Expression of m6A RNA Methylation Regulators and Their Clinical Predictive Value in Intrahepatic Cholangiocarcinoma

Feng, Wei; Zhang, J; Zhao, Yu‐Qing; Lyu, Hongwei; Chen, Fengyuan

doi:10.31083/j.fbl2806120

Cited by 3 publications

(3 citation statements)

References 30 publications

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“…However, prior to the current study, the potential role of METTL16 in CCA was not known. Consistent with the study by Wei et al [ 28 ], we validated the upregulation of METT16 expression in CCA tissues compare to non-tumor tissues. Our experimental results described in this study establish an important oncogenic role of METTL16 in CCA and identify PRDM15 as a key downstream target of METTL16 via an m6A-dependent mechanism.…”

Section: Discussionsupporting

confidence: 90%

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The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression

Liu,

Zhang,

Chen

et al. 2023

J Exp Clin Cancer Res

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Background RNA N6-Methyladenosine (m6A) modification is implicated in the progression of human cancers including cholangiocarcinoma (CCA). METTL16 is recently identified as a new RNA methyltransferase responsible for m6A modification, although the role of METTL16 in CCA has not yet been examined. The current study aims to investigate the effect and mechanism of the RNA methyltransferase METTL16 in CCA. Methods The expression of METTL16 in CCA was examined by analyzing publicly available datasets or by IHC staining on tumor samples. siRNA or CRISPR/Cas9-mediated loss of function studies were performed in vitro and in vivo to investigate the oncogenic role of METTL16 in CCA. MeRIP-Seq was carried out to identify the downstream target of METTL16. ChIP-qPCR, immunoprecipitation, and immunoblots were used to explore the regulation mechanisms for METTL16 expression in CCA. Results We observed that the expression of METTL16 was noticeably increased in human CCA tissues. Depletion of METTL16 significantly inhibited CCA cell proliferation and decreased tumor progression. PRDM15 was identified as a key target of METTL16 in CCA cells. Mechanistically, our data showed that METTL16 regulated PRDM15 protein expression via YTHDF1-dependent translation. Accordingly, we observed that restoration of PRDM15 expression could rescue the deficiency of CCA cell proliferation/colony formation induced by METTL16 depletion. Our subsequent analyses revealed that METTL16-PRDM15 signaling regulated the expression of FGFR4 in CCA cells. Specifically, we observed that PRDM15 protein was associated with the FGFR4 promoter to regulate its expression. Furthermore, we showed that the histone acetyltransferase p300 cooperated with the transcription factor YY1 to regulate METTL16 gene expression via histone H3 lysine 27 (H3K27) acetylation in CCA cells. Conclusions This study describes a novel METTL16-PRDM15-FGFR4 signaling axis which is crucial for CCA growth and may have important therapeutic implications. We showed that depletion of METTL16 significantly inhibited CCA cell proliferation and decreased tumor progression.

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Section: Discussionsupporting

confidence: 90%

“…A recent study shows that METTL16 expression is elevated in pancreatic ductal adenocarcinoma (PDAC) and correlated with better clinical outcomes for patients [ 27 ]. Wei et al reports upregulated expression of METTL16 in cholangiocarcinoma [ 28 ], although the effect and mechanism of METTL16 in CCA remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression

Liu,

Zhang,

Chen

et al. 2023

J Exp Clin Cancer Res

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“…Notably, this correlation was particularly evident in LIHC, KIRC, BRCA, CHOL, and ACC. Previous studies have partially explored the prognostic significance of m6A modification in BRCA and CHOL (Feng et al 2022c ; Wei et al 2023 ). Furthermore, m5C can serve as a potential biomarker for predicting the efficacy of LIHC immunotherapy (Liu et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

A pan-cancer analysis of the oncogenic and immunological roles of transglutaminase 1 (TGM1) in human cancer

Wu,

Li,

Zhang

et al. 2024

J Cancer Res Clin Oncol

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Background There is currently a limited number of studies on transglutaminase type 1 (TGM1) in tumors. The objective of this study is to perform a comprehensive analysis across various types of cancer to determine the prognostic significance of TGM1 in tumors and investigate its role in the immune environment. Method Pan-cancer and mutational data were retrieved from the TCGA database and analyzed using R (version 3.6.4) and its associated software package. The expression difference and prognosis of TGM1 were examined, along with its correlation with tumor heterogeneity, stemness, mutation landscape, and RNA modification. Additionally, the relationship between TGM1 expression and tumor immunity was investigated using the TIMER method. Results TGM1 is expressed differently in various tumors and normal samples and is associated with the overall survival and progression-free time of KIRC, ACC, SKCM, LIHC, and STES. In LICH, we found a negative correlation between TGM1 expression and 6 indicators of tumor stemness. The mutation frequencies of BLCA, LIHC, and KIRC were 1.7%, 0.3%, and 0.3% respectively. In BLCA and BRCA, there was a significant correlation between TGM1 expression and the infiltration of CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells. Conclusion TGM1 has the potential to serve as both a prognostic marker and a drug target.

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Compound 21 Attenuates Isoflurane-Induced Injury in Neonatal Rat Hippocampal Neurons and Primary Rat Neuronal Cells by Upregulating METTL3

Shen,

Wu,

Zhuang

et al. 2024

JIR

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Background Isoflurane, as an anesthetic drug, has a neurotoxic effect on the developing brain tissue. Compound 21 (C21) has been reported to be neuroprotective and ameliorate stroke effects. However, the mechanism by which C21 protects against nerve damage remains unclear. Methods Animal and cellular models of brain injury were constructed using isoflurane (ISO) in neonatal SD rats and primary rat neuronal cells (PRNCs). After treatment with C21, the ultrastructure and morphology of the hippocampus in the model rats were assessed using the transmission electron microscope and H&E staining. Methylation or apoptosis-related genes or proteins were examined using immunohistochemistry, RT-qPCR, and Western blot. The levels of inflammatory factors were monitored using the ELISA kits. m6A modification was analyzed by Dot blot and MeRIP-qPCR. Cell proliferation and apoptosis were also tested using Edu and TUNEL staining. Results C21 suppresses apoptosis and inflammation and improves hippocampal morphology in ISO-induced neonatal rats. Mechanistically, C21 upregulates m6A modification, PPAR-a, BCL-2, and METTL3 in ISO-induced neonatal rats and ISO-treated PRNCs. C21 promotes cell proliferation, enhances BCL-2 m6A modification, and reduces inflammation by upregulating METTL3 by upregulating METTL3 in ISO-treated PRNCs. Conclusion These findings suggest that C21 enhances neuronal cell survival and morphology and up-regulates methylation and Bc1-2 levels, potentially offering a therapeutic strategy for neuroprotection in clinical settings, particularly in cases of neurotoxic exposure. The mechanism may be related to the upregulation of METTL3.

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Expression of m6A RNA Methylation Regulators and Their Clinical Predictive Value in Intrahepatic Cholangiocarcinoma

Cited by 3 publications

References 30 publications

The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression

The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression

A pan-cancer analysis of the oncogenic and immunological roles of transglutaminase 1 (TGM1) in human cancer

Compound 21 Attenuates Isoflurane-Induced Injury in Neonatal Rat Hippocampal Neurons and Primary Rat Neuronal Cells by Upregulating METTL3

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