Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance.
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ABSTRACT:
SUBMITTER: Che X
PROVIDER: S-EPMC8203410 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oxidative stress (OS) refers to endogenous and/or exogenous stimulation when the balance between oxidation and antioxidants in the body is disrupted, resulting in excessive production of free radicals. Excessive free radicals exert a series of negative effects on the body, which can result in the oxidation of and infliction of damage on biological molecules and further cause cell death and tissue damage, which are related to many pathological processes. Pathways related to OS have always been the focus of medical research. Several studies are being conducted to develop strategies to treat cancer by exploring the OS pathways. Therefore, this study is aimed at determining the correlation between the OS pathway and kidney renal clear cell carcinoma (KIRC) through bioinformatics analysis, at proving the effect of common anticancer drugs on the OS pathway, and at constructing a prognosis model of patients with KIRC based on several genes with the strongest correlation between the OS pathway and KIRC. We first collected and analyzed gene expression and clinical information of related patients through TCGA database. Then, we divided the samples into three clusters according to their gene expression levels obtained through cluster analysis. Using these three clusters, we performed GDSC drug analysis and GSEA analysis and examined the correlation among the OS pathway, histone modification, and immune cell infiltration. We also analyzed the response of anti-PD-1 and anti-CTLA-4 to the OS pathway. Thereafter, we used LASSO regression to select the most suitable nine genes, combined with the clinicopathological characteristics to establish the prognosis model of patients with KIRC, and verified the scientific precision of the model. Finally, tumor mutational burden was calculated to verify whether patients would benefit from immunotherapy. The results of this study may provide a reference for the establishment of treatment strategies for patients with KIRC.
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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.
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Project description:Kidney renal clear cell carcinoma (KIRC), a common malignant tumor of the urinary system, is the most aggressive renal tumor subtype. Since the discovery of nuclear factor kappa B (NF-κB) in 1986, many studies have demonstrated abnormal NF-κB signaling is associated with the development of various cancers, including kidney renal clear cell carcinoma. In this study, the relationship between NF-κB and kidney renal clear cell carcinoma was confirmed using bioinformatics analysis. First, we explored the differential expression of copy number variation (CNV), single nucleotide variant (SNV), and messenger RNA (mRNA) in NF-κB-related genes in different types of cancer, as well as the impact on cancer prognosis and sensitivity to common chemotherapy drugs. Then, we divided the mRNA expression levels of NF-κB-related genes in KIRC patients into three groups through GSVA cluster analysis and explored the correlation between the NF-κB pathway and clinical data of KIRC patients, classical cancer-related genes, common anticancer drug responsiveness, and immune cell infiltration. Finally, 11 tumor-related genes were screened using least absolute shrinkage and selection operator (LASSO) regression to construct a prognostic model. In addition, we used the UALCAN and HPA databases to verify the protein levels of three key NF-κB-related genes (CHUK, IKGGB, and IKBKG) in KIRC. In conclusion, our study established a prognostic survival model based on NF-κB-related genes, which can be used to predict the prognosis of patients with KIRC.
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Project description: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.
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Project description:Kidney renal clear cell carcinoma (KIRC) is among the major causes of cancer-caused mortality around the world. Transient receptor potential channels (TRPs), due to their role in various human diseases, might become potential drug targets in cancer. The mRNA expression, copy number variation, single-nucleotide variation, prognostic values, drug sensitivity, and pathway regulation of TRPs were studied across cancer types. The ArrayExpress and The Cancer Genome Atlas (TCGA) databases were used to retrieve KIRC samples. Simultaneously, training, internal, and external cohorts were grouped. In KIRC, a prognostic signature with superior survival prediction in contrast with other well-established signatures was created after a stepwise screening of optimized genes linked to TRPs using univariate Cox, weighted gene co-expression network analysis, multivariate Cox, and least absolute shrinkage and selection operator regression analyses. Subsequent to the determination of risk levels, the variations in the expression of immune checkpoint genes, tumor mutation burden, and immune subtypes and response between low-risk and high-risk subgroups were studied using a variety of bioinformatics algorithms, including ESTIMATE, XCELL, EPIC, CIBERSORT-ABS, CIBERSORT, MCPCOUNTER, TIMER, and QUANTISEQ. Gene set enrichment analysis helped in the identification of abnormal pathways across the low- and high-risk subgroups. Besides, high-risk KIRC patients might benefit from ABT888, AZD6244, AZD7762, Bosutinib, Camptothecin, CI1040, JNK inhibitor VIII, KU55933, Lenalidomide, Nilotinib, PLX4720, RO3306, Vinblastine, and ZM.447439; however, low-risk populations might benefit from Bicalutamide, FH535, and OSI906. Finally, calibration curves were used to validate the nomogram with a satisfactory predictive survival probability. In conclusion, this research provides useful insight that can aid and guide clinical practice and scientific research.
| S-EPMC9277847 | biostudies-literature
Project description:Sunitinib, the first-line targeted therapy for metastatic clear cell renal cell carcinoma (ccRCC), faces a significant challenge as most patients develop acquired resistance. Integrated genomic and proteomic analyses identified PYGL as a novel therapeutic target for ccRCC. PYGL knockdown inhibited cell proliferation, cloning capacity, migration, invasion, and tumorigenesis in ccRCC cell lines. PYGL expression was increased in sunitinib-resistant ccRCC cell lines, and CP-91149 targeting the PYGL could restore drug sensitivity in these cell lines. Moreover, chromatin immune-precipitation assays revealed that PYGL upregulation is induced by the transcription factor, hypoxia-inducible factor 1α. Overall, PYGL was identified as a novel diagnostic biomarker by combining genomic and proteomic approaches in ccRCC, and sunitinib resistance to ccRCC may be overcome by targeting PYGL.
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Project description:BackgroundSyntaxin4 (STX4) gene encodes the protein STX4, a member of soluble N-ethylmaleimide-sensitive factor attachment protein receptors protein, playing a vital role in cell invadopodium formation and invasion, which is associated with the malignant progression of various human cancers. However, the expression and prognostic significance of STX4 in kidney renal clear cell carcinoma (KIRC) remain to be investigated.MethodsIn this study, we collected the mRNA expression of STX4 in 535 KIRC patients from The Cancer Genome Atlasthrough the University of California Santa Cruz Xena database platform. Then we explored the expression of STX4 in KIRC, and the relationship with clinicopathological characteristics and prognostic value. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes function enrichment analyses were used to explore the potential mechanism of STX4 in KIRC. qRT-PCR analysis was performed toverify the above results with real world tissue specimens.ResultsThe results indicated that STX4 was up-expressed in KIRC, and were associated with higher histological grade, advanced stage, and poorer prognosis. Moreover, elevated STX4 expression is an independent risk factor for KIRC. qRT-PCR analysis showed that STX4 was significantly elevated in 10 paired of KIRC samples compared to normal samples. Functional enrichment analysis indicated that endo/exocytosis, autophagy, mTOR signaling pathway, and NOD-like receptor signaling pathway were enriched.ConclusionsIn summary, STX4 is constantly up-expressed in KIRC tissues, associated with a poor prognosis. We suggest that it can be an effective biomarker for the prognosis of KIRC and may be a novel therapeutic target in KIRC.
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Project description:A growing number of studies reveal that alternative splicing (AS) is associated with tumorigenesis, progression, and metastasis. Systematic analysis of alternative splicing signatures in renal cancer is lacking. In our study, we investigated the AS landscape of kidney renal clear cell carcinoma (KIRC) and identified AS predictive model to improve the prognostic prediction of KIRC. We obtained clinical data and gene expression profiles of KIRC patients from the TCGA database to evaluate AS events. The calculation results for seven types of AS events indicated that 46276 AS events from 10577 genes were identified. Next, we applied Cox regression analysis to identify 5864 prognostic-associated AS events. We used the Metascape database to verify the potential pathways of prognostic-associated AS. Moreover, we constructed KIRC prediction systems with prognostic-associated AS events by the LASSO Cox regression model. AUCs demonstrated that these prediction systems had excellent prognostic accuracy simultaneously. We identified 34 prognostic associated splicing factors (SFs) and constructed homologous regulatory networks. Furthermore, in vitro experiments were performed to validate the favorable effect of SFs FMR1 in KIRC. In conclusion, we overviewed AS events in KIRC and identified AS-based prognostic models to assist the survival prediction of KIRC patients. Our study may provide a novel predictive signature to improve the prognostic prediction of KIRC, which might facilitate KIRC patient counseling and individualized management.
| S-EPMC11210227 | biostudies-literature
Project description:RNA binding proteins (RBPs) play a key role in post-transcriptional gene regulation. They have been shown to be dysfunctional in a variety of cancers and are closely related to the occurrence and progression of cancers. However, the biological function and clinical significance of RBPs in clear cell renal carcinoma (ccRCC) are unclear. In our current study, we downloaded the transcriptome data of ccRCC patients from The Cancer Genome Atlas (TCGA) database and identified differential expression of RBPs between tumor tissue and normal kidney tissue. Then the biological function and clinical value of these RBPs were explored by using a variety of bioinformatics techniques. We identified a total of 40 differentially expressed RBPs, including 10 down-regulated RBPs and 30 up-regulated RBPs. Eight RBPs (APOBEC3G, AUH, DAZL, EIF4A1, IGF2BP3, NR0B1, RPL36A, and TRMT1) and nine RBPs (APOBEC3G, AUH, DDX47, IGF2BP3, MOV10L1, NANOS1, PIH1D3, TDRD9, and TRMT1) were identified as prognostic related to overall survival (OS) and disease-free survival (DFS), respectively, and prognostic models for OS and DFS were constructed based on these RBPs. Further analysis showed that OS and DFS were worse in high-risk group than in the low-risk group. The area under the receiver operator characteristic curve of the model for OS was 0.702 at 3 years and 0.726 at 5 years in TCGA cohort and 0.783 at 3 years and 0.795 at 5 years in E-MTAB-1980 cohort, showing good predictive performance. Both models have been shown to independently predict the prognosis of ccRCC patients. We also established a nomogram based on these prognostic RBPs for OS and performed internal validation in the TCGA cohort, showing an accurate prediction of ccRCC prognosis. Stratified analysis showed a significant correlation between the prognostic model for OS and ccRCC progression.
| S-EPMC7817999 | biostudies-literature
Project description:BackgroundEPB41L1 gene (erythrocyte membrane protein band 4.1 like 1) encodes the protein 4.1N, a member of 4.1 family, playing a vital role in cell adhesion and migration, which is associated with the malignant progression of various human cancers. However, the expression and prognostic significance of EPB41L1 in kidney renal clear cell carcinoma (KIRC) remain to be investigated.MethodsIn this study, we collected the mRNA expression of EPB41L1 in KIRC through the Oncomine platform, and used the HPA database to perform the pathological tissue immunohistochemistry in patients. Then, the sub-groups and prognosis of KIRC were performed by UALCAN and GEPIA web-tool, respectively. Further, the mutation of EPB41L1 in KIRC was analyzed by c-Bioportal. The co-expression genes of EPB41L1 in KIRC were displayed from the LinkedOmics database, and function enrichment analysis was used by LinkFinder module in LinkedOmics. The function of EPB41L1 in cell adhesion and migration was confirmed by wound healing assay using 786-O cells in vitro. Co-expression gene network was constructed through the STRING database, and the MCODE plug-in of which was used to build the gene modules, both of them was visualized by Cytoscape software. Finally, the top modular genes in the same patient cohort were constructed through data mining in TCGA by using the UCSC Xena browser.ResultsThe results indicated that EPB41L1 was down-expressed in KIRC, leading to a poor prognosis. Moreover, there is a mutation in the FERM domain of EPB41L1, but it has no significant effect on the prognosis of KIRC. The co-expressed genes of EPB41L1 were associated with cell adhesion and confirmed in vitro. Further analysis suggested that EPB41L1 and amyloid beta precursor protein (APP) were coordinated to regulated cancer cell adhesion, thereby increasing the incidence of cancer cell metastasis and tumor invasion.ConclusionsIn summary, EPB41L1 is constantly down-expressed in KIRC tissues, resulting a poor prognosis. Therefore, we suggest that it can be an effective biomarker for the diagnosis of KIRC.
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