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Updated: Aug 12, 2025
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Integrated analysis of transcription factor-mRNA-miRNA regulatory network related to immune characteristics in
Danfeng Weng1, Long He2, Xiangna Chen1
1Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Background:
Medullary thyroid carcinoma (MTC), a thyroid C cell-derived malignancy, is poorly differentiated and more aggressive than papillary, follicular and oncocytic types of thyroid cancer. The current therapeutic options are limited, with a third of population suffering resistance. The differential gene expression pattern among thyroid cancer subtypes remains unclear. This study intended to explore the exclusive gene profile of MTC and construct a comprehensive regulatory network via integrated analysis, to uncover the potential key biomarkers.
Methods:
Multiple datasets of thyroid and other neuroendocrine tumors were obtained from GEO and TCGA databases. Differentially expressed genes (DEGs) specific in MTC were identified to construct a transcription factor (TF)-mRNA-miRNA network. The impact of the TF-mRNA-miRNA network on tumor immune characteristics and patient survival was further explored by single-sample GSEA (ssGSEA) and ESTIMATE algorithms, as well as univariate combined with multivariate analyses. RT-qPCR, cell viability and apoptosis assays were performed for in vitro validation.
Results:
We identified 81 genes upregulated and 22 downregulated in MTC but not in other types of thyroid tumor compared to the normal thyroid tissue. According to the L1000CDS2 database, potential targeting drugs were found to reverse the expressions of DEGs, with panobinostat (S1030) validated effective for tumor repression in MTC by in vitro experiments. The 103 DEGs exclusively seen in MTC were involved in signal release, muscle contraction, pathways of neurodegeneration diseases, neurotransmitter activity and related amino acid metabolism, and cAMP pathway. Based on the identified 15 hub genes, a TF-mRNA-miRNA linear network, as well as REST-cored coherent feed-forward loop networks, namely REST-KIF5C-miR-223 and REST-CDK5R2-miR-130a were constructed via online prediction and validation by public datasets and our cohort. Hub-gene, TF and miRNA scores in the TF-mRNA-miRNA network were related to immune score, immune cell infiltration and immunotherapeutic molecules in MTC as well as in neuroendocrine tumor of lung and neuroblastoma. Additionally, a high hub-gene score or a low miRNA score indicated good prognoses of neuroendocrine tumors.
Conclusion:
The present study uncovers underlying molecular mechanisms and potential immunotherapy-related targets for the pathogenesis and drug discovery of MTC.
Insights
This study identifies unique gene expression patterns in medullary thyroid carcinoma (MTC), revealing potential drug targets and biomarkers. These findings offer new avenues for MTC treatment and immunotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Medullary thyroid carcinoma (MTC) is an aggressive thyroid cancer subtype with limited therapeutic options.
- Understanding the distinct gene expression profile of MTC is crucial for developing targeted therapies.
- Current treatments face resistance in a significant portion of MTC patients.
Purpose of the Study:
- To identify the exclusive gene profile of MTC.
- To construct a comprehensive regulatory network for MTC.
- To uncover potential key biomarkers and therapeutic targets for MTC.
Main Methods:
- Analysis of gene expression data from public databases (GEO, TCGA).
- Construction of a transcription factor (TF)-mRNA-miRNA regulatory network.
- In vitro validation using RT-qPCR, cell viability, and apoptosis assays.
Main Results:
- Identified 81 upregulated and 22 downregulated genes specific to MTC.
- Discovered potential drug targets, with panobinostat showing efficacy in MTC repression.
- Constructed TF-mRNA-miRNA networks linked to immune characteristics and patient prognosis.
Conclusions:
- Uncovered molecular mechanisms underlying MTC pathogenesis.
- Identified potential immunotherapy-related targets for MTC drug discovery.
- Highlighted the prognostic significance of gene and miRNA scores in neuroendocrine tumors.
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