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PreprintCited by 17RNA modifications and cancerCancer-related gene regulationHepatocellular Carcinoma Treatment and Prognosis

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Therapeutic effect and transcriptome-methylome characteristics of METTL3 inhibition in liver hepatocellular carcinoma

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Liu, Qingbin, Qi, Jingjing, Li, Weiyang, Tian, Xinchen, Zhang, Jiaqi, Liu, Fen, Lu, Xiulian, Zang, Hengchang, Liu, Chenqiao, Ma, Changlin, Yu, Yong, Jiang, Shulong·2023·Cancer Cell International
DOI 10.21203/rs.3.rs-3164252/v1PMC PMC10683134

Preprint — published as 10.1186/s12935-023-03096-1

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Abstract

Methyltransferase-like 3 (METTL3) is the key subunit of methyltransferase complex responsible for catalyzing N6-methyladenosine (m 6 A) modification on mRNA, which is the most prevalent post-transcriptional modification in eukaryotes. In this study, we utilized online databases to analyze the association between METTL3 expression and various aspects of tumorigenesis, including gene methylation, immunity, and prognosis. Our investigation revealed that METTL3 serves as a prognostic marker and therapeutic target for liver hepatocellular carcinoma (LIHC). Through experimental studies, we observed frequent upregulation of METTL3 in LIHC tumor tissue and cells. Subsequent inhibition of METTL3 using a novel small molecule inhibitor, STM2457, significantly impeded tumor growth in LIHC cell lines, spheroids, and xenograft tumor model. Further, transcriptome and m 6 A sequencing of xenograft bodies unveiled that inhibition of METTL3-m 6 A altered genes enriched in SMAD and MAPK signaling pathways that are critical for tumorigenesis. These findings suggest that targeting METTL3 represents a promising therapeutic strategy for LIHC.

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Metadata

Authors
Liu, Q., Qi, J., Li, W., Tian, X., Zhang, J., Liu, F., Lu, X., Zang, H., Liu, C., Ma, C., Yu, Y., & Jiang, S.
Affiliations
  • Shandong University (CN)
  • Johannes Kepler University of Linz (AT)
  • Jining Medical University (CN)
  • Jining First People's Hospital (CN)
  • Cisen Pharmaceutical Co. Ltd, Jining, Jining 272000, China 250100, China
Corresponding author
  • Ma, Changlin
  • Yu, Yong
  • Jiang, Shulong
ORCID
Venue
Cancer Cell International
Publisher
Research Square Platform LLC
Published
2023-07-20
Volume
23
Issue
1
Pages
298-298
ISSN
1475-2867 (ISSN-L)
DOI
10.21203/rs.3.rs-3164252/v1
PMC
PMC10683134
OpenAlex
W4389040025
Cited by
17
References
1
Citations by year
2026: 4 · 2025: 8 · 2024: 5
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell International (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82074360, 81873249, tsqn201909200)
  • Natural Science Foundation of Shandong Province (ZR2019MH058)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
METTL3, hepatocellular carcinoma, N6-methyladenosine, m6A RNA methylation, STM2457, small molecule inhibitors, prognostic factors, therapeutic target, Smad signaling, MAPK signaling, antitumor immunity, DNA methylation

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