Shanghai 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.
Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China.
J Exp Clin Cancer Res. 2022 Sep 8;41(1):270. doi: 10.1186/s13046-022-02478-z.
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.
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.
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.
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.
长链非编码 RNA（lncRNA）作为基因表达的关键调控因子而出现，并在各种类型的癌症中发挥着基本作用。转录组分析的最新进展揭示了 lncRNA 的存在；然而，它们的功能表征仍然是一个挑战。
通过整合肝细胞癌（HCC）中的多种组学数据进行生物信息学筛选，优先考虑一种新型致癌 lncRNA，LINC01132。通过 qRT-PCR 验证 HCC 和对照组织中 LINC01132 的表达。通过 MTT 和 Transwell 测定法检查细胞活力和迁移活性。最后，我们在体内小鼠模型和体外患者来源的肿瘤异种移植实验中证实了我们的结果，以确定作用机制并探索 LINC01132 靶向免疫治疗。
对 lncRNA 全基因组表达模式的系统研究表明，LINC01132 是 HCC 的致癌基因。LINC01132 在肿瘤中显著过表达，并与 HCC 患者的总生存率差相关，这主要是由拷贝数扩增驱动的。功能上，LINC01132 过表达促进了体外和体内细胞的生长、增殖、侵袭和转移。从机制上讲，LINC01132 作为致癌驱动因子，通过与 NRF 相互作用并增强 DPP4 的表达来发挥作用。值得注意的是，沉默 LINC01132 会触发 CD8+T 细胞浸润，LINC01132 敲低结合抗 PD-L1 治疗可提高抗肿瘤免疫，这可能为 HCC 提供一种新的联合治疗方法。
LINC01132 作为一种致癌驱动因子，通过 NRF1/DPP4 轴诱导 HCC 发生。沉默 LINC01132 可能会增强 HCC 患者抗 PD-L1 免疫治疗的疗效。
