Biomedical subjects

Fumitaka Kikkawa

Publications and source records attributed to Fumitaka Kikkawa.

64 records · Page 4Linked to original sources

PubMed2003

Enhancement of aminopeptidase A expression during angiotensin II-induced choriocarcinoma cell proliferation through AT1 receptor involving protein kinase C- and mitogen-activated protein kinase-dependent signaling pathway.

Angiotensin II (Ang II) is a bioactive peptide of the renin-angiotensin system, exerting its actions not only as a vasoconstrictor, but also as a growth promoter. In human placenta, type 1 Ang II receptors (AT(1)R) are predominantly expressed in trophoblasts, and we previously reported that aminopeptidase A (APA), a cell surface peptidase that converts Ang II to Ang III, is also expressed in both normal and neoplastic trophoblasts. However, the roles of Ang II and APA in trophoblast function remain to be clarified. In the present study we examined the effects of Ang II on proliferation and APA expression in trophoblast-like BeWo choriocarcinoma cells. Treatment of BeWo cells with Ang II significantly increased DNA synthesis in a dose-dependent manner. Ang II also enhanced APA mRNA and cell surface expression in BeWo cells analyzed by Northern blotting, flow cytometry, and enzyme activity assay. The Ang II-induced proliferation and APA up-regulation were blocked by the AT(1)R antagonist candesartan, but not by the AT(2)R antagonist PD123319. Furthermore, these Ang II effects were abolished by the protein kinase C inhibitor bisindolylmaleimide I and the MAPK inhibitor PD98059. Immunohistochemistry using choriocarcinoma tissues demonstrated that APA was expressed on the cell surface of AT(1)R-positive cytotrophoblastic cells in vivo. With these findings we demonstrate that Ang II stimulates the proliferation of trophoblastic cells via AT(1)R that are linked to protein kinase C /MAPK-dependent signaling pathways, and that the Ang II-degrading enzyme APA is up-regulated during Ang II-induced cell proliferation. These observations suggest the possible regulatory mechanism by the local renin-angiotensin system, especially the Ang II-AT(1)R-APA system, for the growth of human choriocarcinoma cells.

Aminopeptidases↗

PubMed2003

Possible role of placental leucine aminopeptidase in the antiproliferative effect of oxytocin in human endometrial adenocarcinoma.

PURPOSE: Oxytocin (OT) was reported to inhibit the proliferation of various neoplastic tissues and cells, however, the regulation system remains unclear. This study examined the role of OT and its regulatory ability in endometrial adenocarcinoma. EXPERIMENTAL DESIGN: To investigate the possible function of placental leucine aminopeptidase (P-LAP) in endometrial adenocarcinoma, we transfected P-LAP cDNA into A-MEC cells, showing the lowest enzyme activity of P-LAP. Also we examined P-LAP protein expression in human endometrial adenocarcinoma. RESULTS: We demonstrated the presence of P-LAP, which is identical to cystine aminopeptidase as oxytocinase, in human endometrial adenocarcinoma tissues and found that the expression of P-LAP increase with advances in the grade. Exposure of endometrial adenocarcinoma cell lines to OT caused dose- and time-dependent inhibition of growth. Treatment with 10(-7) M OT for 72 h reduced cell growth by 62, 25, and 30% in A-MEC, HEC1A, and Ishikawa cells, respectively. P-LAP-transfectant cells not only partially recovered from OT-induced growth inhibition but also showed a higher growth rate than parental cells under condition without OT. An OT receptor antagonist and a protein kinase A inhibitor blocked OT-induced growth inhibition in A-MEC and A-MEC-pc cells but not in A-MEC-LAP cells. CONCLUSIONS: These findings suggested that P-LAP might be functionally positive on carcinoma cell growth by degrading suppressive peptides such as OT.

Adenocarcinoma↗

PubMed2002

Bilateral preaxial polydactyly: a possible dominant inheritant.

We described families with the preaxial polydactyly in bilateral hands and feet. An analysis of their pedigree strongly suggested that the polydactyly was controlled under the autosomal dominant inheritance. Despite multiple abnormalities, surgical outcomes were quite satisfactory. These cases would be useful for antenatal diagnoses and counseling.

Cesarean Section↗

PubMed2002

Prolonged survival and decreased invasive activity attributable to dipeptidyl peptidase IV overexpression in ovarian carcinoma.

Dipeptidyl peptidase IV (DPPIV) is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that DPPIV plays an important role in tumor progression in several human malignancies. In the present study, we investigated the correlation between DPPIV expression and progressive potential in ovarian carcinoma. We demonstrated that ovarian carcinoma cell lines with higher DPPIV expression were less invasive. Furthermore, DPPIV overexpression in SKOV3 cells, derived from serous cystadenocarcinoma, with little DPPIV expression induced a dramatic change in cellular morphology and a significant decrease in the abilities of both migration and invasion. In addition, we have also shown that nude mice inoculated with DPPIV-transfected SKOV3 cells showed significantly less peritoneal dissemination and longer survival time than those receiving the parental or vector-only transfected cells (mean survival time, 64.9 +/- 4.7, 35.7 +/- 2.8, and 36.6 +/- 1.8 days, respectively). This evidence implies that DPPIV may functionally suppress peritoneal dissemination in ovarian carcinoma.

Animals↗

PubMed2002

Ap-2 and Ikaros regulate transcription of human placental leucine aminopeptidase/oxytocinase gene.

P-LAP is identical with cystine aminopeptidase as oxytocinase. We previously located on the placental leucine aminopeptidase (P-LAP) gene the footprint site with the high promoter activity (FP3: -214 to -183) and found a possible interaction between it and AP-2 in choriocarcinoma cells. Here, we investigated FP3 in detail and identified the elements responsible for the high basal rate of transcription. Electrophoretic mobility shift assays demonstrated that FP3 would interact with Ikaros as well as AP-2. Further analysis using antibody against Ikaros confirmed that Ikaros was indeed present and bound to FP3. In addition, AP-2alpha and AP-2gamma antibodies supershifted the second complex at FP3. Functionally, mutations that eliminate AP-2 binding reduced promoter activity significantly, while those that eliminate Ikaros binding reduced promoter activity insignificantly. Double mutations of AP-2 and Ikaros decreased promoter activity progressively. We conclude that AP-2 is the main activator and Ikaros functions cooperatively with it for maximal expression of the human P-LAP gene.

Binding Sites↗

PubMed2002

Prognostic factors of secondary ovarian carcinoma.

OBJECTIVE: Although the ovaries are common sites of metastases from a variety of primary neoplasms excluding carcinomas of the genital tract, there were few reports concerning survival and prognostic factors. The objective of this study was to assess the clinical factors affecting survival. METHODS: Fifty-three secondary ovarian carcinomas excluding metastases from genital tract carcinoma were registered by the Tokai Ovarian Tumor Study Group from 1989 to 1999. FIGO staging was set without considering the pathologic findings of the lymph nodes and the primary tumors. RESULTS: Twenty-four patients were stage I, 11 were stage II, 16 were stage III, and 2 were stage IV. There were significant differences in the survival curves between the early stages (I and II) and advanced stages (III and IV). The 5-year survival rate for patients without residual tumors was 39.9%, while all patients with residual tumors after surgery died within 33 months. The most frequent primary tumor was large intestinal carcinoma, and the second was gastric carcinoma. The 5-year survival rate for patients with large intestinal primary tumors was significantly better than that with stomach tumors. Multivariate analysis demonstrated that tumor stage and primary tumor sites were significant prognostic factors. CONCLUSION: FIGO staging without considering lymph node involvement and the primary tumor was a significant prognostic factor, and prognostic factors for primary ovarian carcinomas can be applied to secondary ovarian carcinomas. Furthermore, the primary tumor site was also an important prognostic factor for survival.

Ascites↗

PubMed2002

Irinotecan (CPT-11) and cisplatin as first-line chemotherapy for advanced ovarian cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of a combination of irinotecan (CPT-11) and cisplatin as first-line chemotherapy in advanced ovarian cancer. METHODS: Twenty-six patients with previously untreated advanced epithelial ovarian cancer were enrolled in this study. CPT-11 60 mg/m(2) was administered intravenously on days 1, 8, and 15 in combination with cisplatin 60 mg/m(2) on day 1. Cycles were repeated every 28 days for at least two cycles. The median patient age was 55 years (range, 37-75), and the median performance status was 1. RESULTS: Objective responses were recorded in 19 of 25 eligible patients (76%; 95% confidence interval, 55-91%). Complete responses were obtained in 2 patients (8%), and partial response in 17 patients (68%). Stable disease was recorded in 2 patients (8%) and progressive disease in 2 (8%). The median time to response was 62 days (range, 28-234 days). The median survival time for all 25 patients was 30.9+ months (range, 4.1-60.0+ months). The major toxic effects were leukopenia, neutropenia, and diarrhea. Grade 3 or 4 leukopenia, neutropenia, and diarrhea occurred in 17 (68%), 20 (83.3%), and 5 patients (20%), respectively. Thrombocytopenia was less common. No treatment-related deaths occurred. CONCLUSION: The combination of CPT-11 and cisplatin showed significant activity in chemotherapy-naive patients with advanced ovarian cancer. Neutropenia was the dose-limiting adverse effect, whereas diarrhea was mainly mild to moderate.

Adult↗

PubMed2002

Preoperative findings in non-gynecologic carcinomas metastasizing to the ovaries.

This study evaluated whether preoperative findings are useful prognostic indicators in patients with non-gynecologic carcinomas metastasizing to the ovaries. Fifty-three patients were analyzed. Primary sites of carcinoma were discovered after gynecologic surgery in 20 patients. In 10 patients, primary sites of carcinoma were discovered during gynecologic surgery. Thirty-one patients received surgery on the primary site before gynecologic surgery. The primary site could not be identified in 2 patients. The 5-year survival rate was 40.0% in patients, who underwent surgery on the primary site before gynecologic surgery. However, the 5-year survival rate was 12.2% in patients, who underwent surgery on the primary site during or after gynecologic surgery. The CEA level was significantly lower in the stomach primary group than in the intestine primary group. However, CA125 was the only marker significantly affecting survival. In comparison with primary ovarian carcinoma, the sensitivity of CEA was significantly higher for non-gynecologic ovarian carcinoma, while that of CA125 was significantly less sensitive for non-gynecologic ovarian carcinoma. In conclusion, the prognosis was better in patients, who had undergone resection of primary carcinoma before gynecologic surgery on non-gynecologic ovarian carcinoma. CEA is a useful marker to distinguish non-gynecologic from primary ovarian carcinoma, while CA125 is the only significant prognostic marker for non-gynecologic ovarian carcinoma.

Abdominal Pain↗

PubMed2002

Existence of placental leucine aminopeptidase/oxytocinase/insulin-regulated membrane aminopeptidase in human endometrial epithelial cells.

Human endometrial epithelial cells are known to express oxytocin receptors around the time of ovulation. Moreover, oxytocin (OT) and OT-induced prostaglandins appear to play a pivotal role in the switching of endometrial glands from the proliferative to the secretory phase. However, there have been few studies of oxytocinase (OTase), which is identical to placental leucine aminopeptidase (P-LAP)/insulin-regulated membrane aminopeptidase (IRAP). We confirmed the expression of P-LAP/OTase in human endometrium and also observed the changes in the expression of P-LAP/OTase throughout the menstrual cycle. P-LAP/OTase and its mRNA were localized in endometrial epithelial cells but not in stromal cells. In the follicular phase, immunoreactive P-LAP/OTase was homogeneously distributed on the plasma membrane and in cytoplasmic granules. Immunoblot analysis demonstrated that the majority of P-LAP/OTase was produced around the time of ovulation. After ovulation, the immunostaining was restricted to the glycogen-rich subnuclear vacuoles, a glandular marker of progesterone release from the corpus luteum. Thereafter, the membrane-bound P-LAP/OTase was released by apocrine secretion during the period of blastocyst implantation and became depleted toward the time of menstruation. Further understanding of the function of P-LAP/OTase in the endometrium appears likely to yield insights into the cyclic changes during the normal menstrual cycle.

Adult↗

PubMedDate not supplied

Expression of adipocyte-derived leucine aminopeptidase in endometrial cancer. Association with tumor grade and CA-125.

Adipocyte-derived leucine aminopeptidase (A-LAP) is a novel zinc-metallopeptidase involved in angiotensin II (AngII) metabolism, cell migration and antigen presentation. These functions are implicated in the progression of cancer, whereas A-LAP expression and involvement have not been studied in any type of cancer. We investigated the expression of A-LAP in endometrial cancer as well as its association with angiogenesis and clinicopathological features. Immunohistochemical staining of 58 endometrial endometrioid adenocarcinoma specimens revealed that 37 were A-LAP immunoreactive. We also found that A-LAP staining correlated with histological tumor grade in a significant and reverse manner. In addition, serum CA-125 levels in patients with A-LAP positive cancers were significantly higher. However, contrary to our hypothesis that A-LAP suppresses angiogenic activity via AngII metabolism, A-LAP expression was not associated with the microvessel count determined by CD34 immunostaining. Our results suggest that A-LAP is involved in endometrial cancer cell growth and differentiation. However, further studies, especially of the biological roles of A-LAP, are required to confirm this notion.

Adipocytes↗