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| 1.
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Nozaki, Shinichi ; Endo, Yoshio ; Nakahara, Hirokazu ; Yoshizawa, Kunio ; Hashiba, Yukari ; Kawashiri, Shuichi ; Tanaka, Akira ; Nakagawa, Kiyomasa ; Matsuoka, Yudai ; Kogo, Mikihiko ; Yamamoto, Etsuhide
概要:
金沢大学医学部附属病院<br />There have been reports of strong correlations between poor prognosis in various cancers and concomitan
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t expression of urokinase-type plasminogen activator (uPA) and its surface receptor (uPAR). We and others have previously shown that the uPA system plays a significant role in a subset of head and neck squamous cell carcinoma. In the present study, we found that uPAR is required for invasion and metastasis of highly malignant oral cancer cells (OSC-19). Treating OSC-19 cells with antisense oligonucleotides (AS) targeting uPAR resulted in a dramatic decrease of uPAR mRNA expression. Furthermore, pretreatment with AS or siRNA targeting uPAR inhibited progression of OSC-19 cells in experimental models. These results suggest that overexpression of uPAR increases the invasiveness and metastasis of OSC-19 cells, and that uPAR is a promising therapeutic target for regulation of progression of oral cancer.
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| 2.
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Nishida, Yuki ; Miyamori, Hisashi ; Thompson, Erik W. ; Takino, Takahisa ; Endo, Yoshio ; Sato, Hiroshi
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金沢大学がん研究所がん病態制御<br />The suggested model for pro-matrix metalloproteinase-2 (proMMP-2) activation by membrane type 1 MMP
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(MT1-MMP) implicates the complex between MT1-MMP and tissue inhibitor of MMP-2 (TIMP-2) as a receptor for proMMP-2. To dissect this model and assess the pathologic significance of MMP-2 activation, an artificial receptor for proMMP-2 was created by replacing the signal sequence of TIMP-2 with cytoplasmic/transmembrane domain of type II transmembrane mosaic serine protease (MSP-T2). Unlike TIMP-2, MSP-T2 served as a receptor for proMMP-2 without inhibiting MT1-MMP, and generated TIMP-2-free active MMP-2 even at a low level of MT1-MMP. Thus, MSP-T2 did not affect direct cleavage of the substrate testican-1 by MT1-MMP, whereas TIMP-2 inhibited it even at the level that stimulates proMMP-2 processing. Expression of MSP-T2 in HT1080 cells enhanced MMP-2 activation by endogenous MT1-MMP and caused intensive hydrolysis of collagen gel. Expression of MSP-T2 in U87 glioma cells, which express a trace level of endogenous MT1-MMP, induced MMP-2 activation and enhanced cell-associated protease activity, activation of extracellular signal-regulated kinase, and metastatic ability into chick embryonic liver and lung. MT1-MMP can exert both maximum MMP-2 activation and direct cleavage of substrates with MSP-T2, which cannot be achieved with TIMP-2. These results suggest that MMP-2 activation by MT1-MMP potentially amplifies protease activity, and combination with direct cleavage of substrate causes effective tissue degradation and enhances tumor invasion and metastasis, which highlights the complex role of TIMP-2. MSP-T2 is a unique tool to analyze physiologic and pathologic roles of MMP-2 and MT1-MMP in comparison with TIMP-2. ©2008 American Association for Cancer Research.全文公開200911
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| 3.
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Kitano, Ayako ; Shimasaki, Takeo ; Chikano, Yuri ; Nakada, Mitsutoshi ; Hirose, Mayumi ; Higashi, Tomomi ; Ishigaki, Yasuhito ; Endo, Yoshio ; Takino, Takahisa ; Sato, Hiroshi ; Sai, Yoshimichi ; Miyamoto, Ken-ichi ; Motoo, Yoshiharu ; Kawakami, Kazuyuki ; Minamoto, Toshinari
概要:
Background and Purpose: The major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resis
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tance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) regulates multiple cellular pathways and is implicated in various diseases including cancer. Here we investigate a pathological role for GSK3β in the invasive and treatment resistant phenotype of pancreatic cancer. Methods: Pancreatic cancer cells were examined for GSK3β expression, phosphorylation and activity using Western blotting and in vitro kinase assay. The effects of GSK3β inhibition on cancer cell survival, proliferation, invasive ability and susceptibility to gemcitabine and radiation were examined following treatment with a pharmacological inhibitor or by RNA interference. Effects of GSK3β inhibition on cancer cell xenografts were also examined. Results: Pancreatic cancer cells showed higher expression and activity of GSK3β than non-neoplastic cells, which were associated with changes in its differential phosphorylation. Inhibition of GSK3β significantly reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their migration and invasion. These effects were associated with decreases in cyclin D1 expression and Rb phosphorylation. Inhibition of GSK3β also altered the subcellular localization of Rac1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the reduced secretion of matrix metalloproteinase-2 (MMP-2) and decreased phosphorylation of focal adhesion kinase (FAK). The effects of GSK3β inhibition on tumor invasion, susceptibility to gemcitabine, MMP-2 expression and FAK phosphorylation were observed in tumor xenografts. Conclusion: The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer. © 2013 Kitano et al.
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| 4.
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打林, 忠雄 ; 江川, 雅之 ; 浅利, 豊紀 ; 中嶋, 和喜 ; 久住, 治男 ; 遠藤, 良夫 ; 田中, 基裕 ; 佐々木, 琢磨 ; Uchimayashi, Tadao ; Egawa, Masayuki ; Asari, Toyoki ; Nakajima, Kazuyoshi ; Hisazumi, Haruo ; Endo, Yoshio ; Tanaka, Motohiro ; Sasaki, Takuma
概要:
継代培養細胞株 (B16-F10メラノーマ, ヒト膀胱癌由来培養細胞株KK-47) および臨床材料 (腎細胞癌5例, 尿路移行上皮癌9例) を用いて鶏卵法による温熱と抗癌剤併用効果の検討を行なった. その結果マウスB16-F10メラノーマで
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はADR単独処理群およびCDDP+温熱, ADR+温熱, CY+温熱併用群において有意に高い腫瘍発育阻止率が認められた (P<0.05, P<0.01). KK-47ではCY単独処理群およびCY+温熱処理群において有意に高い腫瘍発育阻止率が認められた (P<0.05). 臨床材料を用いた検討では14例中11例 (79%) において感受性試験の評価が可能であり, 今後これらの結果を臨床応用し, その相関性につき検討していく予定である. The chorioallantoic membarane of chick embryo was used to examine the responses of tumor cell lines and surgically resected specimens to anticancer agents in combination with or without hyperthermia. B16-F10 melanoma, KK-47 cell line derived from a transitional cell carcinoma of the bladder and surgical specimens from urological malignancies were transplanted onto the chorioallantoic membrane of chick embryo 10 days after fertilization. The effects of intravascularlly injected cyclophosphamide, cisplatin, adriamycin, mitomycin C, vincristine and vinblastine, in combination with or without hyperthermia, on the growth of the grafts were investigated. A 15-minute 42.5°C hyperthermia exhibited most favorable anticancer effects in B16-F10 grafts (P<0.01) of all heating conditions tested. A combined use of hyperthermia and cisplatin, cyclophosphamide or adriamycin demonstrated a significantly high tumor regression rate in B16-F10 grafts (P<0.01). In KK-47 grafts, a single use of cyclophosphamide and a combined use of hyperthermia and cyclophosphamede exhibited a highly significant antitumor regression (P<0.05). Surgical specimens from 14 urological malignancies were subjected to this assay. Growth which was adequate for sensitivity test was obtained in 11 of the 14 malignancies. The results obtained suggest that this assay system may be a useful chemohyperthermia sensitivity test.
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| 5.
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Li, Zichen ; Takino, Takahisa ; Endo, Yoshio ; Sato, Hiroshi
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An artificial receptor for proMMP-9 was created by fusing tissue inhibitor of MMP-1 (TIMP-1) with type II transmembrane
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mosaic serine protease (MSP-T1). Expression of MSP-T1 in 293T cells induced binding of proMMP-9, which was processed by MMP-2 activated by membrane type 1 MMP (MT1-MMP). HT1080 cells transfected with the MSP-T1 gene produced activated MMP-9 in collagen gel, and addition of proMMP-2 to the culture augmented it, which resulted in intensive collagen digestion. These cells metastasized into chick embryonic liver more than control cells. Treatment of HT1080 cells with concanavalin A in the presence of exogenous proMMP-2 induced activation of not only proMMP-2 but also proMMP-9. Knockdown of MT1-MMP or TIMP-2 expression with siRNA suppressed activation of both proMMP-2 and proMMP-9. Transfection of TIMP-1 siRNA suppressed cell binding and activation of proMMP-9, but not proMMP-2 activation. Knockdown of a disintegrin and metalloproteinase 10 (ADAM10) expression reduced cell binding and processing of proMMP-9. These results suggest that proMMP-9, which binds to a receptor complex containing TIMP-1 and ADAM10, is activated by the MT1-MMP/MMP-2 axis, and MMP-9 thus activated stimulates cellular proteolysis and metastasis. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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| 6.
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Gantulga, Davaakhuu ; Tuvshintugs, Baljinnyam ; Endo, Yoshio ; Takino, Takahisa ; Sato, Hiroshi ; Murakami, Seishi ; Yoshioka, Katsuji
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金沢大学がん研究所がん分子細胞制御<br />Scaffold proteins for MAP kinase (MAPK) signalling modules play an important role in the specific
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and efficient signal transduction of the relevant MAPK cascades. Here, we investigated the function of the scaffolding protein c-Jun NH2-terminal kinase (JNK)-associated leucine zipper protein (JLP) by depleting it in cultured cells using a short hairpin RNA (shRNA) against human JLP. HeLa and DLD-1 cells stably expressing the shRNA showed a defect in cell migration. The re-expression of full-length shRNA-resistant mouse JLP rescued the impaired cell migration of the JLP-depleted HeLa cells; whereas, a C-terminal deletion mutant of mouse JLP, which failed to bind the G protein Gα13, showed little or no effect on the cell migration defect. Furthermore, although a constitutively active Gα13 enhanced the migration of control HeLa cells, the Gα13-induced cell migration was significantly suppressed in the JLP-depleted HeLa cells. Taken together, these results suggest that JLP regulates cell migration through an interaction with Gα13. © The Authors 2008. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
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| 7.
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Gantulga, D. ; Tuvshintugs, Baljinnyam ; Endo, Yoshio ; Takino, Takahisa ; Sato, H. ; Murakami, S. ; Yoshioka, Katsuji
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Division of Molecular Cell Signaling
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| 8.
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Abd El-Aziz, S.H. ; Endo, Yoshio ; Miyamori, H. ; Takino, Takahisa ; Sato, H.
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Division of Molecular Viology and Oncology
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| 9.
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Endo, Yoshio ; Obata, T. ; Sasaki, T.
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Division of Molecular Viology and Oncology
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| 10.
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Endo, Yoshio ; Obata, T. ; Murata, D. ; Ito, M. ; Kadohira, M. ; Sasaki, T.
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