Hepsin and Maspin are Inversely Expressed in Laser Capture Microdissectioned Prostate Cancer

Chen, Zuxiong; Fan, Zhuangzhuang; McNeal, John E.; Nolley, Rosalie; Caldwell, Mitchell; Mahadevappa, M.; Zhang, Zhaomei; Warrington, Janet A.; Stamey, Thomas A.

doi:10.1097/01.ju.0000050648.40164.0d

Cited by 73 publications

(43 citation statements)

References 15 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: 75%

“…Similarly, little is known of the potential roles of the transmembrane serine proteases and their inhibitors. However, recent data from microarray profiling studies have linked hepsin with prostate cancer pathogenesis (Dhanasekaran et al, 2001;Stamey et al, 2001;Ernst et al, 2002;Chen et al, 2003).…”

mentioning

confidence: 99%

“…Moreover, transmembrane serine proteases (e.g. hepsin and matriptase) have also been implicated in tumorigenesis, but their roles are as yet unresolved (Dhanasekaran et al, 2001;Stamey et al, 2001;Srikantan et al, 2002;Chen et al, 2003;Galkin et al, 2004).…”

mentioning

confidence: 99%

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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: 75%

mentioning

confidence: 99%

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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: 75%

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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“…A number of molecular profiling studies of human prostate carcinoma have been previously published using grossly dissected tissue specimens. 4 -8 More recent work 9,10 has shown the feasibility of gene expression profiling studies using pure populations of cells obtained with laser capture microdissection (LCM). 11 We modified established protocols [12][13][14] for analyzing mRNA from microdissected frozen tissues and applied this protocol to ethanol-paraffin tissue.…”

Section: (J Mol Diagn 2004 6:371-377)mentioning

confidence: 99%

Comparison of Snap Freezing versus Ethanol Fixation for Gene Expression Profiling of Tissue Specimens

Perlmutter

Best

Gillespie

et al. 2004

The Journal of Molecular Diagnostics

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Frozen tissue specimens are the gold standard for molecular analysis. However, snap freezing presents several challenges regarding collection and storage of tissue, and preservation of histological detail. We evaluate an alternative preservation method, ethanol fixation followed by paraffin embedding, by analyzing expression profiles of microdissected cells on Affymetrix oligonucleotide arrays of three matched benign prostatic hyperplasia (BPH) and tumor samples processed with each preservation method. Frozen samples generated an average present call of 26% of the probe sets, compared to 4.5% in ethanol-paraffin samples. Eighty-eight percent of the probe sets called present in the ethanol-paraffin samples were also present in the frozen specimens. Comparing ethanolparaffin BPH to tumor, 52 probe sets showed a twofold differential expression or higher in at least two cases, 23 of which were also differentially expressed in at least one frozen case. Despite a significant drop in the number of transcripts detectable, the data suggests that the obtainable information in ethanol-fixed samples may be useful for molecular profiling where frozen tissue is not available. However, ethanol fixation and paraffin embedding of tissue specimens is not optimal for high-throughput mRNA expression analysis. Improved methods for transcript profiling of archival samples, and/or tissue processing are still required. Formalin fixation and paraffin embedding is the standard tissue processing method used in histopathology laboratories. This protocol allows for permanent preservation of the tissues, easy storage, and optimal histological quality. Unfortunately, formalin fixation severely compromises analysis of biomolecules, in particular mRNA and proteins. We have recently demonstrated the utility of an alternative fixation method, 70% ethanol followed by paraffin embedding. 1

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Hepsin and Maspin are Inversely Expressed in Laser Capture Microdissectioned Prostate Cancer

Abstract: We conclude that the increased ratio of hepsin-to-maspin may have an important role in prostate cancer progression and invasion.

Cited by 73 publications

References 15 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

Comparison of Snap Freezing versus Ethanol Fixation for Gene Expression Profiling of Tissue Specimens

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