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Alcohol-induced C/EBP β-driven VIRMA decreases oxidative stress and promotes pancreatic ductal adenocarcinoma growth and metastasis via the m6A/YTHDF2/SLC43A2 pathway

Oncogene volume 44, pages 1118–1132 (2025)Cite this article

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Abstract

N6-methyladenosine (m6A) plays a role in the development of tumors. However, the specific role of VIRMA, an RNA methyltransferase, in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study shows that VIRMA expression is elevated in PDAC. Increased VIRMA levels promoted PDAC growth and spread, while reducing VIRMA expression slowed these processes. VIRMA facilitated SLC43A2 mRNA degradation through an m6A-YTHDF2 pathway. The resulting decrease in SLC43A2 reduced phenylalanine absorption and oxidative stress, further driving PDAC progression. Furthermore, alcohol increased C/EBP β expression, which bound to VIRMA’s promoter, enhancing its transcription. These findings suggest a connection between alcohol consumption, m6A modifications, and phenylalanine absorption in PDAC progression, offering a new approach to combat this disease.

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Fig. 1: Elevated VIRMA expression in PDAC correlates with poor prognosis.
Fig. 2: Alcohol-Induced C/EBP β activation triggers VIRMA transcription.
Fig. 3: Role of VIRMA in PDAC progression: in vitro and in vivo analysis.
Fig. 4: SLC43A2 identified as a target of VIRMA.
Fig. 5: VIRMA facilitates SLC43A2 mRNA degradation through the m6A-YTHDF2 pathway.
Fig. 6: SLC43A2’s role in PDAC progression.
Fig. 7: SLC43A2 promotes phenylalanine absorption and ROS accumulation to inhibit PDAC proliferation and metastasis.
Fig. 8: Alcohol-induced C/EBP β-mediated VIRMA suppression leads to downregulation of SLC43A2.

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Data availability

All data listed in this study are available within this publication and supplementary files.

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Acknowledgements

The KPC1199 cell was provided by Dr. Jing Xue from Renji Hospital (Shanghai, China). We are very grateful to Dr. JiWei Li (Lifegenes Biotechnology, Shanghai, China) for contributing to the RNA-Seq and MeRIP-seq analysis.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81770639, 82070657 and 82370651), Applied Technology Research and Development Project of Heilongjiang Province (No. GA20C019), First Affiliated Hospital of Harbin Medical University Fund for Distinguished Young Scholars (No. HYD2020JQ0006), Research Project of Chinese Research Hospital Association (Y2019FH-DTCC-SB1).

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Authors and Affiliations

  1. Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Lei Gao, Gaoyuan Lv, Ziying Liu, Le Li & Gang Wang

  2. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China

    Lei Gao

  3. Department of Oncology and Laparoscopy Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Lei Gao & Gang Wang

  4. Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China

    Yitong Tian

  5. Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China

    Fang Han & Yuhua Zhang

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Contributions

LG: conceptualization, data curation, software, investigation, visualization, writing-original draft; GYL: data curation, validation, investigation; ZYL: data curation, validation, investigation; YTT: data curation; FH: formal analysis; LL: supervision, conceptualization; GW: conceptualization, supervision, methodology, writing-review and editing; YHZ: supervision, conceptualization, methodology.

Corresponding authors

Correspondence to Gang Wang or Yuhua Zhang.

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The authors declare no competing interests.

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All methods in this study were performed in accordance with the relevant guidelines and regulations. This study was approved by the Ethics Committee of the Zhejiang Cancer Hospital (IRB-2022-545) and the First Affiliated Hospital of Harbin Medical University (IRB-AF/SC-04/02.0). Informed consent was obtained from all patients.

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Gao, L., Lv, G., Liu, Z. et al. Alcohol-induced C/EBP β-driven VIRMA decreases oxidative stress and promotes pancreatic ductal adenocarcinoma growth and metastasis via the m6A/YTHDF2/SLC43A2 pathway. Oncogene 44, 1118–1132 (2025). https://doi.org/10.1038/s41388-025-03283-6

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