Dataset Information

M⁶A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.

ABSTRACT: N⁶-methyladenosine (m⁶A) is the most common RNA modification in eukaryotic RNAs. Although the important roles of m⁶A in RNA fate have been revealed, the potential contribution of m⁶A to RNA function in various diseases, including hepatocellular carcinoma (HCC), is still unclear. In this study, we identified a novel m⁶A-modified RNA AC026356.1. We found that AC026356.1 was increased in HCC tissues and cell lines. High expression of AC026356.1 was correlated with poor survival of HCC patients. m⁶A modification level of AC026356.1 was also increased in HCC and more significantly correlated with poor survival of HCC patients. Functional assays showed that m⁶A-modified AC026356.1 promoted HCC cellular proliferation, migration, and liver metastasis. Gene set enrichment analysis showed that AC026356.1 activated IL11/STAT3 signaling. Mechanistic investigation showed that m⁶A-modified AC026356.1 bound to IGF2BP1. The interaction between m⁶A-modified AC026356.1 and IGF2BP1 promoted the binding of IL11 mRNA to IGF2BP1, leading to increased IL11 mRNA stability and IL11 secretion. Functional rescue assays showed that depletion of IL11 reversed the oncogenic roles of AC026356.1. These findings revealed the potential influences of m⁶A modification on RNA biological functions and suggested that targeting m⁶A modification may be a novel strategy for HCC treatment.

SUBMITTER: Wei H

PROVIDER: S-EPMC10625930 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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m6A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.

Wei Huamei H Yang Jinhun J Lu Rongzhou R Huang Yanyan Y Huang Zheng Z Huang Lizheng L Zeng Min M Wei Yunyu Y Xu Zuoming Z Li Wenchuan W Pu Jian J

Scientific reports 20231105 1

N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic RNAs. Although the important roles of m6A in RNA fate have been revealed, the potential contribution of m6A to RNA function in various diseases, including hepatocellular carcinoma (HCC), is still unclear. In this study, we identified a novel m6A-modified RNA AC026356.1. We found that AC026356.1 was increased in HCC tissues and cell lines. High expression of AC026356.1 ...[more]

PMID: 37926706

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Project description:PurposeHepatocellular carcinoma(HCC) is the most common type of liver cancer and the sixth largest common cancer worldwide. Although surgical resection, hepatic arterial chemoembolization, targeted drugs and immunotherapy are currently available, the mortality of advanced patients remains high. Therefore, new therapeutic targets are urgently needed. In recent years, many studies have found that The long non-coding RNA(lncRNA) has multiple functions in human tumors, including participating in epigenetic, transcriptional, post-transcriptional and translational regulation, and is closely related to the progression of HCC. The purpose of this study was to investigate the role of AC006329.1 in HCC progression and provide theoretical guidance for finding new targets.Patients and methodsAC006329.1 was screened out by transcriptome sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Then a series of functional tests in vivo and in vitro were conducted to investigate the effects of AC006329.1 on HCC progression and metastasis. Epithelial-mesenchymal transformation (EMT) of HCC was detected by Western blot and immunofluorescence staining. The targeted miRNA and downstream gene of AC006329.1 were predicted by databases and the pathway regulation axis eventually validated by dual luciferase reporter assays, qRT-PCR and WB.ResultsAC006329.1 was found high expressed in HCC tissues and cell lines by qRT-PCR. The prognosis of HCC patients with high expressed AC006329.1 was poor. In vitro and in vivo, overexpression of AC006329.1 can promote the progression, metastasis and EMT of HCC by acting as a sponge of miR-127-5p to increase the expression of SHC3. In addition, up-regulation of miR-127-5p or knockdown of SHC3 can both reverse the promoting effects of AC006329.1 on progression, metastasis and EMT of HCC. Finally, WB and qRT-PCR analysis was discovered that AC006329.1 can facilitate HCC progression, EMT and metastasis by competitively inhibiting miR-127-5p to activate SHC3/ERK signaling pathway.ConclusionThese above experimental results confirmed that AC006329.1 can facilitate HCC progression, EMT and metastasis by acting as a competing endogenous RNA (ceRNA) to inhibit miR-127-5p and activate SHC3/ERK signaling pathway.

Project description:As the most prevalent epitranscriptomic modification, N6-methyladenosine (m6A) shows important roles in a variety of diseases through regulating the processing, stability and translation of target RNAs. However, the potential contributions of m6A to RNA functions are unclear. Here, we identified a functional and prognosis-related m6A-modified RNA SREBF2-AS1 in hepatocellular carcinoma (HCC). The expression of SREBF2-AS1 and SREBF2 in HCC tissues and cells was measured by RT-qPCR. m6A modification level of SREBF2-AS1 was measured by methylated RNA immunoprecipitation assay. The roles of SREBF2-AS1 in HCC progression and sorafenib resistance were investigated by proliferation, apoptosis, migration, and cell viability assays. The regulatory mechanisms of SREBF2-AS1 on SREBF2 were investigated by Chromatin isolation by RNA purification, RNA immunoprecipitation, CUT&RUN, and bisulfite DNA sequencing assays. Our findings showed that the expression of SREBF2-AS1 was increased in HCC tissues and cells, and positively correlated with poor survival of HCC patients. m6A modification level of SREBF2-AS1 was also increased in HCC and positively correlated with poor prognosis of HCC patients. METTL3 and METTL14-induced m6A modification upregulated SREBF2-AS1 expression through increasing SREBF2-AS1 transcript stability. Functional assays showed that only m6A-modified, but not non-modified SREBF2-AS1 promoted HCC progression and sorafenib resistance. Mechanistic investigations revealed that m6A-modified SREBF2-AS1 bound and recruited m6A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1 to SREBF2 promoter, leading to DNA demethylation at SREBF2 promoter and the upregulation of SREBF2 transcription. Functional rescue assays showed that SREBF2 was the critical mediator of the oncogenic roles of SREBF2-AS1 in HCC. Together, this study showed that m6A-modified SREBF2-AS1 exerted oncogenic roles in HCC through inducing DNA demethylation and transcriptional activation of SREBF2, and suggested m6A-modified SREBF2-AS1 as a prognostic biomarker and therapeutic target for HCC.

Project description:BackgroundHepatocellular carcinoma (HCC) has a hidden onset and high malignancy. Its high metastasis, high recurrence, and short survival time have always been a difficult and hot spot in clinical practice. Our previous study revealed that myc-associated zinc finger protein (MAZ) is highly upregulated in HCC tissues and may promote the proliferation and metastasis of HCC cells by inducing the epithelial-mesenchymal transformation (EMT) process. However, the specific regulatory mechanism by which MAZ functions as an oncogene in HCC has still not been fully elucidated.MethodsImmunohistochemical staining and bioinformatics analyses were conducted to measure the expression of MAZ, key m6A enzymes, and ZEB1 in HCC tissues. RNA sequencing (RNA-seq) of MAZ knockdown HCC cells and human mRNA m6A sequencing (m6A-seq) of HCC tissues were intersected to screen the downstream targets for both MAZ and m6A methylation. The correlations between MAZ and its targets were analyzed by dual-luciferase assays and cell rescue experiments.ResultsHere, we report for the first time that MAZ is involved in m6A methylation of HCC by targeting the transcriptional regulation of key m6A enzymes. MAZ expression was significantly correlated with the expression of key m6A enzymes in HCC tissues and cell lines. Moreover, MAZ could bind to the promoters of key m6A enzymes, and multivariate Cox regression analysis suggested that MAZ and METTL3 expression were independent risk factors for the survival of HCC patients. Through RNA-seq and m6A-seq, we screened out EMT regulators ZEB1 and TRIM50 as the downstream targets for both MAZ and m6A methylation. Mechanistically, m6A sites with high confidence in ZEB1 and TRIM50 mRNA were identified by SRAMP, and there were significant relationships between ZEB1 and METTL3 in HCC tissues and cells. A nomogram model was established to better display the combined effect of MAZ, METTL3, and ZEB1 on HCC prognosis.ConclusionsOur study revealed a promising clinical application of MAZ, METTL3, and ZEB1 in HCC prognosis, further suggesting that MAZ can be used as a potential molecular biomarker for HCC diagnosis and prognosis.

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M⁶A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.

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m<sup>6</sup>A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.

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Dataset Information

M6A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.

Publications

m<sup>6</sup>A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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M⁶A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.