LRPPRC facilitates tumor progression and immune evasion through upregulation of m6A modification of PD-L1 mRNA in hepatocellular carcinoma

Abstract

ObjectiveLRPPRC is a newly discovered N6-methyladenosine (m6A) modification reader, which potentially affects hepatocellular carcinoma (HCC) progression. PD-L1 in tumor cells is essential for tumor immune evasion. This work investigated the LRPPRC-mediated m6A-modification effect on PD-L1 mRNA and immune escape in HCC.MethodsExpression and clinical implication of LRPPRC and PD-L1 were measured in human HCC cohorts. The influence of LRPPRC on malignant behaviors of HCC cells was investigated through in vitro assays and xenograft tumor murine models. The posttranscriptional mechanism of LRPPRC on PD-L1 and anti-tumor immunity was elucidated in HCC cells via RIP, MeRIP−qPCR, RNA stability, immunohistochemical staining, and so forth.ResultsLRPPRC exhibited the notable upregulated in human HCC tissues, which was in relation to advanced stage and worse overall survival and disease-free survival. Impaired proliferative capacity and G2/M phage arrest were found in LRPPRC-knockout cells, with increased apoptotic level, and attenuated migratory and invasive abilities. In HCC patients and murine models, LRPPRC presented a positive interaction with PD-L1, with negative associations with CD8+, and CD4+ T-cell infiltrations and chemokines CXCL9, and CXCL10. LRPPRC loss downregulated the expression of PD-L1 and its m6A level in HCC cells. Moreover, LRPPRC suppression mitigated tumor growth in murine models and improved anti-tumor immunity and immune infiltration in tumors.ConclusionThis work unveiled that LRPPRC may posttranscriptionally upregulate PD-L1 partially with an m6A-dependent manner for heightening mRNA stabilization of PD-L1 and provided a new mechanism for m6A regulator-mediated immunosuppression in HCC.

A Disulfidptosis-Related Gene Signature Associated with Prognosis and Immune Cell Infiltration in Osteosarcoma

“…Notably, this inhibition appears to post-transcriptionally amplify PD-L1, perhaps through an m6A-dependent process, thus enhancing the mRNA stability of PD-L1. Such findings illuminate a fresh avenue by which m6A regulators might facilitate immunosuppression in hepatocellular carcinoma [48]. Further delving into its molecular pathways, LRPPRC supports both Yap-P27-driven cell polyploidy and P62-HDAC6-guided autophagy maturation.…”

LRPPRC promotes glycolysis by stabilising LDHA mRNA and its knockdown plus glutamine inhibitor induces synthetic lethality via m6A modification in triple‐negative breast cancer

“… 31 , 32 Recent studies have shown that LRPPRC upregulates Programmed Death Ligand 1 (PD‐L1) expression by increasing the stability of PD‐L1 mRNA in an m 6 A‐dependent manner. 33 In this regard, LRPPRC acts as a cytoplasmic m 6 A reader protein that also promotes the stability of LDHA and WDR76 mRNA in an m 6 A‐dependent manner. We further examined LDHA and identified the LRPPRC–m 6 A–LDHA axis as a critical molecular signalling pathway involved in LRPPRC‐mediated tumourigenesis and metastasis of TNBC.…”

Novel Disulfidptosis-associated Genetic Signatures to Predict Prognosis in Patients with Hepatocellular Carcinoma

“…However, its impact on HCC remains unexplored. LRPPRC, involved in mitochondrial oxidative phosphorylation, exhibits signi cant upregulation in HCC tissues and is associated with advanced stages and poor overall and disease-free survival [14,15]. Inactivation of LRPPRC with GYS1 acts in concert with glucose starvation to induce disul dptosis [5].…”