m6A‐Mediated TMCO3 Promotes Hepatocellular Carcinoma Progression by Facilitating the Membrane Translocation and Activation of AKT

m6A‐Mediated TMCO3 Promotes Hepatocellular Carcinoma Progression by Facilitating the Membrane Translocation and Activation of AKT

Abstract The transmembrane and coiled‐coil domains 3 (TMCO3) are highly expressed in many tumors. However, the underlying mechanisms governing the way in which TMCO3 affects the progression of hepatocellular carcinoma (HCC) remain unclear. This study screens out the molecule TMCO3 with high N6‐methy...

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Bibliographic Details
Main Authors: Xinxin Li, Mengzhen Han, He Zhu, Yonglong Pan, Chen Su, Yachong Liu, Zhibin Liao, Bixiang Zhang, Xiaoping Chen
Format: Article
Language:English
Published: Wiley 2025-07-01
Series:Advanced Science
Subjects:
AKT
HCC
m6A
MK2206
TMCO3
Online Access:https://doi.org/10.1002/advs.202504187
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Summary:Abstract The transmembrane and coiled‐coil domains 3 (TMCO3) are highly expressed in many tumors. However, the underlying mechanisms governing the way in which TMCO3 affects the progression of hepatocellular carcinoma (HCC) remain unclear. This study screens out the molecule TMCO3 with high N6‐methyladenosine (m6A) modification level in tumor samples compared to the adjacent non‐cancerous tissues of three pairs of HCC patients through Methylated RNA Immunoprecipitation Sequencing (MeRIP‐seq) and RNA sequencing (RNA‐seq). Subsequently, the oncogenic effect of TMCO3 in HCC is verified through in vivo and in vitro experiments. AlkB Homolog 5 (ALKBH5), an m6A demethylase of TMCO3 is then screened out. The following experiments demonstrate that TMCO3 can activate AKT directly through the Phosphatidylinositol‐3–Kinase (PI3K) pathway, thus promoting the progression of HCC. Meanwhile, the phosphorylation site on TMCO3: the 85th amino acid‐serine, and mutation of this site can directly impair the activity and membrane translocation of AKT is found. Finally, the carcinogenic effect of TMCO3 is further elucidated in HCC through the orthotopic treatment model and the hydrodynamic tail vein injection treatment model. The findings can provide a potential target for targeted AKT treatment in patients with HCC and verify a possible prognostic marker in HCC.
ISSN:2198-3844

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