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

## TL;DR

This review explores how HAI-1 and HAI-2 regulate proteases in tissue health and cancer, highlighting their roles as tumor suppressors and potential therapeutic targets.

## Contribution

The paper provides a comprehensive review of the physiological and cancer-related functions of HAI-1 and HAI-2, emphasizing their context-dependent roles and therapeutic potential.

## Key findings

- HAI-1 and HAI-2 are critical for placental, skin, neural, and intestinal development.
- Downregulation of HAIs promotes cancer progression via activation of HGF/c-MET and PAR-2/NF-κB pathways.
- Reduced HAI levels in tumors correlate with metastasis and poor prognosis in several carcinomas.

## Abstract

Pericellular proteolysis is essential for maintaining tissue homeostasis. Central to this process are hepatocyte growth factor activator inhibitor-1 (HAI-1) and HAI-2, membrane-bound inhibitors that regulate type II transmembrane serine proteases, including matriptase and prostasin, through high-affinity Kunitz domains. This review summarizes current understanding of their molecular structures, physiological roles, and cancer-related clinical relevance. Genetic models reveal HAI-1 is critical for placental and skin development, while HAI-2 is crucial for neural tube closure and intestinal integrity. In cancer, HAIs generally act as tumor suppressors. Their downregulation, often via promoter hypermethylation, leads to excessive activation of hepatocyte growth factor/c-MET or protease-activated receptor-2/NF-κB signaling, promoting epithelial–mesenchymal transition and cancer progression. Clinically, reduced HAI levels in tumors correlate with metastasis and poor prognosis in several carcinomas. Paradoxically, elevated HAI expression in certain cancers suggests context-dependent pro-tumor functions. Emerging evidence links HAI loss to immune suppression, notably via M2 macrophage polarization in lung cancer. Finally, we highlight future directions for identifying tissue-specific serine proteases, downstream signaling, and therapeutic strategies, including recombinant mimetics and epigenetic reactivation, in precision oncology. In conclusion, HAI-1 and HAI-2 are key regulators of tissue homeostasis and cancer, with overlapping yet distinct functions, which present promising opportunities for therapeutic targeting.