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Multi-scale transcriptomic integration reveals LINC00152-high tumor cells promote TGCT progression and T cell
Jian Cao1, Fang Zhu2, Kongrong Xu3
1Department of Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China.
Background:
Testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men, yet effective biomarkers and therapeutic targets remain limited. The role of lncRNAs in TGCT remains poorly understood at single-cell resolution.
Methods:
We integrated single-nucleus RNA-seq, spatial transcriptomics, and bulk RNA-seq on TGCT samples. LINC00152 function was assessed by siRNA knockdown, functional assays, CHIRP-MS, RIP-PCR, and xenograft models. T cell exhaustion was assessed by co-culture experiments and recombinant protein rescue assays.
Results:
LINC00152 was identified as a significantly upregulated lncRNA in TGCT, particularly in non-seminomas, and its high expression correlated with advanced tumour stage, lymph node metastasis, and poor prognosis. A LINC00152-high tumour subpopulation showed enhanced proliferation, migration, invasion, and antioxidant capacity. Mechanistically, LINC00152 directly bound to YBX1, inhibiting its proteasomal degradation and thereby activating AKT signaling. Silencing LINC00152 suppressed malignancy in vitro and in vivo. LINC00152-high tumour cells highly expressed HLA molecules and upregulated HAVCR2, promoting T cell exhaustion with reduced IFNG/GZMK expression, rescued by recombinant HAVCR2.
Conclusions:
LINC00152 serves as a promising prognostic biomarker and therapeutic target in TGCT. It promotes tumour malignancy via YBX1/AKT signaling and drives immune evasion by inducing HAVCR2-mediated T cell exhaustion, providing new insights for combination immunotherapy in TGCT.
Insights
Long non-coding RNA LINC00152 promotes testicular germ cell tumor (TGCT) malignancy and immune evasion. Targeting LINC00152 offers a promising therapeutic strategy for TGCT patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Testicular germ cell tumors (TGCTs) are common male cancers with limited biomarkers.
- The role of long non-coding RNAs (lncRNAs) in TGCT is not well understood at the single-cell level.
Purpose of the Study:
- Investigate the role of lncRNAs in TGCT pathogenesis.
- Identify potential biomarkers and therapeutic targets for TGCT.
Main Methods:
- Integrated single-nucleus RNA-seq, spatial transcriptomics, and bulk RNA-seq.
- Assessed LINC00152 function using siRNA knockdown, functional assays, CHIRP-MS, RIP-PCR, and xenograft models.
- Evaluated T cell exhaustion via co-culture and recombinant protein rescue assays.
Main Results:
- LINC00152 was significantly upregulated in TGCT, correlating with advanced stage, metastasis, and poor prognosis.
- LINC00152 promoted tumor proliferation, migration, invasion, and antioxidant capacity by stabilizing YBX1 and activating AKT signaling.
- LINC00152 induced T cell exhaustion via HAVCR2, reducing anti-tumor immunity.
Conclusions:
- LINC00152 is a potential prognostic biomarker and therapeutic target for TGCT.
- LINC00152 drives TGCT malignancy and immune evasion through YBX1/AKT and HAVCR2 pathways.
- Findings offer insights for combination immunotherapy in TGCT.
