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Prognostic significance and tumor-immune infiltration of mTOR in clear cell renal cell carcinoma.

ABSTRACT: Mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in cell proliferation, survival, metabolism and immunity, was reportedly activated in various cancers. However, the clinical role of mTOR in renal cell carcinoma (RCC) is controversial. Here we detected the expression and prognosis of total mTOR and phosphorylated mTOR (p-mTOR) in clear cell RCC (ccRCC) patients, and explored the interactions between mTOR and immune infiltrates in ccRCC. The protein level of mTOR and p-mTOR was determined by western blotting (WB), and their expression was evaluated in 145 ccRCC and 13 non-tumor specimens by immunohistochemistry (IHC). The relationship to immune infiltration of mTOR was further investigated using TIMER and TISIDB databases, respectively. WB demonstrated the ratio of p-mTOR to mTOR was higher in ccRCC than adjacent specimens (n = 3), and IHC analysis elucidated that p-mTOR expression was positively correlated with tumor size, stage and metastasis status, and negatively correlated with cancer-specific survival (CSS). In univariate analysis, high grade, large tumor, advanced stage, metastasis, and high p-mTOR expression were recognized as prognostic factors of poorer CSS, and multivariate survival analysis elucidated that tumor stage, p-mTOR and metastasis were of prognostic value for CSS in ccRCC patients. Further TIMER and TISIDB analyses uncovered that mTOR gene expression was significantly associated with numerous immune cells and immunoinhibitors in patients with ccRCC. Collectively, these findings revealed p-mTOR was identified as an independent predictor of poor survival, and mTOR was associated with tumor immune infiltrates in ccRCC patients, which validated mTOR could be implicated in the initiation and progression of ccRCC.

SUBMITTER: Li N

PROVIDER: S-EPMC8378334 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRenal cell carcinoma (RCC) is a fatal disease, in which the PI3K/AKT/mTOR signaling pathway serves an important role in the tumorigenesis. Previous studies have reported the prognostic significance of PI3K/AKT/mTOR signaling pathway members in RCC; however, there is insufficient evidence to date to confirm this. Thus, the present study aimed to systematically investigate the prognostic roles of multiple PI3K/AKT/mTOR signaling proteins in clear cell RCC (ccRCC) using online large-scale databases.MethodsThe mRNA expression profiles of PI3K/AKT/mTOR signaling pathway proteins PTEN, PIK3CA, PIK3CB, PIK3CD, PIK3CG, AKT1, AKT2, AKT3 and mTOR were investigated using the Gene Expression Profiling Interactive Analysis (GEPIA) and Oncomine databases, and the protein expression levels of PI3K, AKT and mTOR were detected using western blotting (WB) analysis. In addition, the correlation between mRNA or protein expression levels and the prognostic significance was analyzed using the Kaplan-Meier (K-M) plotter (n = 530), the Human Protein Atlas (HPA; n = 528) and The Cancer Protein Atlas (TCPA; n = 445) databases.ResultsThe GEPIA revealed that the mRNA expression of major PI3K/AKT/mTOR pathway members, including PTEN, PIK3CA, PIK3CB, AKT1, AKT2 and AKT3, were negatively correlated with ccRCC stages (P < 0.05), though most of their mRNA and protein expression levels were notsignificantly different between ccRCC and normal tissues using GEPIA, Oncomine and WB analyses (P < 0.05). Meanwhile, using the K-M plotter and HPA prognostic analysis, it was found that the mRNA expression levels of the majority of the PI3K/AKT/mTOR signaling pathway members, including PTEN, PIK3CA, PIK3CB, PIK3CG, AKT3 and mTOR were positively correlated with overall survival (OS), whereas PIK3CD mRNA expression was negatively correlated with OS (P < 0.05). Furthermore, TCPA prognostic analysis observed that several of the key molecules of the PI3K/AKT/mTOR signaling pathway [PTEN, p-AKT (S473) and p-mTOR (S2448)] were also positively correlated with OS in patients with ccRCC (P < 0.05). In conclusion, the present study suggested that several members of the PI3K/AKT/mTOR signaling pathway, especially PTEN, may be favorable prognostic factors in ccRCC, which indicated that the PI3K/AKT/mTOR signaling pathway may be implicated in ccRCC initiation and progression.

Project description:Background Kidney renal clear cell carcinoma (KIRC) is a malignant tumor with a high degree of immune infiltration. Identifying immune biomarkers is essential for the treatment of KIRC. Studies have identified the potential of NEIL3 to modulate the immune microenvironment and promote tumor progression. However, the role of NEIL3 in KIRC remains uncertain. This study was to investigate the effect of NEIL3 on the prognosis and immune infiltration of patients with KIRC. Methods TCGA and GEO databases were used to study the expression of NEIL3 in KIRC. Cox regression analysis was used to examine the relationship between the expression of NEIL3 and clinicopathological variables and survival. Furthermore, Gene Set Cancer Analysis (GSCA) was applied to study the impact of NEIL3 methylation on outcomes of KIRC. Through gene ontology (GO) and Gene set enrichment (GSEA) analysis, the biological processes and signal pathways related to NEIL3 expression were identified. In addition, immune infiltration analysis was conducted via CIBERSORT analysis, ssGSEA analysis and TISIDB database. Results NEIL3 was overexpressed in KIRC, and it was significantly related with histologic grade, pathologic stage, T stage, M stage, and vital status of KIRC patients (P < 0.001). The expression of NEIL3 was associated with worse outcomes. Univariate and multivariate Cox analysis showed that NEIL3 may be an indicator of adverse outcomes in KIRC. GSEA analysis revealed that NEIL3 may be involved in signal pathways including cell cycle, DNA replication, mismatch repair, P53 signal pathway, and antigen processing and presentation. In addition, immune infiltration analysis showed a positive correlation between NEIL3 expression and multiple immune cells (activated CD8 T cells, activated dendritic cells, myeloid-derived suppressor cells, follicular helper T cells, and regulatory T cells) and immunoinhibitors (PD1, CTLA4, LAG3, TIGHT, IL10, and CD96). Conclusion NEIL3 is a potential independent biomarker of KIRC, which is relevant to immune infiltration.

Project description:Lactate dehydrogenase (LDH) is a crucial glycolytic enzyme which mediates the metabolic plasticity of cancer cells, however its clinical significance in renal cell carcinoma (RCC) is poorly understood. Herein, we examined the prognostic significance of the two primary components of LDH, i.e., LDHA and LDHB, in clear cell RCC (ccRCC) patients and further explored their association with immune infiltration in ccRCC. In this study, the expression levels of LDHA and LDHB were examined in ccRCC and adjacent normal tissues by Gene Expression Profiling Interactive Analysis 2 (GEPIA2), UALCAN, and western blotting (WB) analyses, and their prognostic values were estimated in 150 ccRCC and 30 adjacent normal tissues by immunohistochemistry (IHC) analysis. The relationship to immune infiltration of LDHA and LDHB genes was further investigated using tumor immune estimation resource 2 (TIMER2) and Tumor-Immune System Interactions and DrugBank (TISIDB) databases, respectively. Public databases and WB analyses demonstrated higher LDHA and lower LDHB in ccRCC than in non-tumor tissues. IHC analysis revealed that LDHA and LDHB expression profiles were significantly associated with tumor grade, stage, size, and overall survival (OS). Univariate survival analysis displayed that high grade, advanced stage, large tumor, metastasis, high LDHA, and low LDHB expression were significantly associated with a poorer OS, and multivariate analysis revealed tumor stage and LDHB were identified as independent predictors for OS in patients with ccRCC. Further TIMER2 and TISIDB analyses demonstrated that LDHA and LDHB expression was significantly related to multiple immune cells and immune inhibitors in over 500 ccRCC patients. These findings revealed that LDHB was an independent favorable predictor, and LDHA and LDHB correlated with tumor immune infiltrates in ccRCC patients, which indicated LDHA/LDHB could be implicated in the tumorigenesis of ccRCC and might be potential therapeutic targets for patients with ccRCC.

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Prognostic significance and tumor-immune infiltration of mTOR in clear cell renal cell carcinoma.

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