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Long noncoding RNA LINC01132 enhances immunosuppression and therapy resistance via NRF1/DPP4 axis in hepatocellular
Jiwei Zhang1, Tao Pan2, Weiwei Zhou3
1Shanghai Key Laboratory of Compound Chinese Medicines, The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Background:
Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in various types of cancer. Current developments in transcriptome analyses unveiled the existence of lncRNAs; however, their functional characterization remains a challenge.
Methods:
A bioinformatics screen was performed by integration of multiple omics data in hepatocellular carcinoma (HCC) prioritizing a novel oncogenic lncRNA, LINC01132. Expression of LINC01132 in HCC and control tissues was validated by qRT-PCR. Cell viability and migration activity was examined by MTT and transwell assays. Finally, our results were confirmed in vivo mouse model and ex vivo patient derived tumor xenograft experiments to determine the mechanism of action and explore LINC01132-targeted immunotherapy.
Results:
Systematic investigation of lncRNAs genome-wide expression patterns revealed LINC01132 as an oncogene in HCC. LINC01132 is significantly overexpressed in tumor and associated with poor overall survival of HCC patients, which is mainly driven by copy number amplification. Functionally, LINC01132 overexpression promoted cell growth, proliferation, invasion and metastasis in vitro and in vivo. Mechanistically, LINC01132 acts as an oncogenic driver by physically interacting with NRF and enhancing the expression of DPP4. Notably, LINC01132 silencing triggers CD8+ T cells infiltration, and LINC01132 knockdown combined with anti-PDL1 treatment improves antitumor immunity, which may prove a new combination therapy in HCC.
Conclusions:
LINC01132 functions as an oncogenic driver that induces HCC development via the NRF1/DPP4 axis. Silencing LINC01132 may enhance the efficacy of anti-PDL1 immunotherapy in HCC patients.
Insights
This study identifies LINC01132 as a novel oncogene in hepatocellular carcinoma (HCC). Silencing this long noncoding RNA (lncRNA) shows potential for enhancing anti-PDL1 immunotherapy in HCC patients.
Area of Science:
- Molecular Biology
- Cancer Research
- Genomics
Background:
- Long noncoding RNAs (lncRNAs) are critical gene expression regulators in cancer.
- Functional characterization of lncRNAs remains a significant challenge in cancer research.
Purpose of the Study:
- To identify and characterize novel oncogenic lncRNAs in hepatocellular carcinoma (HCC).
- To investigate the mechanistic role of LINC01132 in HCC development and progression.
- To explore the potential of LINC01132 as a therapeutic target for HCC immunotherapy.
Main Methods:
- Bioinformatics screening integrating multi-omics data for HCC.
- Validation of LINC01132 expression using qRT-PCR.
- In vitro assays (MTT, transwell) and in vivo mouse models for functional analysis.
- Investigation of LINC01132's mechanism of action and its interaction with NRF1 and DPP4.
- Assessment of LINC01132 knockdown effects on CD8+ T cell infiltration and combination therapy with anti-PDL1.
Main Results:
- LINC01132 is significantly overexpressed in HCC and associated with poor patient survival, driven by copy number amplification.
- Overexpression of LINC01132 promotes HCC cell growth, proliferation, invasion, and metastasis in vitro and in vivo.
- LINC01132 physically interacts with NRF1, enhancing DPP4 expression, thereby driving HCC.
- LINC01132 silencing increases CD8+ T cell infiltration and enhances antitumor immunity when combined with anti-PDL1 therapy.
Conclusions:
- LINC01132 acts as an oncogenic driver in HCC development through the NRF1/DPP4 axis.
- Targeting LINC01132 by silencing could improve the efficacy of anti-PDL1 immunotherapy in HCC patients.
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