Jeon-Uk Lee
Kyoto University
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Featured researches published by Jeon-Uk Lee.
European Journal of Cancer | 1998
Koji Fujimoto; Ryo Hosotani; Michihiko Wada; Jeon-Uk Lee; Takatomo Koshiba; Yoshiharu Miyamoto; Shoichiro Tsuji; Sanae Nakajima; Ryuichiro Doi; Masayuki Imamura
Tumour angiogenesis, as assayed by microvessel density (MVD), and the expression of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) have become established as important prognostic indicators for many tumour types. In this study, MVD and the expression of VEGF and PD-ECGF were examined by immunohistochemical staining of 50 pancreatic cancer tissues, and the relationships between either MVD or the expression of these two angiogenic factors and the clinicopathological features, including survival, were analysed. The expression of VEGF and PD-ECGF proteins were confirmed by Western blot analysis and VEGF mRNA isoforms were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) in five pancreatic cancer cell lines. Twenty-eight (56%) of 50 pancreatic cancers were positive for VEGF protein in cancer cells, and 16 (32%) showed strong PD-ECGF staining in cancer and infiltrating cells. VEGF121 and VEGF165 were identified as the predominant species produced in pancreatic cancer cells. The overexpression of VEGF and PD-ECGF protein significantly correlated with high MVD (P = 0.002, 0.044, respectively). Advanced stage of disease was significantly more frequent in patients with high MVD (P = 0.025). No significant association was found between the expression of VEGF or PD-ECGF and clinicopathological features, except for tumour histology. The expression of PD-ECGF correlated with poor survival (P = 0.011), but MVD and VEGF expression were not found to be useful for the prediction of overall survival. This study suggests that VEGF and PD-ECGF may play an important role in tumour angiogenesis, and that PD-ECGF expression seems to be useful for establishing prognoses for pancreatic cancer.
Cancer | 1998
Takatomo Koshiba; Ryo Hosotani; Michihiko Wada; Yoshiharu Miyamoto; Koji Fujimoto; Jeon-Uk Lee; Ryuichiro Doi; Shigeki Arii; Masayuki Imamura
Activation of matrix metalloproteinase‐2 (MMP‐2) has been implicated in the progression, invasion, and metastasis of various cancers, but little information is available with regard to its role in pancreatic carcinoma with poor prognosis.
Oncology | 1999
Yoshiharu Miyamoto; Ryo Hosotani; Michihiko Wada; Jeon-Uk Lee; Takatomo Koshiba; Koji Fujimoto; Shouichirou Tsuji; Sanae Nakajima; Ryuichiro Doi; Masayuki Kato; Yuta Shimada; Masayuki Imamura
Expression of several members of the Bcl-2 family proteins was investigated by means of both immunohistochemical analysis in 30 invasive ductal adenocarcinomas and 23 intraductal papillary-mucinous tumors (IPMTs) and immunoblot analysis in 6 cancer tissues and 7 pancreatic cancer cell lines. We found that Bcl-2 was expressed in 23%, Bax in 53%, Bcl-X in 90%, and Mcl-1 in 90% of the invasive ductal adenocarcinomas. In intraductal papillary-mucinous adenocarcinomas, the expression rate of Bax was 44% and those of Bcl-XL and Mcl-1 were 88%; these values were higher than those for intraductal papillary-mucinous adenomas. Immunoblot analysis identified Bcl-XL as the predominant form of the Bcl-X protein in both pancreatic cancer tissues and cell lines, and demonstrated that both Bcl-XL and Mcl-1 protein levels were uniformly high in all cell lines. These results suggest that an imbalance between antiapoptosis proteins (such as Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (such as Bax and Bcl-Xs) is involved in the distinctive biologic features of adenocarcinomas of the pancreas. Furthermore, predominantly high expressions of Bcl-XL and Mcl-1 in intraductal papillary-mucinous adenocarcinomas might be involved in the carcinogenesis in IPMT of the pancreas.
European Journal of Cancer | 1999
Jeon-Uk Lee; Ryo Hosotani; Michihiko Wada; Ryuichiro Doi; T Kosiba; Koji Fujimoto; Yoshiharu Miyamoto; Shoichiro Tsuji; Sanae Nakajima; Yasumasa Nishimura; Masayuki Imamura
The aim of this study was to examine Bax, Bcl-2 and Bcl-XL proteins in human pancreatic cancer cell lines and to clarify the mechanism of radiation resistance. PANC-1 and AsPC-1 pancreatic cell lines were used, both having mutated p53. Radioresistant PANC-1/Rad cells and AsPC-1/Rad cells were obtained by repeated 5 Gy irradiation of PANC-1 cells and AsPC-1 cells, respectively. Radiation was found to inhibit the growth of PANC-1 cells and AsPC-1 cells. After exposure to radiation, detached cells were subjected to FITC-TUNEL staining to calcualte the ratio of apoptosis. TUNEL positive ratios increased dose-dependently in both cell lines. Western blotting showed that the basal level of the Bax/Bcl-2 ratio reflected the radiosensitivity of these cell lines, and Bax expression was obviously upregulated after irradiation in the presence of mutated p53, but Bcl-2 expression remained almost constant. Both PANC-1/Rad and AsPC-1/Rad cells had greater Bcl-XL expression than the parental cells, and the basal level of the Bax/Bcl-2 ratio was no longer predictive of radiosensitivity. Upregulated expression of Bax protein after irradiation was not related to induction of apoptosis in these cells, suggesting that overexpression of Bcl-XL and functional reconstruction of Bcl-2 family proteins are important factors in acquired radioresistance.
International Journal of Pancreatology | 1999
Takatomo Koshiba; Ryo Hosotani; Yoshiharu Miyamoto; Michihiko Wada; Jeon-Uk Lee; Koji Fujimoto; Shoichiro Tsuji; Sanae Nakajima; Ryuichiro Doi; Masayuki Imamura
SummaryBackgroundA considerable amount of evidence collected from several experimental systems and clinical studies with nonsteroidal Anti-inflammatory drugs (NSAIDs) indicates that Cox-2 may play a major role in colorectal tumorigenesis, but little information about Cox-2 expression in pancreatic tumors is available. In this study, we investigated Cox-2 expression by means of both immunohistochemical analysis and immunoblot analysis in pancreatic tumors.MethodsFifty invasive ductal adenocarcinomas and 26 intraductal papillary-mucinous tumors (IPMTs) were used for immunohistochemical analysis, and five pancreatic cancer tissues and five pancreatic cancer cell lines for immunoblot analysis.ResultsCox-2 was expressed in 72% of the invasive ductal adenocarcinomas, 31% of intraductal papillary-mucinous adenocarcinomas, and none of intraductal papillary-mucinous adenomas. The expression rate of Cox-2 in intraductal papillary-mucinous adenocarcinomas was significantly higher than that in intraductal papillary-mucinous adenomas, and that in invasive ductal adenocarcinomas was significantly higher than that in intraductal papillary-mucinous carcinomas. However, there was no significant correlation between Cox-2 expression and the prognosis and clinicopathological factors. Immunoblot analysis identified Cox-2 in all of pancreatic cancer tissues and 60% of cell lines.ConclusionThe biological role of cyclooxygenase-2 (Cox-2) in carcinoma cells should be investigated with reference to the cancer progression of the pancreas.
International Journal of Cancer | 1999
Koji Fujimoto; Ryo Hosotani; Ryuichiro Doi; Michihiko Wada; Jeon-Uk Lee; Takatomo Koshiba; Yoshiharu Miyamoto; Shoichiro Tsuji; Sanae Nakajima; Masayuki Imamura
In this study, we investigated the effect of a novel retinobenzoic acid, 4‐[3,5‐bis (trimethylsilyl) benzamido] benzoic acid (TAC‐101), on the growth of 4 human pancreatic‐cancer cell lines; BxPC‐3, MIAPaCa‐2, CFPAC‐1 and AsPC‐1. TAC‐101 significantly inhibited the proliferation of BxPC‐3 and MIAPaCa‐2 cells in a time‐ and concentration‐dependent manner, but not the proliferation of AsPC‐1 cells. Furthermore, the anti‐proliferative effects of TAC‐101 on BxPC‐3 and MIAPaCa‐2 cells were stronger than those of all‐trans retinoic acid. Flow‐cytometric analyses indicated that treatment of BxPC‐3 with TAC‐101 strongly induces cell‐cycle arrest at the G1 phase. The cell‐cycle arrest induced by TAC‐101 was accompanied by reduction of retinoblastoma‐gene product (RB) phosphorylation and an increase of 2 cyclin‐dependent kinase (CDK) inhibitors, p21WAF1/Cip1 (p21) and p27Kip1 (p27). TAC‐101 also caused a decrease in cyclin A and thymidylate synthase, which are E2F‐regulated gene products. No changes were observed in the expression of cyclin D1, cyclin E on CDK2. In addition, Hoechst staining, gel electrophoresis and flow‐cytometric analysis indicated that a marked reduction in the number of BxPC‐3 cells with TAC‐101 was related to the induction of apoptosis. Our results suggest that TAC‐101 inhibits the growth of certain pancreatic‐cancer cells by means of G1‐phase cell‐cycle arrest resulting from the reduction of RB phosphorylation and the up‐regulation of p21 and p27 as well as the induction of apoptosis. TAC‐101 may therefore be a useful agent for new therapeutic strategies focusing on inhibition of pancreatic‐cancer‐cell proliferation. Int. J. Cancer 81:637–644, 1999.
Surgery Today | 1997
Takatomo Koshiba; Ryo Hosotani; Michihiko Wada; Koji Fujimoto; Jeon-Uk Lee; Ryuichiro Doi; Shigeki Arii; Masayuki Imamura
Destruction of the basement membrane (BM) is mandatory for tumor spread, and matrix metalloproteinases MMPs) are known to be implicated in colon cancer invasion and metastasis by digesting type IV collagen, a main component of the BM. The current study analyzed the expression of MMP-2 and MMP-9 in pancreatic cancer tissues. Frozen specimens of pancreatic cancer (n = 10), a liver metastatic nodule from pancreatic cancer (n = 1), and normal pancreas (n = 3) were homogenized and analyzed by zymography. The activated form of MMP-9 (82kDa) was detected in all of the normal and malignant tissues, while the activated form of MMP-2 (62kDa) was detected in all of the pancreatic cancers and its metastatic tissue, but not in the normal pancreatic tissues. These results indicate that expression of the activated form of MMP-2 may be specific to pancreatic cancer, while that of MMP-9 may be unrelated to it.
Pancreas | 1997
Michihiko Wada; Ryuichiro Doi; Ryo Hosotani; Jeon-Uk Lee; Koji Fujimoto; Takatomo Koshiba; Yoshiharu Miyamoto; Shin-Ichi Fukuoka; Masayuki Imamura
Obstruction of the pancreatic duct induces acinar cell deletion followed by duct proliferation and interstitial fibrosis. Apoptosis has been reported to be involved in the induction of acinar cell deletion after pancreatic duct ligation (PDL) in rats, however, the mechanism of pancreatic duct cell proliferation is still unknown. We hypothesized that Bcl-2 (antiapoptosis protein) and PCNA (cell cycle-related protein) could be involved in the mechanism of pancreatic duct cell proliferation after PDL. In PDL rats, acinar cells decreased in number and disappeared completely after duct ligation and duct-lining cells increased in number and formed duct-tubular complexes. Immunohistochemical study showed that PCNA expression appeared in the ductules and centroacinar cells from early stages after duct ligation and that Bcl-2 expression in duct cells, which was faint in normal pancreas, increased significantly when acinar cells were diminishing. Western blotting demonstrated that Bcl-2 was detected as a single band at 26 kDa, and the intensity of Bcl-2 in PDL rats was approximately ninefold stronger than in normal pancreas. Expression of Bcl-2 and PCNA after pancreatic duct ligation may be related to the prevention of apoptosis and cell proliferation of pancreatic duct cells in rats.
Digestion | 1997
Koji Fujimoto; Ryo Hosotani; Ryuichiro Doi; Michihiko Wada; Jeon-Uk Lee; Takatomo Koshiba; Yoshiharu Miyamoto; Masayuki Imamura
We investigated the role of neutrophils and the involvement of apoptosis in cerulein-induced acute pancreatitis. Male Sprague-Dawley rats were divided into 2 groups. In the control group, acute pancreatitis was induced by subcutaneous injections of cerulein. In methotrexate-treated group, the rats received intraperitoneal injections of methotrexate to produce neutrophil depletion before the injections of cerulein. The rats were sacrificed at the indicated time points until 72 h after the first injection of cerulein. Neutrophil depletion ameliorated pancreatic edema and vacuole formation in acinar cells during the early stages of cerulein-induced acute pancreatitis. Electron microscopy, DNA gel electrophoresis and in situ nick end-labeling revealed the involvement of apoptosis in acinar cells in cerulein-induced acute pancreatitis. Furthermore, the number of apoptotic acinar cells in neutrophil-depleted rats showed an about 2-fold increase during the late stages when compared with those in the control rats. Our results suggest that neutrophil depletion in cerulein-induced pancreatitis leads to amelioration of pancreatic injury during the early stage, and enhancement of apoptosis by neutrophil depletion occurs during the late stage.
Pancreas | 1997
Ryuichiro Doi; Michihiko Wada; Ryo Hosotani; Jeon-Uk Lee; Takatomo Koshiba; Koji Fujimoto; Chisato Mori; Noriko Nakamura; Masayuki Imamura
It has been recognised in mammals that after pancreatic duct obstruction, acinar cells progressively disappear and pancreatic islets are preserved. Previous studies by electron microscopy have suggested the involvement of apoptosis in acinar cell deletion. In the present study, we employed molecular biological methods and investigated whether acinar cell deletion is due to apoptosis. In male Sprague-Dawley rats, pancreatic duct ligation was performed through a left paramedian incision. Pancreatic tissue was studied at each of the following intervals after ligation: 3, 6, 12, 18, and 24 h and 2, 3, 5, and 7 days. DNA fragmentation was determined by in situ labeling of DNA strand breaks on tissue sections [fluorescein-labeled terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method (TUNEL)] and by electrophoretic detection of the fragments of extracted DNA. Tissue sections were also examined by hematoxylin/eosin staining and immunohistochemical staining of insulin. Pancreatic duct ligation induced acinar cell deletion by day 5. Pancreatic tissue from control rats demonstrated no TUNEL-positive nuclei. In contrast, acinar cells from rats 12 h to 5 days after duct ligation showed TUNEL-positive nuclei. The number of TUNEL-positive nuclei was maximum 2 days after duct ligation. Electrophoresis showed DNA fragmentation after duct ligation. Control rats showed a genomic DNA pattern. Islets were preserved throughout the experimental period in duct-ligated rats and control rats. The results suggest that apoptosis may be the dominant form of acinar cell death in the rat pancreatic duct ligation model.