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PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis

Liwen Li1,2, Fan Sun1,2, Lei Han1,2

  • 1UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.

JCI Insight
|February 4, 2021
PubMed

Insights

Lung tumor suppressor PDZ-LIM domain-containing protein 2 (PDLIM2) is downregulated in alveolar macrophages (AMs) during cancer. This promotes tumor growth by activating STAT3 signaling and reducing AMs ability to fight cancer.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • The transition from tumor immunosurveillance to tumor-promoting inflammation is a critical challenge in cancer research.
  • Alveolar macrophages (AMs) play a complex role in lung tumorigenesis, capable of both suppressing and promoting tumor growth.

Purpose of the Study:

  • To identify key regulators of AM function during lung tumorigenesis.
  • To elucidate the molecular mechanisms by which AMs shift from a tumor-suppressive to a tumor-promoting phenotype.

Main Methods:

  • Investigated the role of PDZ-LIM domain-containing protein 2 (PDLIM2) in lung tumor suppression.
  • Analyzed the regulation of PDLIM2 expression by ROS-activated transcription repressor BTB and CNC homology 1 (BACH1).
  • Examined the downstream effects of PDLIM2 downregulation on STAT3 activation, AM polarization, monocyte differentiation, and phagocytosis.

Main Results:

  • PDLIM2, a tumor suppressor, acts as a checkpoint for AMs in lung cancer.
  • During lung tumorigenesis, reactive oxygen species (ROS) activate BACH1, which downregulates PDLIM2 expression in AMs.
  • PDLIM2 downregulation leads to constitutive STAT3 activation, promoting AM protumorigenic polarization, monocyte recruitment, suppression of cytotoxic T lymphocytes, and reduced AM phagocytosis.

Conclusions:

  • The ROS/BACH1/PDLIM2/STAT3 signaling axis is identified as a critical pathway driving AMs towards a tumor-promoting role in lung cancer.
  • Restoring PDLIM2 function in AMs may represent a potential therapeutic strategy for lung cancer.
Keywords:
CancerLung cancerMacrophagesOncology

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