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Article: The inhibition of YTHDF3/m6A/LRP6 reprograms fatty acid metabolism and suppresses lymph node metastasis in cervical cancer

TitleThe inhibition of YTHDF3/m6A/LRP6 reprograms fatty acid metabolism and suppresses lymph node metastasis in cervical cancer
Authors
Keywordscervical cancer
fatty acid metabolism
LRP6
lymph node metastasis
m6A
YTHDF3
Issue Date12-Jan-2024
PublisherIvyspring International Publisher
Citation
International Journal of Biological Sciences, 2024, v. 20, n. 3, p. 916-936 How to Cite?
AbstractThe lipid synthesis of fatty acid (FA) represents a significant hallmark in the occurrence and progression of malignant tumor, which are associated with lymph node (LN) metastasis. Elucidation of the molecular mechanisms underlying LN metastasis could provide therapeutic strategies for cervical cancer (CCa). N6-Methyladenosine (m6A), the most prevalent and abundant RNA modification, exerts specific regulatory control over a series of oncogene expressions. This study demonstrated a clinical correlation between the upregulation of the m6A reader YTHDF3 and LN metastasis, thereby contributing to poor overall survival probability (OS) among CCa patients. The mechanistic investigation revealed that SREBF1 transcriptionally activated YTHDF3 expression by binding to its promoter. Functional experiments demonstrated that the upregulation of YTHDF3 significantly enhanced the in vitro proliferative, migratory, and invasive capacities of CCa cells, while also promoting lymphangiogenesis and facilitating LN metastasis in vivo. Mechanistically, the upregulation of LRP6 through YTHDF3-mediated m6A modification resulted in increased expression of FASN and ACC1, leading to both lipolysis of lipid droplets and synthesis of free fatty acid. Ultimately, this promoted fatty acid metabolism and enhanced LN metastasis by activating the LRP6-YAP-VEGF-C axis, which could induce lymphangiogenesis in CCa. Our study highlighted that YTHDF3 can serve as a promising therapeutic target and predictive biomarker for CCa patients with LN metastasis.
Persistent Identifierhttp://hdl.handle.net/10722/339855
ISSN
2023 Impact Factor: 8.2
2023 SCImago Journal Rankings: 2.114
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhong, S-
dc.contributor.authorGuo, Q-
dc.contributor.authorChen, X-
dc.contributor.authorLuo, X-
dc.contributor.authorLong, Y-
dc.contributor.authorChong, T-
dc.contributor.authorYe, M-
dc.contributor.authorHe, H-
dc.contributor.authorLu, A-
dc.contributor.authorAo, K-
dc.contributor.authorYin, M-
dc.contributor.authorXu, A-
dc.contributor.authorLi, X-
dc.contributor.authorHao, Y-
dc.contributor.authorGuo, X-
dc.date.accessioned2024-03-11T10:39:48Z-
dc.date.available2024-03-11T10:39:48Z-
dc.date.issued2024-01-12-
dc.identifier.citationInternational Journal of Biological Sciences, 2024, v. 20, n. 3, p. 916-936-
dc.identifier.issn1449-2288-
dc.identifier.urihttp://hdl.handle.net/10722/339855-
dc.description.abstractThe lipid synthesis of fatty acid (FA) represents a significant hallmark in the occurrence and progression of malignant tumor, which are associated with lymph node (LN) metastasis. Elucidation of the molecular mechanisms underlying LN metastasis could provide therapeutic strategies for cervical cancer (CCa). N6-Methyladenosine (m<sup>6</sup>A), the most prevalent and abundant RNA modification, exerts specific regulatory control over a series of oncogene expressions. This study demonstrated a clinical correlation between the upregulation of the m<sup>6</sup>A reader YTHDF3 and LN metastasis, thereby contributing to poor overall survival probability (OS) among CCa patients. The mechanistic investigation revealed that SREBF1 transcriptionally activated YTHDF3 expression by binding to its promoter. Functional experiments demonstrated that the upregulation of YTHDF3 significantly enhanced the <i>in vitro</i> proliferative, migratory, and invasive capacities of CCa cells, while also promoting lymphangiogenesis and facilitating LN metastasis <i>in vivo</i>. Mechanistically, the upregulation of LRP6 through YTHDF3-mediated m<sup>6</sup>A modification resulted in increased expression of FASN and ACC1, leading to both lipolysis of lipid droplets and synthesis of free fatty acid. Ultimately, this promoted fatty acid metabolism and enhanced LN metastasis by activating the LRP6-YAP-VEGF-C axis, which could induce lymphangiogenesis in CCa. Our study highlighted that YTHDF3 can serve as a promising therapeutic target and predictive biomarker for CCa patients with LN metastasis.-
dc.languageeng-
dc.publisherIvyspring International Publisher-
dc.relation.ispartofInternational Journal of Biological Sciences-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectcervical cancer-
dc.subjectfatty acid metabolism-
dc.subjectLRP6-
dc.subjectlymph node metastasis-
dc.subjectm6A-
dc.subjectYTHDF3-
dc.titleThe inhibition of YTHDF3/m6A/LRP6 reprograms fatty acid metabolism and suppresses lymph node metastasis in cervical cancer-
dc.typeArticle-
dc.identifier.doi10.7150/ijbs.87203-
dc.identifier.pmid38250152-
dc.identifier.scopuseid_2-s2.0-85183082210-
dc.identifier.volume20-
dc.identifier.issue3-
dc.identifier.spage916-
dc.identifier.epage936-
dc.identifier.eissn1449-2288-
dc.identifier.isiWOS:001165345100005-
dc.identifier.issnl1449-2288-

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