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UPF1 Inhibits Hepatocellular Carcinoma Growth through DUSP1/p53 Signal Pathway

Suman Lee1, Yukyung Hwang1, Tae Hun Kim2

  • 1Graduate School for Biomedical Science & Engineering, Hanyang University, Seoul 04763, Korea.

Biomedicines
|April 23, 2022
PubMed

Insights

Overexpression of UPF1 variants, not UPF1-mediated mRNA decay, inhibits hepatocellular carcinoma (HCC) growth. This occurs via increased dual specificity phosphatase 1 (DUSP1), activating tumor suppressor pathways and reducing HCC tumorigenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • Hepatocellular carcinoma (HCC) presents a significant global health challenge due to limited effective therapies.
  • UPF1, a key factor in nonsense-mediated mRNA decay (NMD), has been implicated in reducing HCC growth, but the precise mechanism remains elusive.
  • Understanding UPF1's role in RNA stability and HCC proliferation is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To elucidate the mechanism by which UPF1 expression influences hepatocellular carcinoma (HCC) progression.
  • To investigate whether UPF1-mediated nonsense-mediated mRNA decay (NMD) or other UPF1 functions are responsible for inhibiting HCC growth.
  • To identify downstream targets and signaling pathways affected by UPF1 modulation in HCC.

Main Methods:

  • Utilized various UPF1 variants to differentiate between NMD-dependent and independent functions.
  • Performed transcriptome analysis to identify gene expression changes upon UPF1 variant overexpression.
  • Assessed the impact of UPF1 variant overexpression on HCC tumorigenesis in vitro and in xenograft mouse models.
  • Investigated the posttranscriptional regulation of target genes, specifically dual specificity phosphatase 1 (DUSP1).

Main Results:

  • Overexpression of UPF1 variants, independent of UPF1-mediated NMD, significantly reduced HCC tumorigenesis.
  • UPF1 variant overexpression led to increased levels of dual specificity phosphatase 1 (DUSP1) through posttranscriptional regulation.
  • UPF1 variant-induced DUSP1 activation of tumor suppressor signaling pathways resulted in inhibited HCC cell growth.
  • Tumorigenesis was suppressed in xenografted mice following UPF1 variant administration.

Conclusions:

  • UPF1 functions as a tumor suppressor in hepatocellular carcinoma (HCC).
  • The tumor-suppressive role of UPF1 in HCC is mediated by its variants, not solely by its canonical NMD function.
  • UPF1 variants promote HCC inhibition by upregulating DUSP1, which subsequently activates anti-tumorigenic signaling cascades.
Keywords:
DUSP1UPF1hepatocellular carcinomaposttranscriptional regulation

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