Hepsin is Highly Over Expressed in and a New Candidate for a Prognostic Indicator in Prostate Cancer

Stephan, Carsten; Yousef, George M.; Scorilas, Andreas; Jung, Klaus; Jung, Monika; Kristiansen, Glen; Hauptmann, Steffen; Kishi, Tadaaki; Nakamura, Toshio; Loening, Stefan A.; Diamandis, Eleftherios P.

doi:10.1097/01.ju.0000101622.74236.94

Cited by 111 publications

(89 citation statements)

References 16 publications

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“…The marked elevation of hepsin in malignant prostate tissues and correlation with increasing Gleason score were in agreement with other data from microarray analyses and real-time PCR studies (Dhanasekaran et al, 2001;Stamey et al, 2001;Ernst et al, 2002;Chen et al, 2003;Riddick et al, 2003;Stephan et al, 2004). The functional importance of hepsin has been shown by its overexpression in a transgenic mouse model of prostate tumorigenesis, which led to basement membrane disorganisation and enhanced metastasis (Klezovitch et al, 2004).…”

Section: Serine Proteases and Inhibitorssupporting

confidence: 76%

Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues

et al. 2005

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Extracellular proteases of the matrix metalloproteinase (MMP) and serine protease families participate in many aspects of tumour growth and metastasis. Using quantitative real-time RT -PCR analysis, we have undertaken a comprehensive survey of the expression of these enzymes and of their natural inhibitors in 44 cases of human prostate cancer and 23 benign prostate specimens. We found increased expression of MMP10, 15, 24, 25 and 26, urokinase plasminogen activator-receptor (uPAR) and plasminogen activator inhibitor-1 (PAI1), and the newly characterised serine proteases hepsin and matriptase-1 (MTSP1) in malignant tissue compared to benign prostate tissue. In contrast, there was significantly decreased expression of MMP2 and MMP23, maspin, and the protease inhibitors tissue inhibitor of metalloproteinase 3 (TIMP3), TIMP4 and RECK (reversion-inducing cysteine-rich protein with Kazal motifs) in the cancer specimens. The expression of MMP15 and MMP26 correlated positively with Gleason score, whereas TIMP3, TIMP4 and RECK expression correlated negatively with Gleason score. The cellular localisation of the expression of the deregulated genes was evaluated using primary malignant epithelial and stromal cell cultures derived from radical prostatectomy specimens. MMP10 and 25, hepsin, MTSP1 and maspin showed predominantly epithelial expression, whereas TIMP 3 and 4, RECK, MMP2 and 23, uPAR and PAI1 were produced primarily by stromal cells. These data provide the first comprehensive and quantitative analysis of the expression and localisation of MMPs and their inhibitors in human prostate cancer, leading to the identification of several genes involved in proteolysis as potential prognostic indicators, in particular hepsin, MTSP1, MMP26, PAI1, uPAR, MMP15, TIMP3, TIMP4, maspin and RECK.

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Section: Serine Proteases and Inhibitorssupporting

confidence: 76%

Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues

et al. 2005

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“…Hepsin RNA levels were found to be low in normal prostate and benign hyperplasia but strongly increased in prostate carcinoma, particularly in advanced stages (8 -10). Hepsin protein staining with a monoclonal anti-hepsin antibody showed that hepsin expression was highest at sites of bone metastasis and in late stage primary tumors (12), which is consistent with the finding that increased hepsin RNA levels correlated with higher Gleason grades and tumor progression (7)(8)(9)(10)13). In contrast, using a different antibody Dhanasekaran et al (6) found the strongest hepsin expression in high grade prostate intraneoplastic lesions and lower expression in primary carcinoma and in metastatic lesions.…”

supporting

confidence: 76%

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

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Hepsin, a type II transmembrane serine protease, is strongly up-regulated in prostate cancer. Hepsin overexpression in a mouse prostate cancer model resulted in tumor progression and metastasis, associated with basement membrane disorganization. We investigated whether hepsin enzymatic activity was linked to the basement membrane defects by examining its ability to initiate the plasminogen/plasmin proteolytic pathway. Because plasminogen is not processed by hepsin, we investigated the upstream activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator. Enzymatic assays with a recombinant soluble form of hepsin demonstrated that hepsin did not cleave pro-tissue-type plasminogen activator but efficiently converted pro-uPA into high molecular weight uPA by cleavage at the Lys 158 -Ile 159 (P 1 -P 1 ) peptide bond. uPA generated by hepsin displayed enzymatic activity toward small synthetic and macromolecular substrates indistinguishable from uPA produced by plasmin. The catalytic efficiency of pro-uPA activation by hepsin (k cat /K m 4.8 ؋ 10 5 M ؊1 s ؊1 ) was similar to that of plasmin, which is considered the most potent pro-uPA activator and was about 6-fold higher than that of matriptase. Conversion of pro-uPA was also demonstrated with cell surface-expressed full-length hepsin. A stable hepsinoverexpressing LnCaP cell line converted pro-uPA into high molecular weight uPA at a rate of 6.6 ؎ 1.9 nM uPA h ؊1 , which was about 3-fold higher than LnCaP cells expressing lower hepsin levels on their surface. In conclusion, the ability of hepsin to efficiently activate pro-uPA suggests that it may initiate plasmin-mediated proteolytic pathways at the tumor/stroma interface that lead to basement membrane disruption and tumor progression.Hepsin is a type II transmembrane serine protease expressed on the surface of epithelial cells. The 417-amino acid protein is composed of a short N-terminal cytoplasmic domain, a transmembrane domain, and a single scavenger receptor cysteinerich domain that packs tightly against the C-terminal protease domain (1). The physiologic function of hepsin remains unknown. Despite its expression in the very early stages of embryogenesis (2), hepsin-deficient mice were viable and developed normally (3, 4). The studies further showed that hepsin was not essential for liver regeneration and for coagulationrelated physiological functions (3, 4). However, hepsin has been implicated in ovarian cancer (5) and prostate cancer (6 -11), where several gene expression studies have identified it as one of the most highly induced genes. Hepsin RNA levels were found to be low in normal prostate and benign hyperplasia but strongly increased in prostate carcinoma, particularly in advanced stages (8 -10). Hepsin protein staining with a monoclonal anti-hepsin antibody showed that hepsin expression was highest at sites of bone metastasis and in late stage primary tumors (12), which is consistent with the finding that increased hepsin RNA levels correlated with higher Gleason grades...

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“…In this study, we establish that Ln-332, an important basement membrane component that is apparently down-regulated in human prostate cancer (13)(14)(15)(16), is cleaved by hepsin, a serine protease that is overexpressed in more than 90% of human prostate cancer cases (36). In this report, the experimental evidence that hepsin proteolytically cleaves the Ln-332 ␤3 chain is as follows: 1) treatment of purified Ln-332 with catalytically active hepsin produces an ϳ100-kDa fragment both in a time-and dose-dependent fashion; 2) production of this fragment is abolished by KD1, a specific inhibitor of hepsin; 3) catalytically inactive EGR-hepsin does not promote cleavage; 4) the ϳ100-kDa fragment reacts by Western blot with antibodies against the C terminus of the ␤3 chain; and 5) the sequences of peptides from the ϳ100 kDa band, determined by mass spectrometry, are identical to peptides from the C-terminal region of the rat Ln-332 ␤3 chain.…”

Section: Discussionmentioning

confidence: 99%

“…Loss or down-regulation of various tumor suppressor genes (30,31), as well as up-regulation or overexpression of various genes, has been reported (32)(33)(34). One of the genes found to be up-regulated in more than 90% of human prostate cancer cases is the cell surface protease, hepsin (35,36). Recently, a prostate cancer mouse model demonstrated that hepsin overexpression causes disorganization of BM and promotes prostate cancer progression and metastasis (37).…”

mentioning

confidence: 99%

Laminin-332 Is a Substrate for Hepsin, a Protease Associated with Prostate Cancer Progression

Tripathi

Nandana

Yamashita

et al. 2008

Journal of Biological Chemistry

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Hepsin, a cell surface protease, is widely reported to be overexpressed in more than 90% of human prostate tumors. Hepsin expression correlates with tumor progression, making it a significant marker and target for prostate cancer. Recently, it was reported that in a prostate cancer mouse model, hepsin up-regulation in tumor tissue promotes progression and metastasis. The underlying mechanisms, however, remain largely uncharacterized. Hepsin transgenic mice displayed reduced laminin-332 (Ln-332) expression in prostate tumors. This is an intriguing cue, since proteolytic processing of extracellular matrix macromolecules, such as Ln-332, is believed to be involved in cancer progression, and Ln-332 expression is lost during human prostate cancer progression. In this study, we provide the first direct evidence that hepsin cleaves Ln-332. Cleavage is specific, since it is both inhibited in a dose-dependent manner by a hepsin inhibitor (Kunitz domain-1) and does not occur when catalytically inactive hepsin is used. By Western blotting and mass spectrometry, we determined that hepsin cleaves the ␤3 chain of Ln-332. N-terminal sequencing identified the cleavage site at ␤3 Arg 245 , in a sequence context (SQLR 245 2LQGSCFC) conserved among species and in remarkable agreement with reported consensus target sequences for hepsin activity. In vitro cell migration assays showed that hepsin-cleaved Ln-332 enhanced motility of DU145 prostate cancer cells, which was inhibited by Kunitz domain-1. Further, hepsin-overexpressing LNCaP prostate cancer cells also exhibited increased migration on Ln-332. Direct cleavage of Ln-332 may be one mechanism by which hepsin promotes prostate tumor progression and metastasis, possibly by up-regulating prostate cancer cell motility.Prostate cancer is the second leading cause of cancer death in men in the United States; according to the American Cancer Society, 186,320 new prostate cancer cases and 28,660 deaths from prostate cancer are projected to occur in 2008 (1). This high rate of mortality is largely due to metastasis of the primary tumor (2). For metastasis to occur, primary tumor cells must breach the basement membrane (BM) 3 by degrading extracellular matrix (ECM) molecules to initiate the invasion process (3). Escaped tumor cells interact with neighboring ECM molecules to promote this activity. This interaction sometimes promotes remodeling of the ECM to create a more conducive environment for tumor cell migration and invasion and thereby aids in cancer progression (4). The remodeling of certain ECM molecules has been reported to occur as a direct result of protease processing, which results in increased tumor cell migration and invasion (5-7).Laminin-332 (Ln-332; previously known as laminin-5), an ECM molecule, is an important component of BM (8). It is a trimeric glycoprotein consisting of disulfide-bonded subunits: ␣3, ␤3, and ␥2 polypeptide chains (9). The importance of Ln-332 in BM assembly was established by the discovery of the occurrence of a lethal skin blistering disorder, jun...

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Hepsin is Highly Over Expressed in and a New Candidate for a Prognostic Indicator in Prostate Cancer

Cited by 111 publications

References 16 publications

Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues

Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Laminin-332 Is a Substrate for Hepsin, a Protease Associated with Prostate Cancer Progression

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