Increasing expression of serine protease matriptase in ovarian tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters

Jin, Jong‐Shiaw; Hsieh, Dar-Shih; Loh, Shih‐Hurng; Chen, Ann; Yao, Chen‐Wen; Yen, Ching‐Yu

doi:10.1038/modpathol.3800495

Cited by 37 publications

(25 citation statements)

References 24 publications

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“…Such a concept is consistent with the hepsin-mediated tumor progression and the associated basement membrane disruption in a mouse model of prostate cancer (16). The ability of hepsin to activate pro-uPA as well as pro-HGF (17,18) is akin to the transmembrane serine protease matriptase (20,32,33), which like hepsin is overexpressed in prostate and ovarian cancer (51)(52)(53)(54)(55). Therefore, hepsin and matriptase may engage in overlapping functions that contribute to tumor progression.…”

Section: Discussionmentioning

confidence: 56%

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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Section: Discussionmentioning

confidence: 56%

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

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

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“…Genetic profiling, such as a gene expression array analysis, revealed that overexpression of ST14/Prss14 was frequently found in advanced epithelial cancers [32–34]. However, as the name suggests, ‘suppression’ of tumors by ST14/Prss14 was claimed based on the observation that the expression is reduced in colon cancer [6].…”

Section: Introductionmentioning

confidence: 99%

Impact of suppression of tumorigenicity 14 (ST14)/serine protease 14 (Prss14) expression analysis on the prognosis and management of estrogen receptor negative breast cancer

et al. 2016

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To elucidate the role of a type II transmembrane serine protease, ST14/Prss14, during breast cancer progression, we utilized publically accessible databases including TCGA, GEO, NCI-60, and CCLE. Survival of breast cancer patients with high ST14/Prss14 expression is significantly poor in estrogen receptor (ER) negative populations regardless of the ratios of ST14/Prss14 to its inhibitors, SPINT1 or SPINT2. In a clustering of 1085 selected EMT signature genes, ST14/Prss14 is located in the same cluster with CDH3, and closer to post-EMT markers, CDH2, VIM, and FN1 than to the pre-EMT marker, CDH1. Coexpression analyses of known ST14/Prss14 substrates and transcription factors revealed context dependent action. In cell lines, paradoxically, ST14/Prss14 expression is higher in the ER positive group and located closer to CDH1 in clustering. This apparent contradiction is not likely due to ST14/Prss14 expression in a cancer microenvironment, nor due to negative regulation by ER. Genes consistently coexpressed with ST14/Prss14 include transcription factors, ELF5, GRHL1, VGLL1, suggesting currently unknown mechanisms for regulation. Here, we report that ST14/Prss14 is an emerging therapeutic target for breast cancer where HER2 is not applicable. In addition we suggest that careful conclusions should be drawn not exclusively from the cell line studies for target development.

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“…Expression of matriptase in pancreatic ductal adenocarcinoma (PDAC) was evaluated by IHC analyses on TMAs and large-area tissue sections as described above. In total, 55 tissues of PDAC (46 from tumor stage 3, 6 from tumor stage 4, as well as 3 without indicated tumor stage) were compared to 31 samples of normal pancreatic tissue from either disease-free pancreas (12) or peritumoral pancreatic tissues (19).…”

Section: Resultsmentioning

confidence: 99%

“…Matriptase has been shown to be overexpressed in a wide variety of cancers such as ovarian (19,20), breast (21,22), cervical (23,24) and prostate (25,26) carcinoma. In most cases, high matriptase levels have been correlated with poor clinical outcome (27,28), indicating a functional involvement in oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

Use of IHC and newly designed matriptase inhibitors to elucidate the role of matriptase in pancreatic ductal adenocarcinoma

Schweinitz¹

2009

Int J Oncol

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Abstract. Matriptase, also known as MT-SP1, is a type II transmembrane serine protease strongly implicated in both the development and progression of a variety of epithelial cancers. Evidence comes from studies of its expression in human cancers and from mouse models of spontaneous cancer. Matriptase is considered to be a major activator of two key stimulators of invasive growth, namely hepatocyte growth factor/scatter factor and urokinase-type plasminogen activator. The aim of this study was to examine the role of matriptase in pancreatic ductal adenocarcinoma by expression analysis and functional assays in vitro. Immunohistochemical analysis of matriptase performed on microtissue arrays and large samples of 55 pancreatic ductal adenocarcinomas and on 31 samples of normal pancreatic ducts revealed that although matriptase expression differed greatly in both malignant and normal ductal pancreatic tissue, matriptase scores were significantly (p=0.02) elevated in pancreatic ductal adenocarcinoma compared to normal pancreatic ducts. To evaluate the role of matriptase during development of pancreatic cancer, we studied the effects of newly designed matriptase inhibitors on the processing of the zymogen of urokinase-type plasminogen activator in the human adenocarcinoma cell lines AsPC-1 and BxPC-3. In both cell lines, at 1 μM, all matriptase inhibitors completely prevented zymogen activation. At lower inhibitor concentrations, the degree of inhibition of zymogen processing correlated with the affinities of the inhibitors towards matriptase indicating that this is a specific result of matriptase inhibition. Furthermore, matriptase inhibitors reduced the phosphorylation of the HGF receptor/cMet and the overall cellular invasiveness of the human pancreatic adenocarcinoma cell line AsPC-1. Our findings demonstrate for the first time that matriptase may be involved in the progression of pancreatic ductal adenocarcinoma and that matriptase inhibition may contribute to preventing the progression of this devastating disease.

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Increasing expression of serine protease matriptase in ovarian tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters

Cited by 37 publications

References 24 publications

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

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

Impact of suppression of tumorigenicity 14 (ST14)/serine protease 14 (Prss14) expression analysis on the prognosis and management of estrogen receptor negative breast cancer

Use of IHC and newly designed matriptase inhibitors to elucidate the role of matriptase in pancreatic ductal adenocarcinoma

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