Long noncoding RNA LINC01132 enhances immunosuppression and therapy resistance via NRF1/DPP4 axis in hepatocellular carcinoma

Author:

Zhang Jiwei,Pan Tao,Zhou Weiwei,Zhang Ya,Xu Gang,Xu Qi,Li Si,Gao Yueying,Wang Zhengtao,Xu Juan,Li Yongsheng

Abstract

Abstract 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.

Funder

Hainan Province Science and Technology Special Fund

Hainan Provincial Natural Science Foundation of China

National Natural Science Foundation of China

Shanghai Pujiang talent program

Major Science and Technology Program of Hainan Province

HMU MarshalI Initiative Funding

Marshal Initiative Funding of Hainan Medical University

Hainan Province Clinical Medical Center

National Key R&D Program of China

Natural Science Foundation for Distinguished Young Scholars of Heilongjiang Province

Heilongjiang Touyan Innovation Team Program

Hainan Provincial Key Laboratory of Carcinogenesis and Intervention

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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