngeal squamous cell carcinoma (SCC) is not well understood. RESULTS: Using two independent oropharyngeal SCC cohorts with a focus on the tonsillar region, we identified a miRNA profile differentiating SCC tissue from normal. Both miR-21 and miR-499 were highly expressed in tonsil SCC tissues displaying a loss of PDCD4. Interestingly, expression of the miRNA machinery, Dicer1, Drosha, DDX5 (Dead Box Helicase 5) and DGCR8 (DiGeorge Syndrome Critical Region Gene 8) were all elevated by greater than 2 fold in the tonsil SCC tissue. The 3'UTR of PDCD4 contains three binding-sites for miR-499 and one for miR-21. Using a wild-type and truncated 3'UTR of PDCD4, we demonstrated that the initial suppression of PDCD4 was mediated by miR-21 whilst sustained suppression was mediated by miR-499. Moreover the single miR-21 site was able to elicit the same magnitude of suppression as the three miR-499 sites. CONCLUSION: This study describes the regulation of PDCD4 specifically in tonsil SCC by miR-499 and miR-21 and has documented the loss of PDCD4 in tonsil SCCs. These findings highlight the complex interplay between miRNAs and tumour suppressor gene regulation and suggest that PDCD4 loss may be an important step in tonsillar carcinogenesis.
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Both miR21 and miR499 are highly expressed in tonsil squamous cell carcinoma tissues down-regulating PDCD4 expression.
“Zhang et al. [61] reported that both miR21 and miR499 are highly expressed in tonsil squamous cell carcinoma (SCC) tissues down-regulating PDCD4 expression.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [61]
Besides miR21, many other microRNAs such as miR182, miR16, miR150, and miR499 target PDCD4 mRNA down-regulating PDCD4 expression in different cellular systems.
“Besides miR21, many other kinds of microRNA such as miR182, miR16, miR150, miR499 and other microRNAs has been shown to target the PDCD4 mRNA down-regulating PDCD4 expression in different cellular systems [58,59,60,61].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [61]
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- Authors
- Zhang, X., Gee, H., Rose, B., Lee, C. S., Clark, J., Elliott, M., Gamble, J. R., Cairns, M. J., Harris, A., Khoury, S., & Tran, N.
- Affiliations
- The University of Sydney (AU)
- Centenary Institute (AU)
- Hunter Medical Research Institute (AU)
- Cancer Research UK (GB)
- University of Technology Sydney (AU)
- Corresponding author
- Tran, Nham
- ORCID
- Venue
- BMC Cancer
- Published
- 2016-02-11
- Volume
- 16
- Issue
- 1
- Pages
- 86-86
- ISSN
- 1471-2407 (ISSN-L)
- PMC
- PMC4750294
- OpenAlex
- W2267406668
- Cited by
- 65
- References
- 50
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 9 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 11 · 2017: 7 · 2016: 5
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- UTS ePRESS (University of Technology Sydney) (submittedVersion, cc-by)
- NOVA (University of Newcastle Australia) (submittedVersion, cc-by)
- Funders
- Cancer Research UK (11359, 16466, 18974)
- National Institute for Health and Care Research (NF-SI-0611-10163)
- NIHR Oxford Biomedical Research Centre
- 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 › Otorhinolaryngology › Head and Neck Cancer Studies
- Keywords
- PDCD4, miR-499, miR-21, oropharyngeal squamous cell carcinoma, tonsillar carcinoma, microRNA binding sites, 3' untranslated region, DICER1, Drosha, DDX5, DGCR8, tumor suppressor loss
- MeSH terms
- Carcinoma, Squamous Cell, Humans, Oropharyngeal Neoplasms, Gene Expression Regulation, Neoplastic, RNA-Binding Proteins, MicroRNAs, Ribonuclease III, Cell Line, Tumor, Cell Proliferation, Apoptosis Regulatory Proteins, DEAD-box RNA Helicases, Carcinogenesis
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