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Kijima, Hiroshi ; Sato, Fuyuki ; Bhawal, Ujjal Kumar ; Kawamoto, Takeshi ; Fujimoto, Katsumi ; Imaizumi, Tadaatsu ; Imanaka, Tadanobu ; Kondo, Jun ; Koyanagi, Satoru ; Noshiro, Mitsuhide ; Yoshida, Hidemi ; Kato, Yukio
概要:
The circadian rhythms in mammals are regulated by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus
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. Five clock-gene families, i.e. Clock, Bmal, Per, Cry and Dec, have been found to be involved in a transcription-translation feedback loop that generates the circadian rhythm at the intracellular level. In this study, we examined functional analysis of the Dec gene. DEC1 and DEC2 are basic-helix-loop-helix （bHLH） transcription factors, involved in cellular diff erentiation, responses to hypoxia, and circadian rhythms. We recently showed that the expression of DEC1 and DEC2 was upregulated by hypoxia, however, the functions of these two factors under hypoxic conditions have not been elucidated in detail. It is well established that the expression of vascular endothelial growth factor （VEGF） is upregulated by hypoxia, and the expression of VEGF in response to hypoxia depends on transcriptional activation by a heterodimer comprising hypoxia-inducible factor 1 α （HIF-1α） and arylhydrocarbon receptor nuclear translocator 1 （ARNT1）. In the present study, we showed that DEC2, but not DEC1, suppressed VEGF gene expression under hypoxic conditions. DEC2 protein was co-immunoprecipitated with HIF-1α but not with ARNT1. The binding of HIF-1α to the hypoxia response element（ HRE） in the VEGF promoter was decreased by DEC2 overexpression, and increased by DEC2 knockdown. We also showed that the circadian expression of VEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a circadian oscillation in implanted Sarcoma 180 cells. We conclude that DEC2 negatively regulates VEGF expression and plays an important role in the pathological conditions in which VEGF is involved.
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| 2.
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Kondo, Jun ; Sato, Fuyuki ; Wu, Yunyan ; Seino, Hiroko ; Morohashi, Satoko ; Kijima, Hiroshi
概要:
Claudin is one of tight junction proteins which connect with the actin cytoskeleton and participate in the intracellular
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signaling. However, the significance of claudin in pancreatic cancer is understood not yet extensively. We examined the relationship between claudin-1 and invasion in PANC-1 and MIA PaCa-2 human pancreatic cancer cells, and investigated the functions of claudin-1 in invasive growth of pancreatic cancer cells. Claudin-1 knockdown by siRNA （claudin siRNA） affected the subcellular localization in the pancreatic cancer cells, and claudin-1 siRNA increased numbers of invasive pancreatic cancer PANC-1 and MIA PaCa-2 cells. Claudin-1 siRNA did not significantly affect expression levels of β-catenin, E-cadherin, α-smooth muscle actin, Bcl-2, and Bax in PANC-1 and MIA PaCa-2 cells. In addition, claudin-1 siRNA showed no significant change in the cell proliferation. We concluded that claudin-1 is significantly associated with invasive growth of human pancreatic cancer cells.
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| 3.
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Takasugi, Kaori ; Morohashi, Satoko ; Haga, Toshihiro ; Toba, Takahito ; Seino, Hiroko ; Wu, Yunyan ; Suzuki, Takahiro ; Hanabata, Norihiro ; Sasaki, Yoshihiro ; Fukuda, Shinsaku ; Kijima, Hiroshi
概要:
Recently, laterally spreading tumor （LST） of early colorectal carcinoma has been treated by endoscopic submucosal dissec
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tion （ESD） more frequently. Many cases of early colorectal carcinomas are diagnosed as well differentiated adenocarcinomas, but histological and/or immunohistorogical heterogeneity is often seen in LSTs. In this study, we analyzed morphological characteristics of 61 lesions of LST-type early colorectal carcinoma by using histolosical and immunohistochemical procedures. Presence of high grade atypia components was significantly correlated with depth of submucosal invasion （P=0.0102）, and these were predominantly located to the invasive front（deep part） of the submucosal carcinoma. Allred scores of p53 and Ki-67 labeling indices were increased in the component of high grade atypia regardless of depth of invasion. Expressions of CDX2 and CD10 were significantly upregulated in a depth-of-invasion dependent manner, and these tended to be highly expressed in the high grade atypias. In onclusion, the present study indicates that the majority of LST is histologically heterogeneic. The component of high grade atypia of LST upregulates cell proliferation, which may leed to increase the malignant potential of LST for invading the submucosa.
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| 4.
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Yakoshi, Yuta ; Kudo, Daisuke ; Toyoki, Yoshikazu ; Ishido, Keinosuke ; Kimura, Norihisa ; Wakiya, Taiichi ; Sakuraba, Shingo ; Yoshizawa, Tadashi ; Sakamoto, Yoshiyuki ; Kijima, Hiroshi ; Hakamada, Kenichi
概要:
Aim: Hepatic steatosis is a major cause of steatohepatitis and is observed in several diffuse liver diseases. We studied
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the efficacy of a novel ultrasound application, acoustic structure quantification （ASQ）, for analyzing the amount of fat deposition in the liver parenchyma. Methods: Forty-three patients who received a hepatectomy at our institution participated in this study. An ultrasound machine equipped with a software application for ASQ was used to detect steatosis prior to surgery. Non-tumoral liver parenchyma obtained by hepatectomy was pathologically evaluated according to the three-grade system. Results: Histopathologically, twenty-three patients did not present steatosis, seventeen presented grade 1, and the remaining three presented grade 2 steatosis. The median “focal disturbance ratio”（ FD-ratio）, a representative index obtained by ASQ, decreased with the steatosis grade, from 0.157（ range: 0.039-0.410） at steatosis grade 0, 0.085（ range: 0.021-0.159） at steatosis grade 1, and 0.039（ range: 0.021-0.048） at steatosis grade 2. There were significant differences in the FD-ratio between steatosis grades 0 and 1 and between steatosis grades 0 and 2 （p = 0.001 and p = 0.007, respectively）.Conclusions: ASQ can be useful during a quantitative examination of the fat accumulation in the liver parenchyma and offers a reliable marker for the early detection of liver injury.
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Sakuraba, Shingo ; Morohashi, Satoko ; Yoshizawa, Tadashi ; Tsutsumi, shinji ; Kimura, Norihisa ; Kudo, Daisuke ; Ishido, Keinosuke ; Toyoki, Yoshikazu ; Hakamada, Kenichi ; Kijima, Hiroshi
概要:
Both pancreas head ductal carcinoma（ PHDC） and distal bile duct carcinoma（ DBDC） are located within the pancreas head/in
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tra-pancreatic bile duct region, and are the most aggressive malignancies with poor patient prognosis. In the present study, we demonstrated clinicopathological features and patients prognosis of PHDC/DBDC. We examined total 87 surgically resected cases of PHDC （40 cases） and DBDC （47 cases）. PHDC showed frequent neural invasion （85.0%） and lymph node metastasis （77.5%）, compared with DBDC （57.4% and 40.4% respectively）, resulting in the poorer prognosis（ P=0.0219） than DBDC. In addition, PHDC expressed MUC2（ 10.0%）and MUC6 （25.0%） less frequently, compared with DBDC （36.2% and 55.3%, respectively）. MUC5AC-negative PHDC exhibited significantly poorer patient’s prognosis, compared with MUC5AC-positive PHDC （P=0.0111）, MUC5ACpositive DBDC （P=0.000162）, and MUC5AC-negative DBDC （P=0.00416）. In conclusion, MUC5AC-negative PHDC showed significantly poor patient’s prognosis.
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| 6.
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Urushizaka, Mayumi ; Okudera, Koichi ; Takanashi, Shingo ; Yamabe, Hideaki ; Kijima, Hiroshi
概要:
Patients with chronic respiratory diseases have been found to develop malnutrition as a result of enhanced resting metab
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olic rate （RMR） associated with exacerbated ventilatory impairment. It is therefore necessary to measure each individual’s required amount of energy in order to provide nutritional support. There are few reports regarding the RMR of patients with chronic respiratory diseases that have used indirect calorimetry. We investigated the association between body composition, pulmonary function, and dyspnea grade by measuring RMR using indirect calorimetry in 23 patients with chronic obstructive pulmonary disease （COPD） and 21 patients with interstitial pneumonia （IP）. We found no increase in RMR in COPD patients without any decrease in weight or muscle mass and increase in RMR in IP patients. Fat mass was suggested to influence RMR in IP patients. Early nutritional support for COPD patients in whom no reduction in body weight or muscle mass is seen may possibly prevent RMR enhancement and malnutrition. RMR measurements using indirect calorimetry are an easy means of ascertaining the amount of energy required for nutritional support, and are easy enough to use when evaluating the nutritional status of patients with chronic respiratory diseases.
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| 7.
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Furudate, Ken ; Matsumiya, Tomoh ; Hayakari, Ryo ; Xing, Fei ; Kubota, Kosei ; Sakaki, Hirotaka ; Tamura, Yoshihiro ; Kijima, Hiroshi ; Imaizumi, Tadaatsu ; Kimura, Hiroto ; Kobayashi, Wataru
概要:
Tumor microenvironment is related to growth, survival, invasion, and metastasis of tumor cells. Several studies have pro
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ved that stromal fibroblasts play an important role in the tumor microenvironment to convert cancer-associated fibroblast （CAFs）. Clock genes are known to regulate circadian rhythms, angiogenesis, and immunoreaction. In addition, clock genes play an important role in cancer development. However, little has been shown about how these clock genes function in the tumor microenvironment. In the present study, we investigated to evaluate the effect of co-culture fibroblasts with oral cancer cells on the expression of clock genes. Following the coculture of human primary fibroblasts with human gingival carcinoma Ca9-22 cells, the expression levels of clock genes were analyzed by real-time quantitative PCR. We found that the rhythmic expression of clock genes were altered, enhanced, or disappeared by the co-culture. Such effect was observed not only in fibroblasts in the presence of Ca9-22 cells but also in Ca9-22 cells in the presence of fibroblasts. Our results suggested that clock genes might affect an important role in the tumor microenvironment.
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| 8.
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Yoshida, Kenta ; Sasaki, Yoshihiro ; Hanabata, Norihiro ; Mikami, Tatsuya ; Kijima, Hiroshi ; Fukuda, Shinsaku
概要:
White zone visualized by magnifying endoscopy with narrow-band imaging （M-NBI） corresponds to stratified alignments of t
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he gastric epithelium. In this study, we develop an image processing method for white zone with high sensitivity. Eleven specimens of endoscopic submucosal resection from 8 patients with gastric cancer were used. M-NBI was taken serially along the line of interest. The pictures were processed by low-pass filter for white zone area （%）, and visually classified into the presence （WZ+） or absence of white zone （WZ-） by a single endoscopist. The formalin-fixed-specimen was sliced along the same line of interest. The histological pictures was processed for averaged epithelial area（ μm×mm） at 1mm intervals. A total of 123 intervals were analyzed. In cancer, 36 intervals were visually classified as WZ- and 30 as WZ+. Averaged epithelial area and white zone area were significantly lower in WZ- than in WZ+. But, in background, two variables did not significantly differ between WZand WZ+. A total of 117 intervals had averaged epithelial area > 20 μm×mm and white zone area > 21.0 % with no correlation between two variables. Low-pass filter was found to visualize white zone in 41 intervals classified as WZ-.
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| 9.
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Haga, Toshihiro ; Yoshizawa, Tadashi ; Morohashi, Satoko ; Hirai, Hideaki ; Saitou, Kensuke ; Ota, Rie ; Takatsuna, Masafumi ; Wu, Yuyan ; Fukuda, Shinsaku ; Kijima, Hiroshi
概要:
Early biliary tract carcinomas（ BTCs） are divided into three groups: early gallbladder carcinoma（ GBC）,early extrahepati
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c bile duct carcinoma （EBC）, and early duodenal ampullary carcinoma （DAC）. These earlycarcinomas frequently show metaplastic changes. However, phenotypic characterization has not yet been examined.We examined 76 lesions of surgically resected early biliary tract carcinomas （pTis/pT1 tumors according to TNMclassification）. The predominant carcinoma phenotypes were classified with hematoxylin and eosin （HE） stain, andimmunohistochemical examinations （MUC1, MUC2, MUC5AC, MUC6, and CD10） were performed. We also analyzedphenotypes of the surrounding non-neoplastic mucosa. Of the 33 early GBCs, 18 （54.5%） were biliary type, and 15（45.5%） were metaplastic type （gastric foveolar type/intestinal type） carcinoma. Of the 26 early EBCs, 18 （69.2%）were biliary type carcinoma, and eight（ 30.8%） were metaplastic type carcinoma. Of the 17 early DACs, eight（ 47.1%）were biliary type carcinoma, nine （52.9%） were metaplastic type carcinoma. Biliary type carcinomas less frequentlyshowed metaplastic changes, while metaplastic type carcinomas were frequently surrounded by the metaplasticmucosa. Early GBC and early DAC more frequently showed metaplastic changes, compared to the early EBC. Inconclusion, we speculated that two carcinogenesis pathways of early BTC （GBC, EBC, and DAC）: （1） carcinomasarising from the proper epithelium （mainly EBC） and （2） carcinomas from the metaplastic epithelium （mainly GBC and DAC）.
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| 10.
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Morohashi, Satoko ; Morohashi, Hajime ; Yoshizawa, Tadashi ; Tanaka, Masanori ; Mikami, Tatsuya ; Kagiya, Takuji ; Saito, Takeshi ; Hirai, Hideaki ; Haga, Toshihiro ; Wu, Yunyan ; Hakamada, Kenichi ; Kijima, Hiroshi
概要:
There are no reports on the degree of inflammation in the residual rectal mucosa inasymptomatic UC patients after an ope
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ration for ileal pouch anal canal anastomosis（ IACA）.Methods: We studied the residual rectal mucosal biopsies and rectal mucosa from the surgical specimens of 12asymptomatic postoperative UC cases. We analyzed the degree of inflammation, including crypt architecture andmucus content in the rectal mucosa.Results: Two pathological active cases （16.7%）, four resolving cases （33.3%）, and six remission cases （50%） wereobserved in the residual rectal mucosa. In terms of the degree of pathological inflammation in the residual rectalmucosa, one case （1/12, 8.3%） was upregulated, seven cases （7/12, 58.3%） were stable, and four cases （4/12, 33.3%）were downregulated compared with the rectal mucosa of the surgical specimens.Conclusions: We determined the natural history of the degree of inflammation on the residual rectal mucosa inpostoperative UC patients. Eight cases （8/12, 66.6%） of asymptomatic UC patients were associated with prolongedinflammation after an IACA operation in the residual rectal mucosa compared with that in the rectal mucosa of thesurgical specimens. Therefore, we could identify patients with prolonged inflammation in asymptomatic UC cases by a residual rectal mucosal biopsy.
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