Autophagy-related gene LAPTM4B promotes the progression of renal clear cell carcinoma and is associated with immunity

Abstract

Renal cell carcinoma (RCC) is a common urologic disease. Currently, surgery is the primary treatment for renal cancer; immunotherapy is not as effective a treatment strategy as expected. Hence, understanding the mechanism in the tumor immune microenvironment (TME) and exploring novel immunotherapeutic targets are considered important. Recent studies have demonstrated that autophagy could affect the immune environment of renal cell carcinoma and induce proliferation and apoptosis of cancer cells. By comparing lysosomal genes and regulating autophagy genes, we identified the LAPTM4B gene to be related to RCC autophagy. By analyzing the TCGA-KIRC cohort using bioinformatics, we found M2 macrophages associated with tumor metastasis to be significantly increased in the immune microenvironment of patients with high expression of LAPTM4B. GO/KEGG/GSEA/GSVA results showed significant differences in tumor autophagy- and metastasis-related pathways. Single-cell sequencing was used to compare the expression of LAPTM4B in different cell types and obtain the differences in lysosomal and autophagy pathway activities in different ccRCC cells. Subsequently, we confirmed the differential expression of LAPTM4B in renal cell carcinoma of different Fuhrman grades using western blotting. Downregulation of LAPTM4B expression significantly reduced the proliferation of renal cell carcinoma cells and promoted cell apoptosis through cell experiments. Overall, our study demonstrated that the autophagy-related gene LAPTM4B plays a critical role in the TME of RCC, and suggested that LAPTM4B is a potential therapeutic target for RCC immunotherapy.

Blockade of V‐domain immunoglobulin suppressor of T‐cell activation reprograms tumour‐associated macrophages and improves efficacy of PD‐1 inhibitor in gastric cancer

“…Furthermore, we found α‐VISTA‐treated TAMs showed decreased expression of TAP2 , LAPTM4B , CXCL12 , LTC4S and NRROS , yet increased expression of FCN1 , GFAP , CCL19 and CLEC6A , indicating a proinflammatory phenotype after blockade of VISTA (Figure 5B,C ). 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 Blockade of VISTA activated the genes associated with immune responses (Figure 5D ), especially the genes modulating proinflammatory phenotype of macrophages and CD8 + T‐cell activation (Figure 5E ). By means of FC/ICFC, we also validated that blockade of VISTA significantly up‐regulated the expression of TNF‐α and IL‐12, yet down‐regulated the expression of Arg‐1 and LAP/TGF‐β within TAMs (Figures 5F and S10 ).…”

Prognostic Risk Models Using Epithelial Cells Identify β-Sitosterol as a Potential Therapeutic Target Against Esophageal Squamous Cell Carcinoma

“… 35 In renal cell carcinoma, downregulation of LAPTM4B expression significantly reduces proliferation and promotes apoptosis. 36 Moreover, LAPTM4B regulates the RPS9/STAT3 axis to promote acute myeloid leukemia progression. 37 LAPTM4B is therefore essential for tumor cell proliferation, survival, invasion, metastasis, and immune escape.…”

Genes associated with inflammation for prognosis prediction for clear cell renal cell carcinoma: a multi-database analysis

“…The expression level of FCER1G combined with the expression of CD68 is expected to be the prognostic index of patients with ccRCC after surgery ( 18 ). LAPTM4B and TRAF2 can promote the polarisation of M2 macrophages through autophagy-dependent pathways, which in turn affects the prognosis of ccRCC patients ( 19 , 20 ). CCL5 can block epithelial-mesenchymal transformation in ccRCC cells via the PI3K/AKT pathway.…”