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A novel pVHL-independent but NEMO-driven pathway in renal cancer promotes HIF stabilization

A M Nowicka1, I Häuselmann2, L Borsig2

  • 1Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.

Oncogene
|October 27, 2015
PubMed

Insights

Nuclear factor (NF)-κB essential modulator (NEMO) drives clear cell renal cell carcinoma (ccRCC) progression independently of the von Hippel-Lindau (VHL) protein. NEMO stabilizes hypoxia-inducible factor alpha (HIFα), promoting tumor survival and metastasis, suggesting NEMO as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Clear cell renal cell carcinoma (ccRCC) pathogenesis often involves hypoxia-inducible factor (HIF) activation due to loss of von Hippel-Lindau protein (pVHL) function.
  • A pVHL-independent mechanism of HIF regulation and its role in ccRCC progression remain incompletely understood.

Purpose of the Study:

  • To identify novel factors regulating HIF in ccRCC.
  • To investigate the role of nuclear factor (NF)-κB essential modulator (NEMO) in ccRCC progression and its relationship with the VHL/HIF pathway.

Main Methods:

  • Immunohistochemistry on 157 human ccRCC samples to assess NEMO protein expression.
  • In vitro studies to examine NEMO's interaction with HIFα and its effect on NF-κB signaling.
  • Analysis of NEMO's impact on tumor cell survival, apoptosis, and epithelial-to-mesenchymal transition (EMT).

Main Results:

  • Over 60% of ccRCCs exhibited negative or weak NEMO expression; moderate/strong expression was more common in VHL wild-type tumors.
  • NEMO directly interacts with HIFα, stabilizing it independently of NF-κB signaling.
  • NEMO promotes ccRCC progression by enhancing tumor cell survival, inhibiting apoptosis, and activating EMT, thereby facilitating metastasis.

Conclusions:

  • NEMO is a novel oncogenic factor in ccRCC, driving HIF activation through a pVHL-independent mechanism.
  • NEMO links the NF-κB and VHL/HIF pathways in ccRCC progression.
  • Targeting NEMO could represent a new therapeutic strategy for metastatic ccRCC, particularly in patients with functional pVHL.

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