RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway

Qiao, Kun; Liu, Yantao; Xu, Zheng; Zhang, Haohao; Zhang, Heng; Zhang, Chao; Chang, Zhi; Lu, Xinyan; Li, Zhongwei; Luo, Ce; Liu, Yanrong; Yang, Cheng; Sun, Tao

doi:10.1007/s10456-020-09744-8

Cited by 73 publications

(53 citation statements)

References 50 publications

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“…Another study revealed that reperfusion-mediated energetic crises were attenuated by mitochondrial fission suppression in a mouse model of cardiac ischemia/reperfusion injury [67]. It was also reported that intimal thickening after coronary damage was enhanced by mitochondrial fission due to dysregulated macrophage function [68,69]. Further, it was demonstrated that inflammation and apoptosis of coronary endothelial cells were reduced via inhibition of mitochondrial fission or activation of mitophagy [70].…”

mentioning

confidence: 98%

Coronary Endothelium No‐Reflow Injury Is Associated with ROS‐Modified Mitochondrial Fission through the JNK‐Drp1 Signaling Pathway

Chen

Liu

Zhou

et al. 2021

Oxidative Medicine and Cellular Longevity

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Coronary artery no-reflow is a complex problem in the area of reperfusion therapy, and the molecular mechanisms underlying coronary artery no-reflow injury have not been fully elucidated. In the present study, we explored whether oxidative stress caused damage to coronary endothelial cells by inducing mitochondrial fission and activating the JNK pathway. The hypoxia/reoxygenation (H/R) model was induced in vitro to mimic coronary endothelial no-reflow injury, and mitochondrial fission, mitochondrial function, and endothelial cell viability were analyzed using western blotting, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Our data indicated that reactive oxygen species (ROS) were significantly induced upon H/R injury, and this was followed by decreased endothelial cell viability. Mitochondrial fission was induced and mitochondrial bioenergetics were impaired in cardiac endothelial cells after H/R injury. Neutralization of ROS reduced mitochondrial fission and protected mitochondrial function against H/R injury. Our results also demonstrated that ROS stimulated mitochondrial fission via JNK-mediated Drp1 phosphorylation. These findings indicate that the ROS-JNK-Drp1 signaling pathway may be one of the molecular mechanisms underlying endothelial cell damage during H/R injury. Novel treatments for coronary no-reflow injury may involve targeting mitochondrial fission and the JNK-Drp1 signaling pathway.

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confidence: 98%

Coronary Endothelium No‐Reflow Injury Is Associated with ROS‐Modified Mitochondrial Fission through the JNK‐Drp1 Signaling Pathway

Chen

Liu

Zhou

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…CAFs, as the most critical stromal cells in TME, participate in the process of tumor growth and development [6][7][8][9][10][11][12][13]. As an important supplement to tumor microcirculation, VM occurs in certain highly aggressive malignancies, and is closely related to tumor progression and poor prognosis [18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

Pan

Wang

Ansari

et al. 2020

Preprint

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Background: Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism.Methods: A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (-) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored. Results: GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the upregulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway.Conclusions: GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is overexpressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.

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“…Angiogenesis is essential for HCC progression and metastasis. Vasculogenic mimicry (VM) formed by aggressive tumor cells has been found in various types of cancer, including ovarian cancer, colorectal cancer, melanoma and HCC, and associated with poor prognosis in patients 124 - 126 . Pathologic angiogenesis is critical for the growth and malignant dissemination of solid tumors by providing oxygen, nutrients, and routes for metastasis 127 .…”

Section: Neovascularizationmentioning

confidence: 99%

“…Several studies demonstrated that m 6 A modification could also influence HCC progression through regulating angiogenesis. Qiao et al showed that silencing METTL3 suppresses VM formation through inhibiting YAP1 expression 124 . Intratumoral hypoxia is a common signature of human solid cancer including HCC and could regulate the expression of genes that involver in regulating angiogenesis, EMT process, self-renewal of cancer stem cells, chemotherapy- and radiation- therapy resistance extracellular matrix remodeling, cancer stem cell maintenance through hypoxia-induced factor (HIF) 128 .…”

Section: Neovascularizationmentioning

confidence: 99%

The emerging roles of m⁶A modification in liver carcinogenesis

Pan¹,

Li²

2021

Int. J. Biol. Sci.

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The 'epitranscriptome', a collective term for chemical modifications that influence the structure, metabolism, and functions of RNA, has recently emerged as vitally important for the regulation of gene expression. N 6 -methyladenosine (m 6 A), the most prevalent mammalian mRNA internal modification, has been demonstrated to have a pivotal role in almost all vital bioprocesses, such as stem cell self-renewal and differentiation, heat shock or DNA damage response, tissue development, and maternal-to-zygotic transition. Hepatocellular carcinoma (HCC) is prevalent worldwide with high morbidity and mortality because of late diagnosis at an advanced stage and lack of effective treatment strategies. Epigenetic modifications including DNA methylation and histone modification have been demonstrated to be crucial for liver carcinogenesis. However, the role and underlying molecular mechanism of m 6 A in liver carcinogenesis are mostly unknown. In this review, we summarize recent advances in the m 6 A region and how these new findings remodel our understanding of m 6 A regulation of gene expression. We also describe the influence of m 6 A modification on liver carcinoma and lipid metabolism to instigate further investigations of the role of m 6 A in liver biological diseases and its potential application in the development of therapeutic strategies.

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RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway

Cited by 73 publications

References 50 publications

Coronary Endothelium No‐Reflow Injury Is Associated with ROS‐Modified Mitochondrial Fission through the JNK‐Drp1 Signaling Pathway

Coronary Endothelium No‐Reflow Injury Is Associated with ROS‐Modified Mitochondrial Fission through the JNK‐Drp1 Signaling Pathway

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

The emerging roles of m⁶A modification in liver carcinogenesis

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RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway

Cited by 73 publications

References 50 publications

Coronary Endothelium No‐Reflow Injury Is Associated with ROS‐Modified Mitochondrial Fission through the JNK‐Drp1 Signaling Pathway

Coronary Endothelium No‐Reflow Injury Is Associated with ROS‐Modified Mitochondrial Fission through the JNK‐Drp1 Signaling Pathway

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

The emerging roles of m6A modification in liver carcinogenesis

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The emerging roles of m⁶A modification in liver carcinogenesis