Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

Hsu, Yu‐Chen; Huang, Hsiang‐Po; Yu, I-Shing; Su, Kang‐Yi; Lin, Shu‐Rung; Lin, Wei-Chou; Wu, Hua‐Lin; Shi, Guey‐Yueh; Tao, Mi‐Hua; Kao, Cheng‐Heng; Wu, Yao‐Ming; Martin, Patricia; Lin, Shuei Liong; Lin, Shu‐Wha

doi:10.1002/hep.25773

Cited by 31 publications

(36 citation statements)

References 32 publications

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“…Hepsin is not an essential gene and Hepsin knockout mice are viable and fertile [32, 33]; however, these animals exhibit hearing loss due to developmental deformities in the cochlea [34]. Moreover, Hepsin knockout mice display enlarged hepatocytes and narrowed liver sinusoids [35]. Consistent with the phenotype of Hepsin knockout mice, we did not observe any prominent deficiency in mice treated with Hepsin inhibitors; however, more careful examination will be necessary in the future.…”

Section: Discussionsupporting

confidence: 58%

Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis

et al. 2014

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The development of effective therapies inhibiting prostate cancer progression and metastasis may substantially impact prostate cancer mortality and potentially reduce the rates of invasive treatments by enhancing the safety of active surveillance strategies. Hepsin (HPN) is a cell surface serine protease amplified in a subset of human sarcomas (7.2%), as well as in ovarian (10%), lung adeno (5.4%), lung squamous cell (4.5%), adenoid cystic (5%), breast (2.6%), uterine (1.7%) and colon (1.4%) carcinomas. While HPN is not amplified in prostate cancer, it is one of the most prominently overexpressed genes in the majority of human prostate tumors and genetic experiments in mice indicate that Hepsin promotes prostate cancer metastasis, particularly metastasis to the bone marrow. We report here the development, analysis and animal trial of the small-molecule Hepsin inhibitor HepIn-13. Long-term exposure to HepIn-13 inhibited bone, liver and lung metastasis in a murine model of metastatic prostate cancer. These findings indicate that inhibition of Hepsin with small-molecule compounds could provide an effective tool for attenuation of prostate cancer progression and metastasis.

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Section: Discussionsupporting

confidence: 58%

Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis

et al. 2014

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“…1 The mass of the active protease domain fragment is 31 kDa and a further processing to a smaller 20-27 kDa form has been observed. 14,25 Three distinct hepsin fragments with expected sizes were detected in mammary epithelial MCF10A cells engineered to constitutively overexpress ectopic hepsin. The authenticity of the 31 kDa catalytically active form was verified by shRNA knockdown (Figures 1e and f).…”

Section: Resultsmentioning

confidence: 99%

“…10,12,13 Studies in hepsin knockout mice suggest the involvement of endogenous levels of hepsin in conversion of pro-HGF to HGF and MET receptor activation. 14 Hepsin also cleaves zymogens of other cell-surface serine proteases. Hepsin-mediated cleavage activates, for example, prostasin, a glycosylphosphatidylinositol-anchored serine protease.…”

Section: Introductionmentioning

confidence: 99%

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion

et al. 2015

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Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

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“…It has been shown that hepsin is not an essential gene and knockout mice are viable and fertile [130, 131], although they do exhibit hearing loss due to developmental deformities in the cochlea [132], enlarged hepatocytes, and narrowed liver sinusoids [133]. Further, mice treated with the HepIn-13 inhibitor did not develop any apparent deficiencies [125], suggesting that targeting this TTSP would not cause any major detrimental side effects in humans, although more rigorous studies are needed.…”

Section: Ttsps As Novel Therapeutic Targets In Cancermentioning

confidence: 99%

The role of type II transmembrane serine protease‐mediated signaling in cancer

2016

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Pericellular proteases have long been implicated in carcinogenesis. Previous research focused on these proteins, primarily as extracellular matrix (ECM) protein degrading enzymes which allowed cancer cells to breach the basement membrane and invade surrounding tissue. However, recently, there has been a shift in the view of cell surface proteases, including serine proteases, as proteolytic modifiers of particular targets, including growth factors and protease-activated receptors, which are critical for the activation of oncogenic signaling pathways. Of the 176 human serine proteases currently identified, a subset of 17 known as type II transmembrane serine proteases (TTSPs) [1], many have been shown to be relevant to cancer progression, since they were first identified as a family around the turn of the century. To this end, altered expression of TTSPs appeared as a trademark of several tumor types [2, 3]. However, the substrates and underlying signaling pathways remained unclear. Localization of these proteins to the cell surface places them in the unique position to mediate signal transduction between the cell and its surrounding environment. Many of the TTSPs have already been shown to play key roles in processes such as postnatal development, tissue homeostasis, and tumor progression, which share overlapping molecular mechanisms [2, 4-6]. In this review, we summarize the current knowledge regarding the role of the TTSP family in pro-oncogenic signaling.

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Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

Cited by 31 publications

References 32 publications

Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis

Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion

The role of type II transmembrane serine protease‐mediated signaling in cancer

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