SHMT2 regulates serine metabolism to promote the progression and immunosuppression of papillary renal cell carcinoma

Abstract

Recent research has demonstrated the diverse relationship between tumour metabolism and the tumour microenvironment (TME), for example, abnormal serine metabolism. This study investigated the role of serine metabolism in papillary renal cell carcinoma (pRCC) focusing on the prognostic value and regulatory mechanisms. Gene expression profiles and clinical data of patients with pRCC were obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Kaplan–Meier curves were used for survival analysis and consensus clustering for tumour serine metabolic signatures extraction. Functional analysis, including the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA), was applied to explore the biological characteristics. The gene set variation analysis (GSVA), single-sample GSEA (ssGSEA), and Estimation of Stromal and Immune cells in Malignant Tumour tissues using Expression data (ESTIMATE) methods were utilised to estimate the immune infiltration in the various subtypes. Five serine metabolic genes (SMGs) were used to classify patients with pRCC, with four clusters identified with diverse prognoses and immune features based on these survival-related SMGs. Further analysis of the best and worst clusters (B and D clusters) revealed variations in survival, clinical progression, oncogenic pathways, and TME, which included immune infiltration scores, immunosuppressive cell infiltration, and expression of immune checkpoints. In addition, SMGs, especially SHMT2, exacerbated the carcinogenesis and immunosuppressive cells in pRCC, thus promoting tumour proliferation. In conclusion, higher SHMT2 gene expression and higher serine metabolism in tumour cells are associated with poorer clinical outcomes in pRCC. SHMT2 is a potential novel target gene for targeted therapy and immunotherapy in pRCC.

Immunogenic Cell Death Associated Molecular Patterns and the Dual Role of IL17RA in Interstitial Cystitis/Bladder Pain Syndrome

“…Therefore, the lower expression of HSP90AA1 still indicated the more activated immune status in cluster A. HSP90AA1 belongs to the family of heat shock proteins (HSPs), which play crucial roles in innate and adaptive immunity and are closely linked to the pathophysiology of numerous immune-mediated illnesses [ 35 ]. It has been discovered that HSP90AA1 expression was elevated in the peripheral blood mononuclear cells of a number of autoimmune diseases, including ankylosing spondylitis, systemic lupus erythematosus, and fibromyalgia syndrome [ 36 , 37 , 38 , 39 , 40 ], which was seemingly inconsistent with our results that HSP90AA1 was downregulated in IC/BPS. However, mounting proof indicated that various factors could influence the regulatory effect of HSPs, such as the physio-pathological environment, the concentration of HSPs, and action time, among other factors [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

“…It has been discovered that HSP90AA1 expression was elevated in the peripheral blood mononuclear cells of a number of autoimmune diseases, including ankylosing spondylitis, systemic lupus erythematosus, and fibromyalgia syndrome [ 36 , 37 , 38 , 39 , 40 ], which was seemingly inconsistent with our results that HSP90AA1 was downregulated in IC/BPS. However, mounting proof indicated that various factors could influence the regulatory effect of HSPs, such as the physio-pathological environment, the concentration of HSPs, and action time, among other factors [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. In addition, the tissue difference may also account for this discrepancy.…”

Targeting one‐carbon metabolism for cancer immunotherapy

“…In addition, the expression of SHMT2 was negatively related to tumour‐infiltrating lymphocytes, including CD4 + T cells, CD56 natural killer cells, Th17 cells and immature B cells, in lung adenocarcinoma (LUAD) 37 . Moreover, SHMT2 levels were positively associated with the infiltration of myeloid‐derived suppressor cells and Treg cells, which resulted in accelerated immune escape in papillary renal cell carcinoma 38 . Therefore, SHMT was connected to cancer immunotherapy by influencing the TME.…”

Serine deficiency exacerbates psoriatic skin inflammation by regulating S‐adenosyl methionine‐dependent DNA methylation and NF‐κB signalling activation in keratinocytes

“…Serine metabolism plays an important role in tumour immune evasion by promoting M2 macrophage polarisation 16–19 . Serine metabolism inhibits antiviral innate immunity by preventing interferon‐β production 20,21 .…”

“…15 Serine metabolism plays an important role in tumour immune evasion by promoting M2 macrophage polarisation. [16][17][18][19] Serine metabolism inhibits antiviral innate immunity by preventing interferon-β production. 20,21 Serine significantly decreases macrophage-and neutrophil-mediated inflammatory responses during extracellular infection.…”