Molecular Genetic Profiling of Gleason Grade 4/5 Prostate Cancers Compared to Benign Prostatic Hyperplasia

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

doi:10.1016/s0022-5347(05)65528-0

Cited by 175 publications

(72 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 84%

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

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

supporting

confidence: 84%

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

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…For example, Stephan et al showed that hepsin mRNA levels were significantly higher in prostate cancer of grade 3 than that of grade 2 (46). Stamey et al and Riddick et al also reported the correlation of high hepsin mRNA expression in advanced prostate cancers (35,43,47). These results were confirmed by Xuan et al using monoclonal antibodies against hepsin that were developed in hepsin knockout mice (14, 21).…”

Section: Hepsin In Prostate Cancermentioning

confidence: 94%

Hepsin and prostate cancer

Parry

2007

Front Biosci

View full text Add to dashboard Cite

Hepsin is a membrane serine protease expressed in several human tissues including the liver, kidney, prostate, and thyroid. The physiological function of hepsin remains unknown. In vitro studies have shown that hepsin activates blood clotting factors VII, XII, and IX, pro-urokinase (pro-uPA), and pro-hepatocyte growth factor (pro-HGF). Recently, hepsin has been identified as one of the most up-regulated genes in prostate cancer. The hepsin up-regulation appears to correlate with the disease progression. In a mouse model of prostate cancer, hepsin overexpression promotes cancer progression and metastasis. In culture, anti-hepsin antibodies inhibited the invasion of human prostate cancer cells. This review will outline the molecular biology and biochemistry of hepsin and highlight recent data of hepsin in prostate cancer.

show abstract

“…Several recent reports show that TARP mRNA levels are elevated in prostate cancer using cDNA microarrays (25)(26)(27). Stamey et al (25) showed a 5-fold induction of TARP in cancers with a high Gleason grade, compared with benign prostate hyperplasia.…”

Section: Tarp a Prostate-specific Protein Localized In Mitochondria mentioning

confidence: 99%

“…The finding that mRNA hybridizing with a TCR␥ probe was present at high levels in LNCaP cells and that the mRNA in LNCaP cells differed in size from TCR␥ transcripts found in T cells led us to clone and sequence this mRNA and demonstrate its unusual properties (3). Since our initial observations, several groups have performed cDNA microarray analyses of prostate samples and reported that TCR␥ mRNA, but not TCR␦ mRNA, is expressed in prostate tissue and that TCR␥ is more than 3-fold higher in prostate cancer specimens than in normal prostate (25)(26)(27). For the reasons cited above we believe that the transcript measured encodes TARP and not TCR␥.…”

mentioning

confidence: 99%

The T Cell Receptor γ Chain Alternate Reading Frame Protein (TARP), a Prostate-specific Protein Localized in Mitochondria

Maeda

Nagata

Wolfgang

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

We previously showed that mRNA encoding TARP (T cell receptor ␥ chain alternate reading frame protein) is exclusively expressed in the prostate in males and is up-regulated by androgen in LNCaP cells, an androgen-sensitive prostate cancer cell line. We have now developed an anti-TARP monoclonal antibody named TP1, and show that TARP protein is up-regulated by androgen in both LNCaP and MDA-PCa-2b cells. We used TP1 to determine the subcellular localization of TARP by Western blotting following subcellular fractionation and immunocytochemistry. Both methods showed that TARP is localized in the mitochondria of LNCaP cells, MDA-PCa-2b cells, and PC-3 cells transfected with a TARP-expressing plasmid. We also transfected a plasmid encoding TARP fused to green fluorescent protein into LNCaP, MDA-Pca-2b, and PC-3 cells and confirmed its specific mitochondrial localization in living cells. Fractionation of mitochondria shows that TARP is located in the outer mitochondrial membrane. Immunohistochemistry using a human prostate cancer sample showed that TP1 reacted in a dot-like cytoplasmic pattern consistent with the presence of TARP in mitochondria. These data demonstrate that TARP is the first prostate-specific protein localizing in mitochondria and indicate that TARP, an androgen-regulated protein, may act on mitochondria to carry out its biological functions.Prostate cancer is the most frequently occuring solid cancer in men and the second cause of death from cancer in the United States. Current statistics estimate that 220,900 new cases were diagnosed in 2003 and that about 28,900 males die of this disease (1). Most forms of prostate cancer are initially androgendependent, but the response to androgen ablation therapy is transient. After a few years, most cases of metastatic prostate cancer relapse to the status of androgen independence, resulting in death. No effective treatment options exist against androgen-independent prostate cancers. Improvement in this clinical situation requires novel therapies based on a better understanding of the biochemical basis of prostate cancer initiation and progression.One approach for understanding the progression mechanism of prostate cancer is to identify new prostate-specific genes whose expression is altered in prostate cancer. These prostatespecific genes should enable us to understand more about normal prostate function and contribute to our understanding of prostate cancer progression. Prostate-specific genes also can be useful targets for molecular based therapies using antibodies, vaccines, and small inhibitory molecules. Because the prostate is not a vital organ, its destruction by antibodies or vaccines that target prostate-specific antigens should not adversely affect the prognosis of the patient. Also, prostate-specific genes can be useful diagnostic markers to predict the presence, the spread, and the prognosis of prostate disease using samples such as blood or urine. These three aspects: cancer progression, pharmacology, and diagnostics, have encouraged many research...

show abstract

Molecular Genetic Profiling of Gleason Grade 4/5 Prostate Cancers Compared to Benign Prostatic Hyperplasia

Abstract: We characterize for the first time 64 down-regulated and 22 up-regulated genes in Gleason grade 4/5 cancer, using the gene profile from BPH as control tissue. A number of interesting new genes, previously undescribed in prostate cancer, are presented as possibilities for further study.

Cited by 175 publications

References 16 publications

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

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

Hepsin and prostate cancer

The T Cell Receptor γ Chain Alternate Reading Frame Protein (TARP), a Prostate-specific Protein Localized in Mitochondria

Contact Info

Product

Resources

About