Long Noncoding RNA TUG1 Inhibits Tumor Progression through Regulating Siglec-15-Related Anti-Immune Activity in Hepatocellular Carcinoma
Related Experiment Video
Updated: Oct 1, 2025
Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Yanyi Ren1, Jiayi Lyu2, Yaoguang Guo3
1Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Background:
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, and its biology remains poorly understood, especially in regards to the immunosuppression induced by immune checkpoints, such as Siglec-15. Most cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs display a better therapeutic effect in the clinic, including tumor progression inhibition and immunosuppression breaks. However, two or more drugs will result in a greater possibility of adverse effects. Thus, a double-function target is necessary for developing antitumor drugs, such as RNAi therapy.
Methods:
The expression of TUG1, Siglec-15, and miRNAs was evaluated by qPCR, and protein expression was analyzed by western blotting. The immune responses were evaluated by a Jurkat-reporter gene assay, a T cell-induced cytotoxicity assay, and IFN-γ/IL-2 release. The interactions among TUG1, Siglec-15, and miRNAs were verified by dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. CCK-8 and Transwell assays were used to determine tumor cell proliferation, migration, and invasion.
Results:
In HCC patients and cells, increased TUG1 levels were observed, positively regulating Siglec-15 expression. TUG1-induced Siglec-15 upregulation resulted in the suppression of the immune response of HCC cells. hsa-miR-582-5p directly targeted TUG1 and Siglec-15 mRNA, and ihsa-miR-582-5p knockout prevented the regulation of Siglec-15 induced by THU1. Changes in hsa-miR-582-5p expression negatively regulated Siglec-15 levels and immunosuppression but had no influence on TUG1 levels. siRNA knockdown of TUG1 effectively led to tumor progression inhibition and immune response improvement in HCC cells both in vitro and in vivo.
Conclusion:
TUG1 increases the Siglec-15 level in HCC cells as a sponge to hsa-miR-582-5p, resulting in enhanced immunosuppression. TUG1 knockdown induced by siRNA not only reduces immunosuppression but also suppresses tumor progression both in vitro and in vivo. These novel findings may provide a potential and appropriate target for RNAi therapy to develop drugs with dual antitumor activity.
Insights
TUG1 enhances immunosuppression in hepatocellular carcinoma (HCC) by increasing Siglec-15. Knocking down TUG1 with siRNA inhibits tumor progression and improves immune response, offering a dual-action target for RNAi therapy in HCC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer death with poorly understood immunosuppression mechanisms.
- Immune checkpoints like Siglec-15 play a role in HCC's immunosuppressive microenvironment.
- Current combination therapies for HCC increase adverse effects, necessitating dual-function therapeutic targets.
Purpose of the Study:
- To investigate the role of TUG1 in regulating Siglec-15 expression and immune suppression in HCC.
- To explore the potential of targeting TUG1 for dual antitumor activity via RNAi therapy.
Main Methods:
- Quantitative PCR (qPCR) and Western blotting to assess TUG1, Siglec-15, and miRNA expression.
- Immune response assays including Jurkat-reporter gene and T cell cytotoxicity assays.
- Dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays to confirm molecular interactions.
- Cell proliferation, migration, and invasion assays (CCK-8, Transwell).
Main Results:
- TUG1 expression is elevated in HCC, positively correlating with Siglec-15 levels and suppressing immune responses.
- hsa-miR-582-5p directly targets both TUG1 and Siglec-15 mRNA.
- siRNA-mediated knockdown of TUG1 effectively inhibited tumor progression and enhanced immune responses in HCC cells in vitro and in vivo.
Conclusions:
- TUG1 acts as a sponge for hsa-miR-582-5p, upregulating Siglec-15 and promoting immunosuppression in HCC.
- TUG1 knockdown demonstrates dual antitumor activity by reducing immunosuppression and inhibiting tumor progression.
- Targeting TUG1 with RNAi therapy presents a promising strategy for developing novel drugs against HCC.
Related Concept Videos
02:39lncRNA - Long Non-coding RNAs
02:15Experimental RNAi
02:30siRNA - Small Interfering RNAs
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22MicroRNAs
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...