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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.
