CD26/dipeptidylpeptidase IV (DPPIV) is a 110 kD membrane-bound extracellular peptidase with ubiquitous expressions, and has a variety of functional properties in the development of human malignancies as well as T-cell biology. According to recent reports, stromal cell derived factor-1␣ (SDF-1␣), which is a good substrate for CD26/DPPIV, is expressed in various solid tumors and is involved in tumor development or metastasis. We investigated the expression of SDF-1␣ and its corresponding receptor, CXCR4, in human endometrial carcinoma (EMCA) tissues and the function of SDF-1␣ on EMCA cells with its regulation by CD26/DPPIV. We demonstrated that SDF-1␣ and CXCR4 were expressed in human EMCA, and these immunoreactivities were significantly low in Grade 3 EMCA, which was similar to that of CD26/DPPIV, compared to those in Grade 1 and Grade 2. Key words: CD26/dipeptidyl peptidase IV; SDF-1␣; CXCR4; proliferation; endometrial carcinomaCD26/dipeptidylpeptidase IV (DPPIV) is a 110 kD membranebound extracellular peptidase that is widely expressed in not only T-cells but also various epithelial cells such as renal proximal tubules, intestinal epithelial cells, kidney, liver, placenta and lung. 1 CD26/DPPIV cleaves N-terminal dipeptides from polypeptides with a proline or alanine at the penultimate position. Enzymologically, CD26/DPPIV is capable of degrading various bioactive peptides and cytokines including chemokines that play critical roles in cellular biology. 2 Recent reports have indicated that CD26/ DPPIV has a variety of functions including regulation of inflammatory and immunological response, signal transduction, apoptosis and tumor progression. [3][4][5][6] Chemokines are 8 -10 kD secreted peptides that are potent activators and chemoattractants for leukocytes or several nonhematopoietic cells such as epithelial cells and fibroblasts, especially during immune and inflammatory response. 7-9 Chemokines induce cell migration and activation by binding to specific Gprotein coupled cell surface receptors. Several chemokine receptors are also expressed on non-hematopoietic cells and function. Chemokines play several roles including promotion of cell growth, the modulation of apoptosis and angiogenesis through specific receptors on non-hematopoietic cells. 10 Stromal cell derived factor-1␣ (SDF-1␣) is a chemokine of the CXC subfamily originally characterized as a pre-B-cell stimulatory factor and cloned from bone marrow cell supernatant. 11 SDF-1␣ exerts its activity by interacting with the CXCR4 receptor. Although other chemokines recognize multiple receptors, the interaction between SDF-1␣ and CXCR4 seems to be unique. 12 Recent reports have shown that SDF-1␣ and CXCR4 were expressed in various solid tumors and are involved in tumor development or metastasis. 12-15 SDF-1␣ is a good substrate for CD26/ DPPIV because it contains the essential N-terminal X-Pro motif preferred by CD26/DPPIV. Christopherson et al. 16 showed that inhibiting the endogenous CD26/DPPIV activity on human cord CD34 ϩ progenitor cells by a spec...

Objective: It has recently been appreciated that a local autocrine or paracrine renin-angiotensin system (RAS) may exist in a number of tissues. Angiotensin II (AngII) is a potent RAS-derived vasoconstrictor peptide, and it is involved in tumor angiogenesis. We have cloned human adipocyte-derived leucine aminopeptidase (A-LAP), which degrades Ang II. This study investigated whether the expression of A-LAP, Ang II, angiotensin type I receptor (AT1R) and vascular endothelial growth factor (VEGF) correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma. Methods: Histologic sections of formalin-fixed, paraffin-embedded specimens from 94 primary endometrial carcinomas were stained for A-LAP, AngII, AT1R and VEGF using each antibody. Disease-free survival (DFS) and other clinicopathologic characteristics were analyzed according to the intensity of each staining. Results: Of 94 cases, 91 (96.8%) showed specific A-LAP immunostaining. A-LAP expression demonstrated negative correlations with myometrial invasion (p = 0.01) and vascular infiltration (p = 0.01). Of 94 cases, 77 (81.9%) showed specific AngII immunostaining. We found a positive correlation between AngII expression and surgical stage (p = 0.01). Of 94 cases, 56 (59.6%) showed specific AT1R immunostaining and 73 (77.7%) specific VEGF immunostaining. We found a positive correlation between VEGF expression and lymph node metastasis (p = 0.05). AngII and AT1R expression predicted a significantly poorer prognosis. Contrarily, A-LAP expression indicated a significantly more favorable prognosis in endometrial endometrioid adenocarcinoma patients. Multivariate analysis demonstrated that A-LAP expression (odds ratio, 0.12; 95% confidence interval, 0.025–0.618; p = 0.01) was an independent prognostic factor. Conclusions: In this study, we demonstrated the existence of local RAS and A-LAP in endometrial endometrioid adenocarcinoma as prognostic predictors of clinical outcome. These findings suggest that the assessment of RAS and A-LAP status provides clinically useful prognostic information in patients with endometrial carcinoma.

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Objective: Placental leucine aminopeptidase (P-LAP) is a cell surface aminopeptidase (oxytocinase). We cloned P-LAP cDNA and found a widespread tissue distribution of P-LAP. Since P-LAP can degrade several small peptide hormones such as oxytocin, this enzyme may affect many cellular functions of carcinoma cells as well as normal cells. This study investigated whether the expression of P-LAP correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma. Methods: Histologic sections of formalin-fixed, paraffin-embedded specimens from 99 primary endometrial carcinomas were stained for P-LAP using polyclonal P-LAP antibody. Disease-free survival and other clinicopathologic characteristics were analyzed according to the intensity of P-LAP staining. Results: Of 99 cases, 69 (69.7%) showed specific P-LAP immunostaining. We found a positive correlation between the expression of P-LAP and histological grade (p < 0.01), surgical stage of the disease (p = 0.02), myometrial invasion (p = 0.01), lymph node involvement (p < 0.01), and vascular infiltration (p < 0.01). In patients who had strongly positive P-LAP staining, the disease-free interval was significantly lower than in patients who had negative or weakly positive P-LAP staining (p < 0.01). Multivariate analysis demonstrated that strongly immunoreactive P-LAP (odds ratio, 12.8; 95% confidence interval, 2.84–58.8; p < 0.01) and surgical stage (odds ratio, 8.78; 95% confidence interval, 2.77–27.8; p < 0.01) are independent prognostic factors. Conclusions: This study suggests P-LAP as an independent prognosticator of clinical outcome in patients with endometrial carcinoma. Therefore, assessment of the P-LAP status provides clinically useful prognostic information in patients with endometrial carcinoma.

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