Hepsin: a multifunctional transmembrane serine protease in pathobiology

Abstract

Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in the liver. Recent studies indicate that hepsin activates prohepatocyte growth factor in the liver to enhance Met signaling, thereby regulating glucose, lipid, and protein metabolism. In addition, hepsin functions in nonhepatic tissues, including the adipose tissue, kidney, and inner ear, to regulate adipocyte differentiation, urinary protein processing, and auditory function, respectively. In mouse models, hepsin deficiency lowers blood glucose, lipid, and protein levels, impairs uromodulin assembly in renal epithelial cells, and causes hearing loss. Elevated hepsin expression has also been found in many cancers. As a type II transmembrane protease, cell surface expression and zymogen activation are essential for hepsin activity. In this review, we discuss the current knowledge regarding hepsin biosynthesis, activation, and functions in pathobiology.

The POR rs10954732 polymorphism decreases susceptibility to hepatocellular carcinoma and hepsin as a prognostic biomarker correlated with immune infiltration based on proteomics

“…We identified a significantly altered TME, mainly in immune responses, followed by inflammatory responses, which may be related to reduced HCC risk and better prognosis in the A allele carriers. Among the altered TME, HPN, which has been associated with the growth and progression of various cancers [ 25 – 28 ], might partly account for the A allele carriers association with HCC susceptibility and prognosis. Moreover, in line with our assumptions, further genotyping in validated cohorts in six HCC patients showed that four samples beared the A gene had higher expression trend of HPN compared with the two wild type GG .…”

“…Tumor-infiltrating lymphocytes play vital roles in tumor development. HPN, a protein involved in immune reactions and metabolism, was previously reported to regulate the TME [ 26 , 28 , 47 – 50 ]. Here, we report that HPN expression is associated with several immune infiltrating cells and many immune cell makers, including T helper cells (Th1, Th2 and Tfh), in HCC through correlation analysis.…”

“…We used this approach with 34 normal livers and peritumors of 60 HCC samples to elucidate changes in the tumor microenvironment (TME) related to the POR rs10459732 ( G > A ) polymorphism and to identify mechanisms for HCC susceptibility and prognosis associated with this polymorphism. Among the altered TME, hepsin (HPN), which has been associated with the growth and progression of of various cancers [ 25 – 28 ], showed the most significant alteration in our discovery cohort. In contrast to the significant down-regulation in the HCC group, expression of HPN was firstly discovered with higher expression in HCC bearing POR rs10459732 A allele mutation compared with wild-type, which may partly account for decreased HCC susceptibility underlying the rs10954732 A allele.…”

Clinical Significance of Hepsin and Underlying Signaling Pathways in Prostate Cancer

“…Although ubiquitous expression of hepsin has been reported in normal tissues, its mRNA is highly expressed in the liver and kidneys. Hepsin is physiologically involved in multiple cellular functions, including cell growth, blood coagulation, metabolism, the maintenance of cell morphology and membrane integrity, cleaving extracellular substrates, and contributing to the proteolytic processing of growth factors [ 13 , 24 ].…”

“…The increased expression of hepsin at both the mRNA and protein levels has been reported in some solid cancers, including prostate [ 11 , 13 , 14 , 18 , 30 ], ovary [ 31 , 32 ], kidney [ 33 ], and breast cancers [ 34 , 35 , 36 ]. Biological functional studies have demonstrated oncogenic roles for hepsin in the regulation of cancer cell proliferation, invasion, migration, and metastasis, in in vitro and in vivo model systems [ 24 ].…”