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CLDN4 regulates cell proliferation in small cell lung cancer cells via SAA1 inhibition

Korehito Kashiwagi1, Hanako Sato-Yazawa1, Jun Ishii1

  • 1Department of Pathology, Dokkyo Medical University School of Medicine and Graduate School of Medicine, 880 Kita-kobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.

Biochemical and Biophysical Research Communications
|September 28, 2025
PubMed

Insights

Claudin-4 (CLDN4) suppresses small cell lung cancer (SCLC) proliferation by inhibiting serum amyloid A1 (SAA1). CLDN4, regulated by SP1 and DNA methylation, presents a potential therapeutic target for this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options.
  • Current SCLC treatment relies on platinum-etoposide chemotherapy, highlighting the need for novel strategies.
  • Claudin-4 (CLDN4), a tight junction protein, influences cancer phenotypes, but its role in SCLC is unknown.

Purpose of the Study:

  • To investigate the role of Claudin-4 (CLDN4) in small cell lung cancer (SCLC) phenotypes.
  • To elucidate the downstream effectors and regulatory mechanisms of CLDN4 in SCLC.

Main Methods:

  • Established CLDN4 knockout H1688 SCLC cells for phenotypic evaluation.
  • Assessed proliferation, migration, and invasion in vitro.
  • Utilized RNA-sequencing (RNA-seq) to identify downstream targets.
  • Investigated transcriptional regulation by SP1 and DNA methylation.

Main Results:

  • CLDN4 knockout significantly promoted SCLC cell proliferation by accelerating cell cycle progression.
  • CLDN4 knockout did not affect cell migration or invasion in vitro.
  • Serum amyloid A1 (SAA1) was identified as a key downstream effector upregulated by CLDN4 knockout, partly mediating proliferation.
  • CLDN4 expression is directly regulated by SP1 and influenced by DNA methylation.

Conclusions:

  • CLDN4 suppresses SCLC cell proliferation, partly through inhibition of SAA1 expression.
  • CLDN4 is transcriptionally regulated by SP1 and DNA methylation.
  • CLDN4 represents a potential therapeutic target for SCLC.
Keywords:
ClaudinSerum amyloid A1Small cell lung cancer

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