Characterization of the metabolic alteration-modulated tumor microenvironment mediated by TP53 mutation and hypoxia

Luo, Kunpeng; Qian, Zhipeng; Jiang, Yanan; Lv, Dongxu; Zhu, Kaibin; Shao, Jing; Ying, Haoqiang; Lv, Chengqian; Huang, Qianqian; Gao, Yang; Jin, Shizhu; Shang, Desi

doi:10.1016/j.compbiomed.2023.107078

Cited by 13 publications

(6 citation statements)

References 68 publications

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“…8 It has also been shown that mutant p53 and hypoxia play important roles in altering metabolic pathways in hepatocellular carcinoma leading to alterations in the tumor microenvironment and immune pattern encouraging cancer development, and can thus be adopted as potential targets for cancer therapy. 19 Similarly, another study reported the involvement of p53-G245S in the induction of hnRNPA2B1-AGAP1-mediated exosome formation that promotes ESCC progression. 20 P53-R175H in association with periostin was shown to activate STAT1 and its transcriptional targets in the esophageal cancer tumor microenvironment enabling the invasion of esophageal epithelial cells into the extracellular matrix.…”

Section: Discussionmentioning

confidence: 94%

Novel oncogenic transcriptional targets of mutant p53 in esophageal squamous cell carcinoma

George,

Kotapalli,

Ramaswamy

et al. 2024

J of Cellular Biochemistry

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Missense mutations in the DNA binding domain of p53 are observed frequently in esophageal squamous cell carcinoma (ESCC). Recent studies have revealed the potentially oncogenic transcriptional networks regulated by mutant p53 proteins. However, majority of these studies have focused on common “hotspot” p53 mutations while rarer mutations are poorly characterized. In this study, we report the characterization of rare, “non‐hotspot” p53 mutations from ESCC. In vitro tumorigenic assays performed following ectopic‐expression of certain “non‐hotspot” mutant p53 proteins caused enhancement of oncogenic properties in squamous carcinoma cell lines. Genome‐wide transcript profiling of ESCC tumor samples stratified for p53 status, revealed several genes exhibiting elevated transcript levels in tumors harboring mutant p53. Of these, ARF6, C1QBP, and TRIM23 were studied further. Reverse transcription‐quantitative PCR (RT‐qPCR) performed on RNA isolated from ESCC tumors revealed significant correlation of TP53 transcript levels with those of the three target genes. Ectopic expression of wild‐type and several mutant p53 forms followed by RT‐qPCR, chromatin affinity‐purification (ChAP), and promoter‐luciferase assays indicated the exclusive recruitment of p53 mutants—P190T and P278L, to the target genes leading to the activation of expression. Several functional assays following knockdown of the target genes revealed a significant suppression of tumorigenicity in squamous carcinoma cell lines. Rescue experiments confirmed the specificity of the knockdown. The tumorigenic effects of the genes were confirmed in nude mice xenograft assays. This study has therefore identified novel oncogenic targets of “non‐hotspot” mutant p53 proteins relevant for ESCC besides validating the functional heterogeneity of the spectrum of tumor‐specific p53 mutations.

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Section: Discussionmentioning

confidence: 94%

Novel oncogenic transcriptional targets of mutant p53 in esophageal squamous cell carcinoma

George,

Kotapalli,

Ramaswamy

et al. 2024

J of Cellular Biochemistry

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“…Specific lncRNAs, proteins, and related pathways have been confirmed to be involved in the development of oesophageal squamous cell carcinoma and the regulation of tumour immune infiltration. [42][43][44][45] Luo et al 46 also pointed out metabolic alteration mediated by hypoxia and TP53 mutation is related to regulation of tumour immune microenvironment across cancer types. Tumour immune infiltrating cells are related to the development of digestive system tumours.…”

Section: Discussionmentioning

confidence: 99%

“… 42 , 43 , 44 , 45 Luo et al. 46 also pointed out metabolic alteration mediated by hypoxia and TP53 mutation is related to regulation of tumour immune microenvironment across cancer types. Tumour immune infiltrating cells are related to the development of digestive system tumours.…”

Section: Discussionmentioning

confidence: 99%

An integrated analysis of the anticarcinogenic role of forkhead box protein 1 in oesophageal squamous cell carcinoma

Ye,

Pan,

Zhu

et al. 2024

J Cellular Molecular Medi

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Forkhead box protein 1 (FOXP1) serves as a tumour promoter or suppressor depending on different cancers, but its effect in oesophageal squamous cell carcinoma has not been fully elucidated. This study investigated the role of FOXP1 in oesophageal squamous cell carcinoma through bioinformatics analysis and experimental verification. We determined through public databases that FOXP1 expresses low in oesophageal squamous cell carcinoma compared with normal tissues, while high expression of FOXP1 indicates a better prognosis. We identified potential target genes regulated by FOXP1, and explored the potential biological processes and signalling pathways involved in FOXP1 in oesophageal squamous cell carcinoma through GO and KEGG enrichment, gene co‐expression analysis, and protein interaction network construction. We also analysed the correlation between FOXP1 and tumour immune infiltration levels. We further validated the inhibitory effect of FOXP1 on the proliferation of oesophageal squamous cell carcinoma cells through CCK‐8, colony formation and subcutaneous tumour formation assays. This study revealed the anticarcinogenic effect of FOXP1 in oesophageal squamous cell carcinoma, which may serve as a novel biological target for the treatment of tumour.

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“…Moreover, based on these findings, a potential targeted drug was identified, offering new perspectives for the future treatment and prognosis prediction of renal cancer. 25 In conclusion, high-throughput data provide vast medical information, and the comprehensive exploration of existing data represents an economical and effective scientific research approach in medicine.…”

Section: Discussionmentioning

confidence: 99%

“… 32 Recent studies have revealed that TP53-mediated metabolic alterations are associated with the tumor microenvironment regulation and tumor progression. 25 This research classified liver cancer into two subtypes based on the TP53 mutation status, and these metabolic subtypes exhibited distinct immune-inflammatory microenvironments. 25 In the present study, the correlations between CRYL1 and metabolism and immune response were identified.…”

Section: Discussionmentioning

confidence: 99%

CRYL1 is a Potential Prognostic Biomarker of Clear Cell Renal Cell Carcinoma Correlated with Immune Infiltration and Cuproptosis

Li,

Xu,

Liu

et al. 2024

Technol Cancer Res Treat

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Background Clear cell renal cell carcinoma (ccRCC) is a widespread urogenital neoplasm. However, the therapeutic efficacy of these methods is unsatisfactory. In-depth screening of biomarkers could aid early diagnosis and therapy and predict patient prognosis. Methods The GEO datasets were selected with specific criteria. Differentially expressed gene (DEG), weighted gene coexpression network analysis (WGCNA), protein–protein interaction, LASSO, random forest, and Cox regression analyses were applied to identify the independent prognostic biomarkers. Survival analysis, correlation with clinical features, gene set enrichment analysis (GSEA), GO enrichment, immune infiltration analysis, and correlation with cuproptosis-related genes were carried out to determine the prognostic value and possible molecular mechanisms of the TSVR. Wound healing assays, transwell assays, cell colony formation experiments, flow cytometry, and immunohistochemistry (IHC) analysis were used to validate the functional attributes of CRYL1. Results Four GEO datasets were included to screen for hub genes. DEG combined with WGCNA showed a key module with 300 genes having the strongest correlation with “survival state” (R2 = -0.24 and P = 7e−8); six genes were identified by LASSO, random forest, and Cytoscape. Finally, CRYL1 (hazard ratio (HR) = 2.01, P < 0.001) was selected as an independent prognostic biomarker. The higher CRYL1 expression group had better DFS and overall survival (OS). GSEA demonstrated that the CRYL1-related DEGs were enriched mainly in the metabolism of sugar, fat, and amino acids. CRYL1 is positively correlated with FDX1 and the LIAS pathway, which are important molecule involved in cuproptosis. CRYL1 affects the infiltration abundance of four immune cells and can predict a positive OS. Wound healing, transwell, cell colony formation, and flow cytometry assays demonstrated that CRYL1 silencing enhances migration and proliferation and leads to a decreased apoptotic ratio. IHC analysis suggested that CRYL1 was highly expressed in adjacent tissues. Conclusions CRYL1 is a robust predictive marker for clinicopathological characteristics and survival status in ccRCC patients.

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Characterization of the metabolic alteration-modulated tumor microenvironment mediated by TP53 mutation and hypoxia

Cited by 13 publications

References 68 publications

Novel oncogenic transcriptional targets of mutant p53 in esophageal squamous cell carcinoma

Novel oncogenic transcriptional targets of mutant p53 in esophageal squamous cell carcinoma

An integrated analysis of the anticarcinogenic role of forkhead box protein 1 in oesophageal squamous cell carcinoma

CRYL1 is a Potential Prognostic Biomarker of Clear Cell Renal Cell Carcinoma Correlated with Immune Infiltration and Cuproptosis

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