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Membrane-Anchored Serine Protease Inhibitors: Physiological Functions, Mechanisms, and Roles in Cancer.

Chun-Ying Chen1, Tai-No Lin2, Hsiang-Po Huang2

  • 1School of Medicine, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan.

International Journal of Molecular Sciences
|February 27, 2026
PubMed
Summary

Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) are crucial for tissue balance and cancer. Their altered expression impacts tumor growth, metastasis, and immune response, offering therapeutic potential.

Keywords:
HAI-1HAI-2cancerepigenetic regulationepithelial homeostasishepatocyte growth factor activatormatriptasetype II transmembrane serine protease

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Area of Science:

  • Biochemistry and Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Pericellular proteolysis is vital for tissue homeostasis, regulated by membrane-bound inhibitors like HAI-1 and HAI-2.
  • These inhibitors control type II transmembrane serine proteases via Kunitz domains, impacting cellular signaling pathways.

Purpose of the Study:

  • To review the molecular structures, physiological functions, and clinical relevance of HAI-1 and HAI-2 in cancer.
  • To explore the dual role of HAIs as tumor suppressors and potential pro-tumor factors in various cancers.

Main Methods:

  • Review of existing literature on HAI-1 and HAI-2, including genetic models and clinical studies.
  • Analysis of molecular mechanisms, signaling pathways (e.g., HGF/c-MET, PAR-2/NF-κB), and epigenetic regulation (promoter hypermethylation).

Main Results:

  • HAI-1 is essential for placental and skin development; HAI-2 is critical for neural tube and intestinal integrity.
  • Downregulation of HAIs promotes cancer progression by activating oncogenic signaling pathways and epithelial-mesenchymal transition.
  • Reduced HAI levels correlate with metastasis and poor prognosis, while elevated levels can indicate context-dependent pro-tumor roles.

Conclusions:

  • HAI-1 and HAI-2 are key regulators of tissue homeostasis with distinct yet overlapping functions.
  • Their dysregulation in cancer presents opportunities for therapeutic targeting, including epigenetic reactivation and mimetics.
  • Emerging roles in immune suppression, such as M2 macrophage polarization, warrant further investigation.