Biological significance of 5-hydroxymethylcytosine in oral epithelial dysplasia and oral squamous cell carcinoma

Cuevas‐Nunez, Maria; Gomes, Camilla Borges Ferreira; Woo, Sook‐Bin; Ramsey, Matthew R.; Chen, Xiaoxin L.; Xu, Shuyun; Xu, Ting; Zhan, Qimin; Murphy, Gëorge F.; Lian, Christine G.

doi:10.1016/j.oooo.2017.06.006

Cited by 11 publications

(12 citation statements)

References 26 publications

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“…In line with our findings, organic acids such as citric acid, malic acid, fumaric acid, 2-methylcitric acid, 2-hydroxyglutarate, succinic acid, 2-hydroxyglutaric acid lactone, and α-ketoglutaric acid are directly or indirectly linked with the altered regulation of metabolic pathways in various types cancer cells [ 13 - 28 , 40 - 45 ]. In recent, noticeable metabolic profiling of biological fluids and tumor tissues suggested the enhanced levels of metabolites such as citric acid, malic acid, fumaric acid, 2-methylcitric acid, 2-hydroxyglutarate, cis -aconitic acid, succinic acid, and 2-hydroxyglutaric acid lactone [ 40 - 45 ].…”

Section: Resultssupporting

confidence: 88%

Organic Acids Derived from Saliva-amalgamated Betel Quid Filtrate Are Predicted as a Ten-eleven Translocation-2 Inhibitor

Bhatkar,

Ananda,

Lokhande

et al. 2023

J Cancer Prev

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There is a lack of evidence regarding the use of betel quid (BQ) and its potential contribution to oral cancer. Limited attention has been directed towards investigating the involvement of BQ-derived organic acids in the modulation of metabolic-epigenomic pathways associated with oral cancer initiation and progression. We employed novel protocol for preparing saliva-amalgamated BQ filtrate (SABFI) that mimics the oral cavity environment. SABFI and saliva control were further purified by an in-house developed vertical tube gel electrophoresis tool. The purified SABFI was then subjected to liquid chromatography-high resolution mass spectrometry analysis to identify the presence of organic acids. Profiling of SABFI showed a pool of prominent organic acids such as citric acid. malic acid, fumaric acid, 2-methylcitric acid, 2-hydroxyglutarate, cis- aconitic acid, succinic acid, 2-hydroxyglutaric acid lactone, tartaric acid and β-ketoglutaric acid. SABFI showed anti-proliferative and early apoptosis effects in oral cancer cells. Molecular docking and molecular dynamics simulations predicted that SABFI-derived organic acids as potential inhibitors of the epigenetic demethylase enzyme, Ten-Eleven Translocation-2 (TET2). By binding to the active site of α-ketoglutarate, a known substrate of TET2, these organic acids are likely to act as competitive inhibitors. This study reports a novel approach to study SABFI-derived organic acids that could mimic the chemical composition of BQ in the oral cavity. These SABFI-derived organic acids projected as inhibitors of TET2 and could be explored for their role oral cancer.

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Section: Resultssupporting

confidence: 88%

Organic Acids Derived from Saliva-amalgamated Betel Quid Filtrate Are Predicted as a Ten-eleven Translocation-2 Inhibitor

Bhatkar,

Ananda,

Lokhande

et al. 2023

J Cancer Prev

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“…34 In consequence, therapies targeting OSCC-related biomarkers have become a research hotspot. 35,36 Our previous work indicated that fisetin could play an important part in such therapeutic strategies. However, the results of clinical trial design for therapy of patients with OSCC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

<p>Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways</p>

Li¹,

Jia²,

Dai³

2020

DDDT

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Objective: Human oral squamous cell carcinoma (OSCC) is a major cause of mortality and morbidity worldwide. There is an urgent need to identify bioactive molecules and potential target genes that could inhibit carcinogenesis for OSCC therapy. Fisetin (3,7,3′,4′-tetrahydroxyflavone), a naturally occurring flavonoid, has been previously shown to have anti-proliferative activities in OSCC; however, its molecular mechanism is unknown. Methods: Colony formation, cell viability, Boyden chamber, wound healing, and tumor xenograft assays were used to detect the impact of fisetin on OSCC cells in vitro and in vivo. Western blot analysis was used to examine the corresponding protein expression. Results: Fisetin treatment significantly inhibited proliferation and promoted apoptosis by repressing PAK4 expression. Moreover, fisetin treatment attenuated cell migration by blocking PAK4 signaling pathways. In addition, the tumor xenograft showed anti-tumor growth effects of fisetin exposure in vivo. Conclusion: Fisetin may represent a potential therapeutic strategy for human OSCC by targeting PAK4 signaling pathways.

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“…Nosratzehi et al evaluated four types of salivary matrix metalloproteinases (MMPs) obtained from OLP, OSCC patients and healthy controls, and reported higher levels of MMP‐2 and MMP‐13 in OSCC than in OLP and controls. Similarly, Cuevas‐Nunez et al found that 5‐hydroxylmethylcytosine may serve as a biomarker to distinguish oral epithelial dysplasia (OED) and OSCC by studying the mucosa samples from 9 normal people, 10 OLP, 15 OED and 23 OSCC patients. Yang et al assessed genome‐wide transcriptional profiles of OLP and OSCC by high‐throughput sequencing and enrichment analyses of mRNAs and long noncoding RNAs (lncRNAs), which turned out that keratinization and MHC class I antigen processing were activated during the malignant transformation.…”

Section: Introductionmentioning

confidence: 99%

Metabolic changes during malignant transformation in primary cells of oral lichen planus: Succinate accumulation and tumour suppression

Yang

Sun

Wang

et al. 2019

J Cellular Molecular Medi

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Oral squamous cell carcinoma (OSCC) is usually diagnosed at late stages, which leads to high morbidity. There are evidence that chronic inflammation (eg oral lichen planus [OLP]) was a risk factor of OSCC, but often misdiagnosed or ignored until invasion and metastasis. By applying precision medicine, the molecular microenvironment variations and relevant biomarkers for the malignant transformation from OLP to OSCC can be fully investigated. Several studies pointed out that the metabolic pathway were suppressed in OSCC. However, it remains unclear how the systemic profile of the metabolites change during the malignant transformation. In this study, we examined and compared the mucosa samples from 11 healthy individuals, 10 OLP patients and 21 OSCC patients. Based on the results, succinate, a key metabolite of the tricarboxylic acid cycle pathway, was accumulated in the primary cultured precancerous OLP keratinocytes and OSCC cells. Then, we found that succinate activated the hypoxia-inducible factor-1 alpha (HIF-1α) pathway and induced apoptosis, which could also be up-regulated by the tumour suppressor lncRNA MEG3. These results suggested the critical roles of succinate and MEG3 in the metabolic changes during malignant transformation from OLP to OSCC, which indicated that succinate, HIF1α and downstream proteins might serve as new biomarkers of precancerous OLP for early diagnosis and therapeutic monitoring. In addition, succinate or its prodrugs might become a potential therapy for the prevention or treatment of OSCC. K E Y W O R D SHIF-1α, MEG3, oral lichen planus, oral squamous cell carcinoma, succinate

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Biological significance of 5-hydroxymethylcytosine in oral epithelial dysplasia and oral squamous cell carcinoma

Cited by 11 publications

References 26 publications

Organic Acids Derived from Saliva-amalgamated Betel Quid Filtrate Are Predicted as a Ten-eleven Translocation-2 Inhibitor

Organic Acids Derived from Saliva-amalgamated Betel Quid Filtrate Are Predicted as a Ten-eleven Translocation-2 Inhibitor

<p>Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways</p>

Metabolic changes during malignant transformation in primary cells of oral lichen planus: Succinate accumulation and tumour suppression

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