Hepatocyte growth factor activator inhibitor type-1 in cancer: Advances and perspectives (Review)

Abstract

Abstract. Cancer is one of the most common diseases, with high morbidity and mortality rates. Large-scale efforts have been made to understand the pathogenesis of the disease, particularly in the advanced stages, in order to develop effective therapeutic approaches. Hepatocyte growth factor activator inhibitor type-1 (HAI-1), also known as serine protease inhibitor Kunitz type 1, inhibits the activity of several trypsin-like serine proteases. In particular, HAI-1 suppresses hepatocyte growth factor (HGF) activator and matriptase, resulting in subsequent inhibition of HGF/scatter factor and macrophage-stimulating protein (MSP). HGF and MSP are involved in cancer development and progression, via the receptors Met receptor tyrosine kinase (RTK) and Ron RTK, respectively. Therefore, HAI-1-mediated downregulation of HGF and MSP signaling may suppress tumorigenesis and progression in certain types of cancers. Abnormal HAI-1 expression levels have been observed in various types of human cancer. The exact function of HAI-1 in cancer pathogenesis, however, has not been fully elucidated. In this review, the focus is on the potential impact of aberrant HAI-1 expression levels on tumorigenesis and progression, the underlying mechanisms, and areas that require further investigation to clarify the precise role of HAI-1 in cancer.

The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition

“…The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. An imbalance in the HAI-1:matriptase ratio results in tumorigenesis (21,22). For instance, a mild overexpression of matriptase relative to HAI-1 results in spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1 (22).…”

3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation

“…HAI‐1 is critical to control matriptase proteolytic activity . However, HAI‐1 expression is reduced in many cancer types, which is implicated in the progression of cancer and is associated with a worse prognosis in cancer patients.…”

“…HGF activator inhibitor type‐1 (HAI‐1) is a cognate partner of activated matriptase . Mice embryogenesis perish as a result of HAI‐1 deletions is reversed in matriptase/HAI‐1 double‐deficient mice, whereas ectopically expressed HAI‐1 antagonizes the oncogenic properties of matriptase in mice .…”

“…Upon activation, matriptase is complexed by HAI‐1, which largely quenches matriptase proteolytic activity. This is a major approach for cell to avoid excess and uncontrolled activity of matriptase . The ratio of matriptase/HAI‐1 is generally much higher in cancer cells than in normal cells, rendering the high activating level of matriptase in cancer cells.…”

KLK14 interactions with HAI‐1 and HAI‐2 serine protease inhibitors: A molecular dynamics and relative free‐energy calculations study

“…HAI‐1 is a suggested marker of prostate epithelial cell proliferation (Warren et al, ), and a favorable prognostic marker of prostate cancer (Nagakawa et al, ; Yasuda et al, ; Hu et al, ). HAI‐1 display a marked inhibitory activity against a variety of serine proteases, including HGFA, matriptase, hepsin, prostasin, plasmin, trypsin, TMPRSS13, and HAT (Zheng et al, ). Curiously, HAI‐1 is found at the basolateral surface of prostate epithelial cells (Kataoka et al, ) and this is certainly strategical for modulating HGF activation and downstream signaling.…”