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Journal of Molecular Medicine

, Volume 97, Issue 11, pp 1535–1545 | Cite as

METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN

  • Qiu-Hong TianEmail author
  • Mei-Fang Zhang
  • Jin-Sheng Zeng
  • Rong-Guang Luo
  • Yang Wen
  • Jun Chen
  • Liu-Gen Gan
  • Jian-Ping XiongEmail author
Original Article

Abstract

RNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an independent factor for unfavorable overall survival. In vitro studies demonstrate that METTL1 overexpression promotes cell proliferation and migration, whereas its knockdown results in opposite phenotypes. Gene set enrichment analysis (GSEA) indicates PTEN pathway is activated in patients with low METTL1 expression. Ectopic expression of PTEN or inhibition of AKT activity significantly attenuates the METTL1-mediated malignant phenotypes. In clinical samples, METTL1 expression is reversely associated with PTEN expression. Combination of low METTL1 expression and high PTEN expression is significantly correlated with overall survival, more so than either METTL1 or PTEN expression alone. Collectively, our data suggest that METTL1 serves as a promising prognostic biomarker and that targeting METTL1/PTEN axis may provide therapeutic potential in HCC intervention.

Key messages

  • METTL1 is upregulated in HCC and correlated with poor outcomes.

  • METTL1 promotes cell proliferation and migration in HCC.

  • METTL1 exerts oncogenic activities via suppression of PTEN signaling.

Keywords

METTL1 PTEN Prognosis Hepatocellular carcinoma 

Notes

Funding information

The study was supported by the National Natural Science Foundation of China (No. 81960441).

Compliance with ethical standards

Written informed consent was obtained from all patients involved in this study. The use of tissues in this study has been approved by the Institute Research Medical Ethics Committees of SYSUCC and The First Affiliated Hospital of Nanchang University.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

109_2019_1830_MOESM1_ESM.pdf (32 kb)
Supplementary Figure 1 The genomic alteration of METTL1 in malignancies in TCGA dataset. (PDF 31.9 kb)
109_2019_1830_MOESM2_ESM.jpg (370 kb)
Supplementary Figure 2 AKT activity is involved in METTL1-mediated phenotypes. A. HepG2 and Huh7 cells with METTL1 overexpression were treated with 1 μM MK2206, a specific inhibitor of AKT, for 24 h. Colony formation and transwell assays were performed. B. HCC cells treated with METTL1 siRNA were incubated with 100 nM insulin, an AKT activator, for 24 h. Cell proliferation and migration were evaluated. *P < 0.05. (JPG 369 kb)
109_2019_1830_MOESM3_ESM.jpg (176 kb)
Supplementary Figure 3 The effect of NANOG on METTL1-mediated cell growth and migration. A. Cells were transfected with METTL1 siRNA for 36 h. The expression of METTL1, NANOG and KLF4 were determined by Western blot. B. The effect of NANOG on METTL1-mediated cell proliferation and migration were tested using rescue experiments. All *P < 0.05. (JPG 176 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Qiu-Hong Tian
    • 1
    Email author
  • Mei-Fang Zhang
    • 2
  • Jin-Sheng Zeng
    • 3
  • Rong-Guang Luo
    • 4
  • Yang Wen
    • 1
  • Jun Chen
    • 1
  • Liu-Gen Gan
    • 5
  • Jian-Ping Xiong
    • 1
    Email author
  1. 1.Department of OncologyFirst Affiliated Hospital of Nanchang UniversityNanchangChina
  2. 2.Department of PathologySun Yat-sen University Cancer CenterGuangzhouChina
  3. 3.Department of General SurgeryFirst Affiliated Hospital of Nanchang UniversityNanchangChina
  4. 4.Department of Medical Imaging and Interventional RadiologyFirst Affiliated Hospital of Nanchang UniversityNanchangChina
  5. 5.Department of PathologyFirst Affiliated Hospital of Nanchang UniversityNanchangChina

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