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Oshima, Hiroko ; Kok, Sau-Yee ; Nakayama, Mizuho ; Murakami, Kazuhiro ; Voon, Dominic Chih-Cheng ; Kimura, Takashi ; Oshima, Masanobu ; 大島, 浩子 ; 中山, 瑞穂 ; 村上, 和弘 ; 大島, 正伸
概要:
金沢大学ナノ生命科学研究所<br />Signal transducer and activator of transcription 3 (Stat3) has been shown to play a role in intestina
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l regeneration and colitis-associated colon carcinogenesis. However, the role of Stat3 in the Wnt-driven sporadic intestinal tumorigenesis remains poorly understood. We examined the roles of Stat3 in intestinal regeneration and tumorigenesis by organoid culture experiments using Stat3∆IEC mouse-derived intestinal epithelial cells in which Stat3 was disrupted. The regeneration of intestinal mucosa and organoid formation were significantly suppressed by Stat3 disruption, which was compensated by Wnt activation. Furthermore, once organoids were recovered, Stat3 was no longer required for organoid growth. These results indicate that Stat3 and Wnt signaling cooperatively protect epithelial cells at the early phase of intestinal regeneration. In contrast, intestinal tumorigenesis was not suppressed by Stat3 disruption in adenomatous polyposis coli ( Apc) Δ716 and Apc∆716 Tgfbr2∆IEC mice, thus indicating that Stat3 is not required for Wnt activation-driven intestinal tumorigenesis. Mechanistically, Itga5 and Itga6 were down-regulated by Stat3 disruption, and focal adhesion kinase (FAK) activation was also suppressed. Notably, FAK inhibitor suppressed the organoid formation of wild-type epithelial cells. These results indicate that Stat3 is indispensable for the survival of epithelial cells through the activation of integrin signaling and the downstream FAK pathway; however, it is not required for the Wnt signaling-activated normal or tumor epithelial cells.-Oshima, H., Kok, S.-Y., Nakayama, M., Murakami, K., Voon, D. C.-C., Kimura, T., Oshima, M. Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.
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今井, 一志
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浅田, 康行
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Kawahara, Ei ; Tokuda, Ryouko ; Nakanishi, Isao
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金沢大学大学院医学系研究科保健学専攻<br />Cell migration is involved in carcinoma cell invasion and wound healing. We examined motogenic c
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ytokines that potentiated migration of human HSC-3 carcinoma cells. To assess migratory activity, modified Boyden chambers were used. Among a variety of potential motogenic cytokines, epidermal growth factor (EGF) enhanced migration of HSC-3 cells both on collagen and fibronectin. Phorbol myristate acetate (PMA) also enhanced migration. Inhibitors of protein kinase C completely inhibited PMA-induced migration, but only partly inhibited EGF-induced migration. Protein kinase A was also involved in the EGF-induced signaling pathway for migration. Although the signaling pathways were independent, and the cell shape on collagen was different from that on fibronectin, migratory cells stimulated by EGF or PMA showed common morphology on different ligands. The cells were polygonal or round in shape and the loss of long cytoplasmic extensions was noted. Migratory HSC-3 cells stimulated by EGF or PMA became less adhesive to collagen and fibronectin. Since both EGF- and PMA-stimulated migration did not require de novo protein synthesis, the signaling pathways possibly lead to assembly and disassembly of an actin cytoskeleton. Immunofluorescence for vinculin was concentrated into focal contacts in EGF- and PMA-stimulated HSC-3 cells, whereas the fluorescence signal was hardly detected in non-stimulated cells. Talin and β1 integrin were immunolocalized at focal contacts in non-stimulated cells, and it remained unchanged in stimulated cells. Numerous filopodia visualized with actin immunofluorescence were formed around stimulated HSC-3 cells, whereas filopodia were short and sparse around elongated cytoplasms in non-stimulated cells. Thus, shortening of cytoplasmic extensions with numerous filopodia, loosening of adhesion, and vinculin-associated focal contacts were regarded as migratory phenotypes.
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中田, 光俊
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本研究では、CD133 をマーカーとする幹細胞様グリオーマ細胞の高い浸潤能を規定する分子 を探索した。グリオーマ組織中のCD133 陽性細胞において普遍的にMT1-MMP とintegrin α3 が高発現していることを見出した。ヒト膠芽腫
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組織において、浸潤グリオーマ細胞にMT1-MMP とintegrin α3 の局在を認めた。Integrin α3 の発現とグリオーマ細胞の浸潤能は正の相関 を示し、その下流のシグナルとしてextracellular signal-regulated kinase（ERK）1/2 が示 された。integrin α3 はERK1/2 の活性を介して幹細胞様グリオーマ細胞の遊走・浸潤能を亢 進させることが示唆された。
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山下, 純宏 ; Yamashita, Junkoh
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金沢大学医学部<br />今回の研究で以下の2点を明らかにした。1,細胞外マトリックス分解酵素であるMMP(matrix metalloproteinase)及びそれらの抑制因子であるTIMP(tissue inhibitors of me
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talloproteinases)-1,2の浸潤,髄腔内播種における役割を考察した。手術材料を用い上記分子の産生量,局在を検討し,更に神経膠芽腫細胞株に遺伝子導入し浸潤能への関与を検討した。その結果,悪性神経膠腫の浸潤にはMMP-2と細胞膜貫通型MMP(MT1-MMP)が関与しており,MT1-MMPとTIMP-2の不均衡が神経膠芽腫の髄腔内播種に重要であると考えられた。2,神経膠腫の悪性度が高くなるにつれ,高発現する転写因子Ets-1に着目した。神経膠腫細胞株に,DNA結合能力を有するが転写活性化部位を欠くEtsドミナントネガティブ変異体を遺伝子導入した細胞株を樹立した(U251-DN)。これはurokinase type plasminogen activatorの発現低下をきたし細胞浸潤の低下が起こることを見出しEts-1を主要な浸潤関連転写因子と位置づけた。更に細胞外基質への接着,運動能を検討したところ,ファイブロネクチン上での接着能低下,細胞骨格低形成,細胞移動能低下,focal adhesion kinaseリン酸化低下が示された。そこで接着分子の発現を検討したところ,U251-DNにおいてインテグリンα5およびβ3の発現低下が見いだされた。さらに手術材料を用い,上記分子のmRNA発現量を定量的RT-PCR法により計測した。その結果,インテグリンα5,β3とEts-1の発現量が正の相関関係を示し,神経膠芽腫において両者の高発現が認められた。このことからEts-1が細胞外マトリックス分解酵素のみならず,接着因子の発現調節を担い,神経膠腫の脳実質への浸潤に大きく関与していることが明らかにされた。<br />We revealed two points as follows. 1)Among proteinases, matrix metalloproteinases(MMPs)are thought to play a key role in the tumor progression through the degradation of extracellular matrix. We examined th role of MMP-2(gelatinase A)and membrane type 1-MMP(MT1-MMP, an activator of the zymogen of MMP-2=proMMP-2)together with their inhibitors, tissue inhibitors of metalloproteinases(TIMP-1 and TIMP-2), in the invasion of human astrocytic tumors. The investigations were performed using sandwich enzyme immunoassay systems, quantitative reverse transcription polymerase chain reaction(RT-PCR), gymography, Immunohistochemistry and cell transfection. The results suggest that MT1-MMP may contribute to the invasion and CSF dissemination of glioblastoma cells on the basis of an imbalance to TIMP-2. 2)Ets transcription factors are associated with tumor malignancy. We analyzed effects of Ets-DN-expression on cell adhesion, migration and phosphorylation of focal adhesion kinase(FAK). U251 cells expressing Ets-DN(U251-DN)showed reduced cell adhesion, spreading and extension of actin stress fibers on dishes coated with fibronectin but not on dishes coated with collagen. Phosphorylation levels of FAK in U251-DN cells were also attenuated on dishes coated with fibronectin. Reduced expression level of integrin α5 subunit in U251-DN cells was demonstrated by semi-quantitative RT-PCR analysis. Furthermore, down-regulation of transcription from the integrin α5 promoter by expression of Ets-DN was shown by luciferase reporter assay. Semi-quantitative RT-PCR of surgical samples of brain tumors revealed that the expression level of Ets-1 mRNA correlated with that of integrin α5 mRNA in glioma. These results suggest that Ets-1 contributes to glioma malignancy by upregulating expression of the integrin α5 subunit, which composes integrin α5β1, mediates intracellular signaling and the subsequent acceleration of the invasive process including cell adhesion and migration.<br />研究課題/領域番号:11470286, 研究期間(年度):1999 – 2000<br />出典：「神経膠芽腫の浸潤関連遺伝子の解析」研究成果報告書 課題番号11470286（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-11470286/114702862000kenkyu_seika_hokoku_gaiyo/)を加工して作成
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