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Identification of transforming growth factor beta induced (TGFBI) as an immune-related prognostic factor in clear cell renal cell carcinoma (ccRCC).

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most common subtype among kidney cancer, which has poor prognosis. The aim of this study was to screen out novel prognostic biomarkers and therapeutic targets for immunotherapy, and some novel molecule drugs for ccRCC treatment. Immune scores ranged from -1109.36 to 2920.81 and stromal scores ranged from -1530.11 to 1955.39 were firstly calculated by applying ESTIMATE algorithm. Then 17 DEGs associated with immune score and stromal score were further identified. 6 candidate hub genes were screened out by performing overall survival (OS) and disease-free survival analyses based on TCGA-KIRC data, one of which including TGFBI was further regarded as hub gene associated with prognosis by calculating the R2 (R2 = 0.011, P = 0.018) and AUC (AUC = 0.874). The prognostic value of TGFBI was validated by performing OS, CSS, and PFS analyses based on GSE29609 and E-MTAB-3267. CMap analysis suggested that 3 molecule drugs might be novel choice for ccRCC treatment. Further analysis demonstrated that CNVs of TGFBI was associated with OS of patients with ccRCC. TGFBI expression was also correlated with histologic grade, pathologic stage, and immune infiltration level, significantly. TGFBI was the most relevant gene with OS among the candidate hub genes, which might be novel DNA methylation biomarkers for ccRCC. In conclusion, our findings indicated that TGFBI was correlated with prognosis of patients with ccRCC, which might be novel prognostic biomarkers, and targets for immunotherapy in ccRCC. Three small molecule drugs were also identified, which showed strong potential for ccRCC treatment.

SUBMITTER: Du GW

PROVIDER: S-EPMC7244045 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Identification of transforming growth factor beta induced (TGFBI) as an immune-related prognostic factor in clear cell renal cell carcinoma (ccRCC).

Du Guo-Wei GW Yan Xin X Chen Zhao Z Zhang Ren-Jie RJ Tuoheti Kurerban K Bai Xiao-Jie XJ Wu Hua-Hui HH Liu Tong-Zu TZ

Aging 20200514 9

Clear cell renal cell carcinoma (ccRCC) is the most common subtype among kidney cancer, which has poor prognosis. The aim of this study was to screen out novel prognostic biomarkers and therapeutic targets for immunotherapy, and some novel molecule drugs for ccRCC treatment. Immune scores ranged from -1109.36 to 2920.81 and stromal scores ranged from -1530.11 to 1955.39 were firstly calculated by applying ESTIMATE algorithm. Then 17 DEGs associated with immune score and stromal score were furthe ...[more]

PMID: 32406866

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Project description:Previously studies have shown that apoptosis-related genes play an essential role in normal cell turnover, maintaining the immune system function, and inducing cell death. However, their prognostic roles in clear cell renal cell carcinoma (ccRCC) have not been thoroughly investigated. In the present study, apoptosis-related genes expression profiles from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database were used as training dataset and external validation dataset, respectively. According to the systematical analysis of the apoptosis-related gene expression profile, we constructed a gene signature to determine the role of apoptosis-related genes in the survival of ccRCC. We discovered that patients in the low-risk group have a better survival than high-risk group and the signature could serve as an independent prognostic factor. A nomogram, including a signature and clinical factors, were constructed to estimate the individual survival probability. The Gene set enrichment analysis (GSEA) identified some significant pathways which may contribute to understanding the underlying mechanism of ccRCC. In addition, the prognostic efficiency of the risk model was further validated in the disease free survival (DFS) and the ICGC dataset, respectively. We also identified three molecular subtypes (named C1, C2, and C3) based on apoptosis-related gene expression. We found that C1 was corresponding to a worse survival outcome and showed a high drug sensitivity of sorafenib and sunitinib. C2 and C3 were corresponding to a better survival outcome and presented a low drug sensitivity to sorafenib and sunitinib. Moreover, we found that C2 and C3 have more likelihood to be respond to immunotherapy. Together, the apoptosis-related gene signature and three molecular subtypes may promote the understanding of the underlying molecular mechanism of ccRCC, and provided reference for developing individualized treatment of the ccRCC patients.

Project description:Background: It is anticipated that there will be a large rise in the number of tumor diagnoses and mortality in those aged 65 and older over the course of upcoming decades. Immune checkpoint inhibitors, often known as ICIs, boost immune system activity by selectively targeting ICI genes. On the other hand, old age may be connected with unfavorable results. Methods: The Cancer Genome Atlas (TCGA) provided gene expression data from ccRCC tissue and key clinical variables. ICI gene databases were applied and verified using the GEO database. Results: We identified 14 ICI genes as risk gene signatures among 528 ccRCC patients using univariate and multivariable cox hazard models, and the elderly group was linked with poor survival. Then, by utilizing a new nomogram method, the TNFSF15 gene and age predicting values were estimated at one, three, and five years (85%, 81%, and 81%), respectively, and our age-related risk score was significant even after multivariable analysis (HR = 1.518, p = 0.009, CI = 1.1102.076). TNFSF15 gene expression was lower in elderly ccRCC patients (p = 0.0001). A negative connection between age and the TNFSF15 gene expression was discovered by correlation analysis (p = 0.0001). The verification of the gene by utilizing GEO (GSE167093) with 604 patients was obtained as external validation that showed significant differences in the TNFSF15 gene between young and elderly patients (p = 0.007). Additionally, the protein-protein interactions of the TNFSF15 gene with other ICI genes and aging-related genes was determined. In addition, the TNFSF15 expression was significantly correlated with pathological stages (p = 0.018). Furthermore, it was discovered that the biological processes of senescence, cellular senescence, the immune system, and many immune cell infiltration and immune function types are all closely tied. Conclusions: Along with the risk score evaluation, the ICI gene TNFSF15 was identified as a tumor suppressor gene related to inequalities in age survival and is associated with pathological stages and different immunity statuses. The aging responses of ccRCC patients and related gene expression need further investigation in order to identify potential therapeutic targets.

Project description:BackgroundHigh immunogenicity is an important feature of ccRCC, but its underlying immune-related molecular mechanisms remain unclear. This study aimed to investigate the effect of immune-related gene TEK on ccRCC and its prognostic value.MethodsThe immune-related differentially expressed genes (DEGs) and transcription factors (TFs) in ccRCC were screened based on The Cancer Genome Atlas (TCGA) database, and a regulatory network of TF was constructed. Prognostic-related immune genes were screened by univariate Cox regression analysis and functional annotation was performed. Univariate and multivariate Cox regression analyses were performed to construct the immune gene risk model and identify the hub gene TEK that independently affected the prognosis of ccRCC. The effectiveness of the TEK was verified by external microarray datasets. The relationship between TEK and immune cells in ccRCC was evaluated based on Tumor Immune Estimation Resource (TIMER). The expression of TEK in clinical specimens was verified by qRT-PCR and immunohistochemical (IHC) staining. MTT and cloning formation assay were used to evaluate cell proliferation. Transwell assays were used to assess cell migration. Apoptosis was assessed by flow cytometry, and the expression of related proteins was detected by Western blot and immunofluorescence.ResultsWe constructed a prognostic model consisting of 12 hub genes and performed risk scores to determine the relationship between these scores and prognosis. Through Cox regression analysis and survival analysis, TEK, an immune marker highly related to survival prognosis, was obtained and validated. In vitro experiments showed that knockdown of TEK promoted the proliferation and migration of ccRCC cells, and we found that TEK promoted apoptosis by regulating the phosphorylation of AKT, thereby inhibiting cell proliferation.ConclusionsTEK plays an important role in risk assessment and survival prediction for ccRCC patients as a new immune gene and maybe an emerging target for immunotherapy for ccRCC patients.

Dataset Information

Identification of transforming growth factor beta induced (TGFBI) as an immune-related prognostic factor in clear cell renal cell carcinoma (ccRCC).

Publications

Identification of transforming growth factor beta induced (TGFBI) as an immune-related prognostic factor in clear cell renal cell carcinoma (ccRCC).

Similar Datasets

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