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An In Vitro Protocol for Evaluating MicroRNA Levels, Functions, and Associated Target Genes in Tumor Cells
Published on: May 21, 2019
mRNA export protein THOC5 as a tool for identification of target genes for cancer therapy
Doan Duy Hai Tran1, Shashank Saran1, Alexandra Koch1
1Institut fuer Biochemie, OE4310, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30623 Hannover, Germany.
Abstract:
Recent evidence indicates that mRNA export is selective, giving priority to a subset of mRNAs that control diverse biological processes including cell proliferation, differentiation, stress response, and cell survival as well as tumor development. The depletion of a member of the mRNA export complex, the THO complex, impairs the expression of only a subset of genes, but causes dramatic changes in phenotype, such as cell cycle inhibition, abnormal differentiation, and importantly apoptosis of stem cells and cancer cells but not normal epithelial cells, hepatocytes, or fibroblasts. Recent exosome sequence data revealed that over 100 driver gene mutations with a number of signaling pathways are involved in human cancer formation, indicating that multiple signaling pathways will need to be inhibited for cancer therapy. In this review we firstly describe a basic feature and function of the mRNA export complex, THO, secondly, the biological alteration upon depletion of a member of the THO complex in normal and cancer cells, and thirdly, identification of its target genes. Finally we describe our recent data on selection of targeting candidates from THOC5 dependent genes for application in cancer therapy.
Insights
The THO complex selectively exports mRNAs crucial for cell functions. Its depletion triggers apoptosis in cancer cells, offering a potential therapeutic target for cancer treatment.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- mRNA export is a selective process, prioritizing specific mRNAs involved in vital cellular functions like proliferation, differentiation, stress response, and survival.
- The THO (TRNA-homologous) complex, a key component of the mRNA export machinery, regulates the expression of a subset of genes.
- Depletion of THO complex components leads to significant phenotypic changes, including cell cycle arrest, aberrant differentiation, and apoptosis, particularly in stem and cancer cells, while sparing normal cells.
Purpose of the Study:
- To review the fundamental features and functions of the THO mRNA export complex.
- To elucidate the biological consequences of THO complex member depletion in both normal and cancerous cells.
- To identify target genes regulated by the THO complex and explore their therapeutic potential in cancer.
Main Methods:
- Literature review of mRNA export mechanisms and the THO complex.
- Analysis of phenotypic alterations in cells with depleted THO complex components.
- Identification and validation of THO complex target genes, including THOC5.
- Evaluation of THOC5-dependent genes for potential cancer therapeutic applications.
Main Results:
- The THO complex plays a critical role in the selective export of mRNAs essential for diverse biological processes.
- THO complex depletion induces apoptosis in cancer cells and stem cells, but not in normal somatic cells.
- Identification of specific genes, including THOC5, as key targets of the THO complex.
- Preliminary data suggests THOC5-dependent genes are promising candidates for targeted cancer therapy.
Conclusions:
- The THO complex is a crucial regulator of gene expression with significant implications in cancer biology.
- Targeting THO complex-dependent pathways, particularly THOC5, presents a viable strategy for developing novel cancer therapies.
- Selective induction of apoptosis in cancer cells via THO complex modulation offers a promising therapeutic avenue.
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