Pathophysiological role of the activation of p38 mitogen-activated protein kinases in poorly differentiated gastric cancer.

p38 mitogen-activated protein kinases (MAPK) contribute to the loss of cell-cell contact and the round cell shape characteristic of poorly differentiated gastric cancer. In the present study it is demonstrated that phospho-p38 MAPK level significantly increased in poorly differentiated gastric cancers in comparison to differentiated cancers and normal gastric mucosa by immunohistochemistry. Next, the pathophysiological roles of p38 MAPK activation were investigated in differentiated gastric cancer cell lines MKN7 and MKN28 and poorly differentiated gastric cancer cell lines KATO-III and MKN45 cells by incubating with specific p38 inhibitor SB203580 or inactivating analog SB202474. The distribution of F-actin on phalloidin staining was identified as fine cytoskeletal filaments in MKN7 and MKN28, but as dense membranous accumulation in KATO-III and MKN45 cells. The treatment with SB203580 but not SB202474 reduced irregular accumulation of F-actin in KATO-III and MKN45 cells. The expression of E-cadherin, ZO-1, occludin and claudin 4 was higher in MKN7 and MKN28 than KATO-III and MKN45 cells. The expression of E-cadherin in KATO-III cells was increased following treatment with SB203580, suggesting the suppression of E-cadherin at the transcriptional level independent of its genetic alterations. Thus, p38 MAPK signaling might contribute to the acquisition of malignant properties in poorly differentiated phenotypes.

In situ androgen production in human gastric carcinoma--androgen synthesizing and metabolizing enzymes.

BACKGROUND: It is well known that the incidence of gastric carcinoma is lower in females than in males. Therefore, androgens have been proposed to play an important role in modifying the development of gastric carcinoma. 5Alpha-reductase (5alpha-reductase) types 1 and 2 and 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD type 5) are considered important local regulators of androgen production in human androgen-responsive tissues and cancer. MATERIALS AND METHODS: The immunoreactivities of these steroidogenic enzymes, as well as of the androgen receptor (AR), were evaluated in human gastric carcinoma obtained from endoscopic mucosal resection (EMR) (n = 117). RESULTS: 17beta-HSD type 5 immunoreactivity was detected in 99 cases (85%), 5alpha-reductase type 1 in 69 cases (59%), 5alpha-reductase type 2 in 57 cases (49%) and AR in 46 cases (39%). CONCLUSION: These androgen-producing enzymes are expressed in human gastric carcinomas and are involved in the in situ production and possible regulation of androgenic activity in human gastric carcinoma.

[Nationwide epidemiological survey regarding heartburn and reflux esophagitis in Japanese].

The details on prevalence of heartburn and reflux esophagitis have not been clarified, since no large-scale survey has been conducted to date. Accordingly, we conducted the nationwide survey regarding prevalence of heartburn and reflux esophagitis by asking new outpatients and patients with the first endoscopy to be performed who visited the medical institutions participating in this survey to fill out the questionnaire and undergo endoscopy. The result showed that heartburn was reported from 1,994 patients (42.2%) out of 4,723, and reflux esophagitis classified as grade A-D was reported from 602 patients (16.7%) out of 3,608. Meanwhile, fat intake, sweet food and anti-inflammatory analgesics were proven to be causes of heart-burn. Furthermore, frequency of heartburn and severity of reflux esophagitis were slightly correlated, although those were not necessarily obviously related.

Systemic distribution of estrogen-responsive finger protein (Efp) in human tissues.

Estrogen-responsive finger protein (Efp), a target gene product of estrogen receptor (ER), is considered essential for estrogen-dependent cell proliferation. The biological significance of Efp remains unclear in human tissues, and therefore, we examined systemic distribution of Efp in human adult and fetal tissues using RT-PCR and immunohistochemistry. Efp mRNA expression was marked in the placenta and uterus, high in the thyroid gland, aorta, and spleen in adult, and relatively low in other human adult and fetal tissues examined in this study. Efp immunoreactivity was detected in epithelium of various adult tissues, and was also detected in cytotrophoblasts of the placenta and splenic macrophages. Efp immunolocalization in human fetus was generally similar as that in adult. These Efp-positive cells were previously reported to be associated with ERalpha and/or ERbeta expression. Therefore, these results indicate that Efp is widely expressed and may play important roles in various human tissues possibly through ERs.

Analysis of cell damage in Helicobacter pylori-associated gastritis.

Helicobacter pylori infection is currently considered to be a major cause of acute and chronic gastritis, and of gastric and duodenal ulcers. Superoxide dismutase (SOD) is well known for scavenging superoxide radicals such as reactive oxygen species (ROS), subsequently protecting cells from oxidative injury, and for maintaining tissue homeostasis. In this study, we therefore evaluated the level of SOD activity and protein expression, as well as various factors associated with oxidative injury, in H. pylori-positive (n = 46) and -negative (n = 28) gastric mucosa obtained from endoscopy, in order to elucidate the possible biological significance of SOD in these mucosa. Overall SOD activity was significantly higher in H. pylori-positive mucosa (15.5 +/- 7.0 U/mg protein) than in negative mucosa (9.2 +/- 10.6 U/mg protein), and decreased markedly following H. pylori eradication (8.2 +/- 4.2 U/mg protein). Enzyme-linked immunosorbent assay (ELISA) analysis of SOD revealed that the manganese SOD (Mn-SOD) level in H. pylori-positive mucosa (1166.7 +/- 435.2 ng/mg protein) was significantly higher than in control tissues (446.3 +/- 435.3 ng/mg protein) and in mucosa obtained following eradication therapy (431.9 +/- 189.9 ng/mg protein). The level of Mn-SOD protein showed a significant correlation with degree of inflammation in the gastric mucosa. Moreover, Mn-SOD immunolocalization patterns were well correlated with the activity and protein levels evaluated by ELISA. Factors presumably associated with oxidative injury in human gastric mucosa, including terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, Ki-67, 8-hydroxydeoxyguanosine and single-stranded DNA, were all significantly higher in H. pylori-positive gastric mucosa than in control tissue and in tissue following eradication. These results all suggest that Mn-SOD, but not cytoplasmic copper-zinc SOD, plays an important role as an anti-oxidant against ROS generated in H. pylori-infected gastric mucosa and, subsequently, in the maintenance of cell turnover in gastric mucosa.