Loss of tumor cell surface hepatocyte growth factor activator inhibitor-1 predicts worse prognosis in esophageal squamous cell carcinoma

Yoshiko Umekita; Takumi Kiwaki; Makiko Kawaguchi; Koji Yamamoto; Makoto Ikenoue; Shinsuke Takeno; Tsuyoshi Fukushima; Yuichiro Sato; Hiroaki Kataoka

doi:10.1016/j.prp.2025.155809

Loss of tumor cell surface hepatocyte growth factor activator inhibitor-1 predicts worse prognosis in esophageal squamous cell carcinoma

Pathol Res Pract. 2025 Jan 6:266:155809. doi: 10.1016/j.prp.2025.155809. Online ahead of print.

Authors

Yoshiko Umekita¹, Takumi Kiwaki¹, Makiko Kawaguchi², Koji Yamamoto¹, Makoto Ikenoue³, Shinsuke Takeno³, Tsuyoshi Fukushima¹, Yuichiro Sato¹, Hiroaki Kataoka¹

Affiliations

¹ Section of Oncopathology and Morphological Pathology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
² Section of Oncopathology and Morphological Pathology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. Electronic address: kawaguchi@med.miyazaki-u.ac.jp.
³ Section of Gastrointestinal Endocrine and Pediatric Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

PMID: 39799890
DOI: 10.1016/j.prp.2025.155809

Abstract

Hepatocyte growth factor activator inhibitor-1 (HAI-1) is an epithelial type-1 transmembrane protease inhibitor that regulates the pericellular activities of hepatocyte growth factor activator and type-2 transmembrane serine proteases. It is strongly expressed in the stratified squamous epithelium and functions on the cell surface. We previously reported that the cell surface immunoreactivity of HAI-1 was reduced at the invasion front of oral squamous cell carcinoma. In this study, we investigate the relationship between cell surface HAI-1 (csHAI-1) and prognosis of esophageal squamous cell carcinoma (ESCC) after surgery. The effect of HAI-1 knockdown on cultured ESCC cells was also analyzed in vitro. HAI-1 exhibited distinct cell surface immunoreactivity in normal esophageal epithelium. In contrast, alterations in HAI-1 immunoreactivity were frequent in cancer cells, which exhibited aberrant intracytoplasmic localization and decreased cell surface immunoreactivity. The preservation of csHAI-1 immunoreactivity was a sign of a well-differentiated phenotype of ESCC cells. The decreased csHAI-1 was associated with shorter overall survival (OS) and disease-free survival (DFS) in the patients. In 55 cases of early (T1) ESCC cases, decreased csHAI-1 also predicted poor OS and DFS. The loss of HAI-1 enhanced migration and invasion of ESCC cells in vitro. These results suggest that the decreased cell surface immunoreactivity of HAI-1 is associated with a less differentiated phenotype and worse prognosis in ESCC. The cell surface-localized HAI-1 may serve as a promising marker for predicting recurrence and prognosis of ESCC.

Keywords: Disease-free survival; Esophageal squamous cell carcinoma; Hepatocyte growth factor activator inhibitor-1; Overall survival; SPINT1.