YTHDF2 Is a Therapeutic Target for HCC by Suppressing Immune Evasion and Angiogenesis Through ETV5/PD‐L1/VEGFA Axis

Wen, Jingyuan; Xue, Lin; Wei, Yi; Liang, Junnan; Jia, Wenlong; Yong, Tuying; Chu, Liang; Li, Han; Han, Shenqi; Liao, Jingyu; Chen, Zeyu; Liu, Yiyang; Liu, Qiumeng; Ding, Zeyang; Liang, Huifang; Gan, Lu; Chen, Xiaoping; Huang, Zhao; Zhang, Bixiang

doi:10.1002/advs.202307242

Cited by 5 publications

(1 citation statement)

References 54 publications

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“…Several lncRNAs and miRNAs can exert immunosuppressive influence to facilitate HCC progression, such as lncMALAT1 ( 72 ), lncHULC ( 73 ), lncHOTAIR ( 74 ), lncLINC01132 ( 75 ), lncPVT1 ( 76 ), lncLINC00662 ( 77 ), lncβ-Catm ( 78 ), miR-23a-3p ( 79 ), and miR-146a-5p ( 80 ). Dysregulated expression of epigenetic regulators, including DNMT3α ( 81 ), KDM1A ( 82 , 83 ), YTHDF2 ( 84 ), and RALYL ( 85 ), as well as kinases and phosphatases such as IRAK1 ( 86 ) and SHP2 ( 87 ), may also contribute to the formation of an immunosuppressive TME in HCC. As an intricate malignancy, HCC is characterized by metabolic reprogramming, in which glycolytic and lipid metabolism aberrations can contribute to an immunosuppressive TME.…”

Section: General Concept Of Cancer Stem Cellsmentioning

confidence: 99%

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

Muliawan,

Lee

2024

Front. Immunol.

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Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and has a poor prognosis. Although immune checkpoint inhibitors have entered a new era of HCC treatment, their response rates are modest, which can be attributed to the immunosuppressive tumor microenvironment within HCC tumors. Accumulating evidence has shown that tumor growth is fueled by cancer stem cells (CSCs), which contribute to therapeutic resistance to the above treatments. Given that CSCs can regulate cellular and physical factors within the tumor niche by secreting various soluble factors in a paracrine manner, there have been increasing efforts toward understanding the roles of CSC-derived secretory factors in creating an immunosuppressive tumor microenvironment. In this review, we provide an update on how these secretory factors, including growth factors, cytokines, chemokines, and exosomes, contribute to the immunosuppressive TME, which leads to immune resistance. In addition, we present current therapeutic strategies targeting CSC-derived secretory factors and describe future perspectives. In summary, a better understanding of CSC biology in the TME provides a rational therapeutic basis for combination therapy with ICIs for effective HCC treatment.

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Section: General Concept Of Cancer Stem Cellsmentioning

confidence: 99%

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

Muliawan,

Lee

2024

Front. Immunol.

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The YTH domain‐containing protein family: Emerging players in immunomodulation and tumour immunotherapy targets

Li,

Zeng,

Liu

et al. 2024

Clinical & Translational Med

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BackgroundThe modification of N6‐methyladenosine (m6A) plays a pivotal role in tumor by altering both innate and adaptive immune systems through various pathways, including the regulation of messenger RNA. The YTH domain protein family, acting as “readers” of m6A modifications, affects RNA splicing, stability, and immunogenicity, thereby playing essential roles in immune regulation and antitumor immunity. Despite their significance, the impact of the YTH domain protein family on tumor initiation and progression, as well as their involvement in tumor immune regulation and therapy, remains underexplored and lacks comprehensive review.ConclusionThis review introduces the molecular characteristics of the YTH domain protein family and their physiological and pathological roles in biological behavior, emphasizing their mechanisms in regulating immune responses and antitumor immunity. Additionally, the review discusses the roles of the YTH domain protein family in immune‐related diseases and tumor resistance, highlighting that abnormal expression or dysfunction of YTH proteins is closely linked to tumor resistance.Key points This review provides an in‐depth understanding of the YTH domain protein family in immune regulation and antitumor immunity, suggesting new strategies and directions for immunotherapy of related diseases. These insights not only deepen our comprehension of m6A modifications and YTH protein functions but also pave the way for future research and clinical applications.

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m6A modification of VEGFA mRNA by RBM15/YTHDF2/IGF2BP3 contributes to angiogenesis of hepatocellular carcinoma

Xu,

Wu,

Zhang

et al. 2024

Molecular Carcinogenesis

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Vascular endothelial growth factor A (VEGFA) plays a critical role as a potent angiogenesis factor and is highly expressed in hepatocellular carcinoma (HCC). Although the expression of VEGFA has been strongly linked to the aggressive nature of HCC, the specific posttranscriptional modifications that might contribute to VEGFA expression and HCC angiogenesis are not yet well understood. In this study, we aimed to investigate the epitranscriptome regulation of VEGFA in HCC. A comprehensive analysis integrating MeRIP‐seq, RNA‐seq, and crosslinking‐immunprecipitation‐seq data revealed that VEGFA was hypermethylated in HCC and identified the potential m6A regulators of VEGFA including a m6A methyltransferase complex component RBM15 and the two readers, YTHDF2 and IGF2BP3. Through rigorous cell and molecular biology experiments, RBM15 was validated as a key component of methyltransferase complex responsible for m6A methylation of VEGFA, which was subsequently recognized and stabilized by IGF2BP3 and YTHDF2, leading to enhanced VEGFA expression and VEGFA‐related functions such as human umbilical vascular endothelial cells (HUVEC) migration and tube formation. In the HCC xenograft model, knockdown of RBM15, IGF2BP3, or YTHDF2 resulted in reduced expression of VEGFA, accompanied by significant inhibition of tumor growth closely associated with VEGFA expression and angiogenesis. Furthermore, our analysis of HCC clinical samples identified positive correlations between the expression levels of VEGFA and the regulators RBM15, IGF2BP3, and YTHDF2. Collectively, these findings offer novel insights into the posttranscriptional modulation of VEGFA and provide potential avenues for alternative approaches to antiangiogenesis therapy targeting VEGFA.

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YTHDF2 Is a Therapeutic Target for HCC by Suppressing Immune Evasion and Angiogenesis Through ETV5/PD‐L1/VEGFA Axis

Cited by 5 publications

References 54 publications

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

The YTH domain‐containing protein family: Emerging players in immunomodulation and tumour immunotherapy targets

m6A modification of VEGFA mRNA by RBM15/YTHDF2/IGF2BP3 contributes to angiogenesis of hepatocellular carcinoma

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