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Targeting claudin-4 enhances CDDP-chemosensitivity in gastric cancer

Yukiko Nishiguchi1,2, Rina Fujiwara-Tani1, Takamitsu Sasaki1

  • 1Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan.

Oncotarget
|May 2, 2019
PubMed

Insights

The 4D3 antibody enhances chemotherapy effectiveness in gastric cancer (GC) by targeting CLDN4, a key tight-junction protein. This antibody may improve treatment outcomes by disrupting CLDN4 structure in GC cells.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Claudins (CLDNs) are crucial tight-junction proteins regulating cell polarity and differentiation.
  • CLDN4 is frequently overexpressed in gastric cancer (GC), correlating with differentiation status and CDX2 positivity.
  • Modulating CLDN4 function presents a potential therapeutic strategy for GC.

Purpose of the Study:

  • To investigate the efficacy of the 4D3 antibody targeting the CLDN4 extracellular domain in modulating chemotherapeutic sensitivity in gastric cancer.
  • To explore the underlying mechanisms of CLDN4's role in GC cell behavior and response to treatment.

Main Methods:

  • Analysis of CLDN4 expression in 192 human GC cases.
  • In vitro studies using MKN74 and TMK-1 GC cell lines to assess the synergistic effects of 4D3 antibody and cisplatin (CDDP) treatment, including CLDN4 knockdown.
  • In vivo evaluation of combined 4D3 and CDDP treatment in a nude mouse subcutaneous tumor model.

Main Results:

  • CLDN4 was overexpressed in a majority of GC cases, with higher expression in well-differentiated and CDX2-positive tumors.
  • Co-treatment with the 4D3 antibody synergistically enhanced the anti-tumor effects of CDDP in GC cell lines and in vivo, inhibiting proliferation and increasing apoptosis.
  • Non-tight junction CLDN4 was found to associate with integrin β1, influencing stem cell-associated proteins via FAK-c-SRC signaling in TMK-1 cells.

Conclusions:

  • The 4D3 antibody shows promise in enhancing chemotherapeutic sensitivity in gastric cancer.
  • Targeting CLDN4 with the 4D3 antibody may represent a novel therapeutic approach for GC by disrupting tight-junction integrity.
  • CLDN4's non-tight junction functions may also play a role in GC stemness and therapeutic resistance.
Keywords:
claudintight junction

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