Sialylation-immune-related lncRNA LINC01605 promotes tumor-infiltrating CD8+ T cell exhaustion and malignancy of clear cell renal cell carcinoma.
Dysregulated expression of long non-coding RNAs (lncRNAs) has been shown to play a critical role in the tumorigenicity of clear cell renal cell carcinoma (ccRCC). Meanwhile, sialylation plays a pivotal role in cancer progression and in modulating the tumor immune microenvironment. However, how sialylation-immune-related lncRNAs (SIRLs) influence tumor immune microenvironment and progression of ccRCC remains unclear.
Using comprehensive cancer datasets, we identified key lncRNAs linked to both sialylation and immune modulation, constructing a prognostic risk model centered on the hub gene LINC01605.
Patients classified as high-risk showed significantly poor survival outcomes and poor response to anti-PD-1 immunotherapy compared to low-risk individuals. Functional studies established LINC01605's role in enhancing tumor aggressiveness and CD8+ T cell exhaustion. Knockdown of LINC01605 reduces total sialic acid levels in ccRCC cell membranes. Mechanistically, LINC01605 recruits IGF2BP2 to increase the stability of JAK3 mRNA. Elevated JAK3 expression activates JAK3/STAT3 signaling, and phosphorylated STAT3 subsequently upregulates oncogenes (e.g., MYC) as well as sialyltransferase ST6GALNAC5-which directly increases cell membrane sialylation, a known driver of immune evasion.
Our findings reveal the role of sialylation-immune-related lncRNAs in the immunosuppressive tumor microenvironment and cancer progression in ccRCC, providing a new framework for predicting patient outcomes and therapeutic responses.
Using comprehensive cancer datasets, we identified key lncRNAs linked to both sialylation and immune modulation, constructing a prognostic risk model centered on the hub gene LINC01605.
Patients classified as high-risk showed significantly poor survival outcomes and poor response to anti-PD-1 immunotherapy compared to low-risk individuals. Functional studies established LINC01605's role in enhancing tumor aggressiveness and CD8+ T cell exhaustion. Knockdown of LINC01605 reduces total sialic acid levels in ccRCC cell membranes. Mechanistically, LINC01605 recruits IGF2BP2 to increase the stability of JAK3 mRNA. Elevated JAK3 expression activates JAK3/STAT3 signaling, and phosphorylated STAT3 subsequently upregulates oncogenes (e.g., MYC) as well as sialyltransferase ST6GALNAC5-which directly increases cell membrane sialylation, a known driver of immune evasion.
Our findings reveal the role of sialylation-immune-related lncRNAs in the immunosuppressive tumor microenvironment and cancer progression in ccRCC, providing a new framework for predicting patient outcomes and therapeutic responses.
Authors
Dai Dai, Zhou Zhou, Feng Feng, Zhang Zhang, Ai Ai, Huang Huang, Cen Cen, Liang Liang, Wei Wei, Chen Chen, Luo Luo, Chen Chen
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