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Updated: Jul 29, 2025
Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
The deleted in oral cancer (DOC1 aka CDK2AP1) tumor suppressor gene is downregulated in oral squamous cell carcinoma
Roberto Stabile1, Mario Román Cabezas1, Mathijs P Verhagen1
1Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Abstract:
Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1; also known as deleted in oral cancer or DOC1) is a tumor suppressor gene known to play functional roles in both cell cycle regulation and in the epigenetic control of embryonic stem cell differentiation, the latter as a core subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex. In the vast majority of oral squamous cell carcinomas (OSCC), expression of the CDK2AP1 protein is reduced or lost. Notwithstanding the latter (and the DOC1 acronym), mutations or deletions in its coding sequence are extremely rare. Accordingly, CDK2AP1 protein-deficient oral cancer cell lines express as much CDK2AP1 mRNA as proficient cell lines. Here, by combining in silico and in vitro approaches, and by taking advantage of patient-derived data and tumor material in the analysis of loss of CDK2AP1 expression, we identified a set of microRNAs, namely miR-21-5p, miR-23b-3p, miR-26b-5p, miR-93-5p, and miR-155-5p, which inhibit its translation in both cell lines and patient-derived OSCCs. Of note, no synergistic effects were observed of the different miRs on the CDK2AP1-3-UTR common target. We also developed a novel approach to the combined ISH/IF tissue microarray analysis to study the expression patterns of miRs and their target genes in the context of tumor architecture. Last, we show that CDK2AP1 loss, as the result of miRNA expression, correlates with overall survival, thus highlighting the clinical relevance of these processes for carcinomas of the oral cavity.
Insights
Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) loss in oral cancer is driven by specific microRNAs inhibiting its translation. This miRNA-mediated CDK2AP1 downregulation correlates with patient survival, revealing a key mechanism in oral squamous cell carcinoma progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1), also known as deleted in oral cancer (DOC1), functions as a tumor suppressor involved in cell cycle regulation and epigenetic control.
- CDK2AP1 is a core component of the nucleosome remodeling and histone deacetylation (NuRD) complex, crucial for embryonic stem cell differentiation.
- Reduced or lost CDK2AP1 protein expression is prevalent in oral squamous cell carcinomas (OSCC), despite rare mutations in its coding sequence.
Purpose of the Study:
- To investigate the mechanisms underlying CDK2AP1 protein loss in OSCC.
- To identify specific microRNAs (miRNAs) that regulate CDK2AP1 translation.
- To assess the clinical relevance of miRNA-mediated CDK2AP1 downregulation in oral cancer survival.
Main Methods:
- In silico and in vitro analyses combined with patient-derived data.
- Identification of inhibitory miRNAs targeting CDK2AP1 mRNA using computational and experimental approaches.
- Development of a combined in situ hybridization/immunofluorescence (ISH/IF) tissue microarray technique to analyze miRNA and target gene expression within tumor architecture.
Main Results:
- A set of five specific miRNAs (miR-21-5p, miR-23b-3p, miR-26b-5p, miR-93-5p, and miR-155-5p) were identified as inhibitors of CDK2AP1 translation.
- These miRNAs were found to suppress CDK2AP1 expression in both OSCC cell lines and patient-derived tumors.
- No synergistic effects were observed among the identified miRNAs on the CDK2AP1 3'-untranslated region (3'-UTR).
Conclusions:
- MicroRNA-mediated translational repression is a primary mechanism for CDK2AP1 loss in OSCC.
- The identified miRNAs represent potential therapeutic targets for restoring CDK2AP1 function in oral cancer.
- CDK2AP1 loss due to miRNA expression is clinically relevant, correlating with overall survival in oral cancer patients.
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