Trypsinogens are pancreatic serine proteinases and expressed in several cancers as tumor-associated trypsinogens (TAT). Trypsin mediates activation of pro-uPA and pro-MMPs, thus promoting angiogenesis and tumor invasion. Recently, we described expression of TAT in the human male genital tract and now we studied TAT in relation to PSA in PCa.
TAT expression was studied by immunohistochemistry, in situ hybridization, RT-PCR, DNA-sequencing and IFMA. LNCaP cells were used to study secretion of TAT and PSA after androgen stimulation.
Immunoreactive TAT was localized in all prostatic tumors (n = 109), lymph node (n = 16), and bone metastases (n = 17). Immunostaining intensity increased with higher Gleason's grade, whereas PSA immunostaining decreased significantly. PSA and TAT were not identically distributed in benign and malignant cells. Androgen stimulation of LNCaP cells decreased secretion of TAT and increased that of PSA. TAT mRNA was demonstrated in tissue sections and identified as TAT-1 and -2 by RT-PCR and DNA-sequencing.
Expression of TAT is better preserved than PSA in high-grade PCa. Expression of TAT and PSA is regulated by different mechanisms as demonstrated in tissue sections and in vitro. Locally produced TAT may act in a paracrine mode to promote angiogenesis and tumor invasion in PCa by both activating and degrading of other proteinases. Further studies on the role of TAT in invasive PCa and on the mechanisms involved in the regulation of TAT expression are warranted.
"as pseudotrypsin is theoretically capable of cleaving at position Cys49–Gly50 of NDRG1. In fact, since tumour-associated trypsinogens are present in the DU145, PC3 and LNCaP prostate cancer cell lines , it is plausible that pseudotrypsin could cleave off NDRG1. Tumour-associated trypsin is expressed in a multitude of human cancers [40–44]. "
[Show abstract][Hide abstract] ABSTRACT: N-myc downstream regulated gene-1 (NDRG1) is a metastasis suppressor that is down-regulated in prostate cancer. NDRG1 phosphorylation is associated with inhibition of metastasis and western blots indicate two bands at ~41 and ~46 kDa. Previous investigations by others suggest the higher band is due to NDRG1 phosphorylation. However, the current study using a dephosphorylation assay and the Phos-tag SDS-PAGE assay, demonstrated the 46 kDa NDRG1 protein band was not due to phosphorylation. Further experiments showed the NDRG1 protein bands were not affected upon glycosidase treatment, despite marked effects of these enzymes on the glycosylated protein, fetuin. Analysis using RT-PCR demonstrated only a single amplicon, and thus, the two bands could not a result from an alternatively spliced NDRG1 transcript. Western blot analysis of prostate cancer cell lysates identified the 41 kDa band to be a truncated form of NDRG1, with mass spectrometry confirming the full and truncated proteins to be NDRG1. Significantly, this truncated protein was not present in normal human prostate epithelial cells. Western blot analysis using anti-NDRG1 raised to its N-terminal sequence failed to detect the truncated protein, suggesting it lacked N-terminus amino acids (residues 1-49). Sequence analysis predicted a pseudotrypsin protease cleavage site between Cys49-Gly50. Such cleavage of NDRG1 in cancer cells may result in loss of NDRG1 tumour suppressive activity.
"Lastly, the antiproteinase mediator pancreatic secretory trypsin inhibitor (PSTI) protects from premature activity. An imbalance in this ‘proteinase–antiproteinase-system’ plays a pathophysiological role in the development of pancreatitis and seems to present an increased risk for developing pancreatic adenocarcinoma (29–31) PSTI is excreted by the mucosa of the normal gastrointestinal tract, where it serves to protect the cells from proteolytic breakdown. The same peptide is secreted by tumour cells, and is often referred to as ‘tumour associated trypsin inhibitor’ (TATI), which is identical to PSTI. "
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer is one of the most common malignancy in the world and the second cancer-related death, many molecular and genetic aspects of this disease have been cleared as chromosomal instability and the role of some key proteins as WNT/β catenin, trypsin and others. Also recently the role of folate turnover and some neurotransmitters as serotonin were also considered. The scope of this review is to describe some details about new molecular pathways suggested for occurrence or progress of this disease.
Gastroenterology and hepatology from bed to bench 03/2011; 444(2):43-5243.
"SPINK1 levels are strongly elevated during inflammation and pancreatitis (Paju and Stenman, 2006). Like the pancreas, the prostate gland also secretes a variety of serine proteases, most notably the kallikrein enzyme prostate specific antigen (PSA), but also trypsin, the expression of which is increased in prostate cancer (Bjartell et al., 2005). Thus, SPINK1 outlier expression may have a role in modulating the activity of cancer-related proteases. "
[Show abstract][Hide abstract] ABSTRACT: ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.
Cancer cell 07/2008; 13(6):519-28. DOI:10.1016/j.ccr.2008.04.016 · 23.52 Impact Factor
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