Metabolism‐Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53‐Mutant Colon Cancer

Tang, Meng; Xu, Hui; Huang, Hongyan; Kuang, Hao; Wang, Chenxi; Zhang, Xin; Ge, Yi‐Zhong; Song, Mengmeng; Zhang, Xi; Wang, Ziwen; Ma, Chaobing; Kang, Jinlin; Zhang, Wanfang; Wang, You; Zhang, Bo; Zhang, Xiaowei; Chen, Yongbing; Ma, Cong; Melino, Gerry; Wang, Xiaobin; Zhou, Fuxiang; Sun, Qiang; Shi, Hanping

doi:10.1002/advs.202201992

Cited by 7 publications

(3 citation statements)

References 46 publications

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“…Concerning the modern oncological approaches, a combination of wild type P53 enhanced function and MDM2 decreased oncogenic activity should be a crucial step for handling subgroups of patients with specific genetic signatures (29,30). Interestingly, specific mutant TP53 variants (p53 K120R ) are involved in metabolic process in cancer patients, especially modulating glucose metabolism (31,32). Furthermore, TP53 alterations combined with mucin-5 over expression and microsatellite instability (MSI) are involved in colitis-associated colorectal carcinoma, as a result of a progressive chronic inflammation-dysplasia-cancer carcinogenesis process (33,34).…”

Section: Discussionmentioning

confidence: 99%

Comparative Expression Analysis of TP53 Tumor Suppressor and MDM2 Oncogene in Colorectal Adenocarcinoma

NIOTIS,

DIMITROULIS,

SPYROPOULOU

et al. 2024

CDP

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Background/Aim: The tumor protein 53 (TP53) tumor suppressor protein (17p13.1) acts as a significant regulator for the cell cycle normal function. The gene is frequently mutated in colorectal adenocarcinoma (CRC) patients and is associated to poor prognosis and low response rates to chemo-targeted therapy. Our purpose was to correlate TP53 expression with Mouse Double Minute 2 Homolog (MDM2), a proto-oncogene (12q14.3) and a major negative regulator in the TP53-MDM2 auto-regulatory pathway. Materials and Methods: A total of forty (n=40) colorectal adenocarcinoma (CRC) cases were included in this study. An immunohistochemistry-based assay was implemented by using anti-TP53 and anti-MDM2 antibodies in the corresponding tissue sections. Additionally, a digital image analysis assay was implemented for objectively measuring TP53/MDM2 immunostaining intensity levels. Results: TP53 protein overexpression was detected in 27/40 (67.5%), whereas MDM2 overexpression in 28/40 (70%) cases. Interestingly, in 21/40 (52.5%) cases, a combined TP53/MDM2 co-expression was detected, whereas in 6/40 (15%), a combined loss of expression was identified (overall co-expression: p=0.119). p53 overexpression was significantly correlated to grade of the examined cases (p=0.001), whereas MDM2 to stage and max diameter of the malignancies (p=0.001 and 0.024, respectively). Conclusion: TP53/MDM2 over expression is a frequent and significant genetic event in CRCs associated with an aggressive biological behavior, as a result of increased dedifferentiation grade and advanced stage/elevated tumor volume, respectively. MDM2 oncogene overactivation combined with mutated and overexpressed TP53 is observed in sub-groups of patients leading to specific gene/protein signatures – targets for personalized chemotherapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Comparative Expression Analysis of TP53 Tumor Suppressor and MDM2 Oncogene in Colorectal Adenocarcinoma

NIOTIS,

DIMITROULIS,

SPYROPOULOU

et al. 2024

CDP

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“…In addition, it is involved in the regulation of metabolism, antioxidant responses, and DNA repair. [26][27][28] In the process of P53-dependent cell apoptosis, some P53 proteins translocate to mitochondria to activate the caspase cascade pathway and mediate cell apoptosis. 29,30 Chemotherapy often stimulates hair follicles and leads to hair loss.…”

Section: Discussionmentioning

confidence: 99%

“…The P53 protein induces cell cycle arrest or apoptosis through transcription‐dependent and transcription‐independent mechanisms. In addition, it is involved in the regulation of metabolism, antioxidant responses, and DNA repair 26–28 . In the process of P53‐dependent cell apoptosis, some P53 proteins translocate to mitochondria to activate the caspase cascade pathway and mediate cell apoptosis 29,30 .…”

Section: Discussionmentioning

confidence: 99%

Application of lncRNA–miRNA–mRNA ceRNA network analysis in the treatment of androgenic alopecia

Wei

et al. 2022

Clinical Laboratory Analysis

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Background Long noncoding RNAs (lncRNAs) can be used as competitive endogenous RNAs (ceRNAs) to bind to microRNAs (miRNAs) to regulate gene expression. Previous studies have demonstrated that ceRNAs play an important role in the development of tumors. However, it is not clear whether the lncRNA–miRNA–mRNA ceRNA network plays a role in androgenic alopecia (AGA). Methods The hair follicles of three AGA patients and three healthy individuals were collected for high‐throughput whole transcriptome sequencing to screen for differentially expressed lncRNAs. Differentially expressed lncRNA target genes were subjected to databases to predict miRNA–mRNA and lncRNA–miRNA relationship pairs, and a ceRNA network was constructed using Cytoscape software. Relative expression was verified by real‐time quantitative reverse transcription–polymerase chain reaction (qRT‐PCR). Results 84 lncRNAs were significantly differentially expressed between the hair follicles of AGA patients and those of healthy individuals; 30 were upregulated, and 54 were downregulated. The top 10 upregulated lncRNAs were ENST00000501520, ENST00000448179, ENST00000318291, ENST00000568280, ENST00000561121, ENST00000376609, ENST00000602414, ENST00000573866, ENST00000513358, and ENST00000564194. The top 10 downregulated lncRNAs were ENST00000566804, ENST00000561973, ENST00000587680, ENST00000569927, ENST00000340444, ENST00000424345, ENST00000589787, NR_024344, NR_073026, and NR_110001. The qRT‐PCR validation results and receiver‐operating characteristic curve analysis indicated that one upregulated lncRNA, LOXL1‐AS1 (ENST00000564194), had the most significant clinical diagnostic potential. After further analysis, it was concluded that LOXL1‐AS1 could be used as a sponge to target hsa‐miR‐5193, thereby regulating TP53 expression. Conclusion The ceRNA network‐regulating AGA was constructed through high‐throughput sequencing. Our study also identified a key lncRNA that is possibly related to the AGA pathological process.

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Metabolism‐Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53‐Mutant Colon Cancer

Tang

Huang

et al. 2022

Advanced Science

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Although targeting cancer metabolism is a promising therapeutic strategy, clinical success depends on accurate molecular and metabolic subtyping.Here, this study reports two metabolism-based molecular subtypes associated with the ketogenic treatment of colon cancer: glycolytic (glycolysis + /ketolysis − ) and ketolytic (glycolysis + /ketolysis + ), which are manifested by distinct profiles of metabolic enzymes and mitochondrial dysfunction, and by different responses to ketone-containing interventions in vitro and in vivo. Notably, the glycolytic subtype is able to be transformed into the ketolytic subtype in p53-mutated tumors upon glucose limitation, rendering resistance to ketogenic therapy associated with upregulation of ketolytic enzymes, such as OXCT1 by mutant p53. The allosteric activator of mutant p53 effectively blocks the rewired molecular expression and the reprogrammed metabolism, leading to the suppression of tumor growth. The findings highlight the utility of metabolic subtyping to guide ketogenic therapy in colon cancer and identify mutant p53 as a synthetic lethality target for ketogenic treatment.

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Metabolism‐Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53‐Mutant Colon Cancer

Cited by 7 publications

References 46 publications

Comparative Expression Analysis of TP53 Tumor Suppressor and MDM2 Oncogene in Colorectal Adenocarcinoma

Comparative Expression Analysis of TP53 Tumor Suppressor and MDM2 Oncogene in Colorectal Adenocarcinoma

Application of lncRNA–miRNA–mRNA ceRNA network analysis in the treatment of androgenic alopecia

Metabolism‐Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53‐Mutant Colon Cancer

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