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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
MicroRNA miR-20a-5p targets CYCS to inhibit apoptosis in hepatocellular carcinoma
Olaniyi Olarewaju1,2, Yuhai Hu1,3, Hsin-Chieh Tsay1
1Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany.
Abstract:
Hepatocellular carcinoma is a primary liver cancer, characterised by diverse etiology, late diagnoses, and poor prognosis. Hepatocellular carcinoma is mostly resistant to current treatment options, therefore, identification of more effective druggable therapeutic targets is needed. We found microRNA miR-20a-5p is upregulated during mouse liver tumor progression and in human hepatocellular carcinoma patients. In this study, we elucidated the therapeutic potential of targeting oncogenic miR-20a-5p, in vivo, in a xenograft model and in two transgenic hepatocellular carcinoma mouse models via adeno-associated virus-mediated miR-20a-Tough-Decoy treatment. In vivo knockdown of miR-20a-5p attenuates tumor burden and prolongs survival in the two independent hepatocellular carcinoma mouse models. We identified and validated cytochrome c as a novel target of miR-20a-5p. Cytochrome c plays a key role in initiation of the apoptotic cascade and in the electron transport chain. We show for the first time, that miR-20a modulation affects both these key functions of cytochrome c during HCC development. Our study thus demonstrates the promising 'two birds with one stone' approach of therapeutic in vivo targeting of an oncogenic miRNA, whereby more than one key deregulated cellular process is affected, and unequivocally leads to more effective attenuation of HCC progression and significantly longer overall survival.
Insights
Targeting microRNA miR-20a-5p effectively treats hepatocellular carcinoma (HCC) by impacting cytochrome c. This approach reduces tumor burden and improves survival in mouse models, offering a promising new therapeutic strategy for liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Hepatocellular carcinoma (HCC) presents diverse etiologies, late diagnoses, and poor prognoses.
- Current HCC treatments are often ineffective due to tumor resistance, necessitating novel therapeutic targets.
- MicroRNA miR-20a-5p is upregulated in liver tumor progression and human HCC, suggesting its oncogenic role.
Purpose of the Study:
- To investigate the therapeutic potential of targeting oncogenic miR-20a-5p in vivo for hepatocellular carcinoma.
- To identify and validate novel molecular targets of miR-20a-5p in the context of HCC.
Main Methods:
- Adeno-associated virus-mediated miR-20a-5p knockdown using Tough-Decoy constructs in xenograft and transgenic HCC mouse models.
- Validation of cytochrome c as a direct target of miR-20a-5p.
- Assessment of miR-20a-5p's impact on cytochrome c's roles in apoptosis and the electron transport chain.
Main Results:
- In vivo knockdown of miR-20a-5p significantly attenuated tumor burden in two independent HCC mouse models.
- Targeting miR-20a-5p prolonged overall survival in the studied hepatocellular carcinoma models.
- Cytochrome c was identified and validated as a novel target, with miR-20a-5p modulation affecting its apoptotic and electron transport functions.
Conclusions:
- Therapeutic targeting of oncogenic miR-20a-5p offers a "two birds with one stone" strategy for HCC.
- Simultaneously affecting multiple deregulated cellular processes via miR-20a-5p inhibition leads to effective HCC progression attenuation.
- This approach demonstrates significant potential for improving overall survival in hepatocellular carcinoma patients.
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