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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Utilization of artificial circular RNAs as miRNA sponges and anti-PD-1 scFv expression platforms to suppress
Yongping Lai1,2, Fei Wang3,4, Guang Cai3,4
1Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Background:
Hepatocellular carcinoma (HCC) is characterized by a complex interplay of genetic and epigenetic alterations that contribute to its aggressive nature and resistance to conventional therapies. The recent advent of immune checkpoint inhibitors has shown promise in enhancing the immune system's ability to target cancer cells. However, the efficacy of these therapies is often hindered by the tumor's immunosuppressive microenvironment. Circular RNAs (circRNAs), a class of non-coding RNAs, have emerged as promising candidates for the development of novel therapeutics due to their unique properties, including resistance to degradation and the ability to act as miRNA sponges.
Methods:
In this study, we engineered artificial circRNAs to target oncogenic miRNAs and to express anti-PD-1 scFv antibodies, aiming to simultaneously disrupt oncogenic pathways and enhance the immune response against HCC.
Results:
Our results demonstrate that the engineered circRNAs effectively sponge miR-25, leading to subsequent inhibition of HCC cell proliferation and angiogenesis. Moreover, the expression of anti-PD-1 scFv antibodies from the circRNAs significantly enhanced the cytotoxic T-cell response against HCC cells. In vivo studies revealed a significant reduction in tumor volume and prolonged survival in mice treated with the engineered circRNAs compared to controls.
Conclusions:
Our findings highlight the potential of artificial circRNAs as a novel therapeutic strategy for HCC. By harnessing their ability to act as miRNA sponges and to express immunomodulatory proteins, these engineered circRNAs offer a promising approach to overcome the challenges associated with HCC therapy.
Insights
Engineered circular RNAs (circRNAs) target cancer-promoting miRNAs and enhance immune response against hepatocellular carcinoma (HCC). This novel therapeutic strategy shows significant tumor reduction and improved survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Hepatocellular carcinoma (HCC) exhibits aggressive behavior and resistance to therapies due to complex genetic alterations.
- Immune checkpoint inhibitors show promise but are limited by the tumor's immunosuppressive microenvironment.
- Circular RNAs (circRNAs) are non-coding RNAs resistant to degradation and capable of acting as miRNA sponges, offering therapeutic potential.
Purpose of the Study:
- To engineer artificial circRNAs for simultaneous targeting of oncogenic miRNAs and expression of anti-PD-1 scFv antibodies in HCC.
- To evaluate the therapeutic efficacy of these engineered circRNAs in disrupting oncogenic pathways and enhancing anti-tumor immunity.
Main Methods:
- Artificial circRNAs were engineered to sponge oncogenic miR-25 and express anti-PD-1 scFv antibodies.
- In vitro assays assessed the impact on HCC cell proliferation, angiogenesis, and T-cell responses.
- In vivo studies evaluated tumor volume reduction and survival rates in a mouse model.
Main Results:
- Engineered circRNAs effectively sponged miR-25, inhibiting HCC cell proliferation and angiogenesis.
- Expression of anti-PD-1 scFv antibodies from circRNAs significantly boosted cytotoxic T-cell responses against HCC cells.
- In vivo treatment with engineered circRNAs led to significant tumor volume reduction and prolonged survival.
Conclusions:
- Artificial circRNAs represent a promising novel therapeutic strategy for hepatocellular carcinoma.
- Engineered circRNAs can overcome therapeutic challenges by acting as miRNA sponges and expressing immunomodulatory proteins.
- This approach offers a dual mechanism for combating HCC by targeting oncogenic pathways and enhancing anti-tumor immunity.
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