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| 1.
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論文
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Nakata, Asuka ; Yoshida, Ryo ; Yamaguchi, Rui ; Yamauchi, Mai ; Tamada, Yoshinori ; Fujita, Andre ; Shimamura, Teppei ; Imoto, Seiya ; Higuchi, Tomoyuki ; Nomura, Masaharu ; Kimura, Tatsuo ; Nokihara, Hiroshi ; Higashiyama, Masahiko ; Kondoh, Kazuya ; Nishihara, Hiroshi ; Tojo, Arinobu ; Yano, Seiji ; Miyano, Satoru ; Gotoh, Noriko
概要:
There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TK
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Is) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-β-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a β-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of β-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of β-catenin and treatment with a β-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate β-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-β-catenin pathway to improve the efficacy of EGFR-TKIs.
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| 2.
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Murayama, Takahiko ; Nakaoku, Takashi ; Enari, Masato ; Nishimura, Tatsunori ; Tominaga, Kana ; Nakata, Asuka ; Tojo, Arinobu ; Sugano, Sumio ; Kohno, Takashi ; Gotoh, Noriko
概要:
The CD74-Neuregulin1 (NRG1) fusion gene was recently identified as novel driver of invasive mucinous adenocarcinoma, a m
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alignant form of lung cancer. However, the function of the CD74-NRG1 fusion gene in adenocarcinoma pathogenesis and the mechanisms by which it may impart protumorigenic characteristics to cancer stem cells (CSC) is still unclear. In this study, we found that the expression of the CD74-NRG1 fusion gene increased the population of lung cancer cells with CSC-like properties. CD74-NRG1 expression facilitated sphere formation not only of cancer cells, but also of nonmalignant lung epithelial cells. Using a limiting dilution assay in a xenograft model, we further show that the CD74-NRG1 fusion gene enhanced tumor initiation. Mechanistically, we found that CD74-NRG1 expression promoted the phosphorylation of ErbB2/3 and activated the PI3K/Akt/NF-κB signaling pathway. Furthermore, the expression of the secreted insulin-like growth factor 2 (IGF2) and phosphorylation of its receptor, IGF1R, were enhanced in an NF-κB-dependent manner in cells expressing CD74-NRG1. These findings suggest that CD74-NRG1-induced NF-κB activity promotes the IGF2 autocrine/paracrine circuit. Moreover, inhibition of ErbB2, PI3K, NF-κB, or IGF2 suppressed CD74-NRG1-induced tumor sphere formation. Therefore, our study provides a preclinical rationale for developing treatment approaches based on these identified pathways to suppress CSC properties that promote tumor progression and recurrence. © 2016 American Association for Cancer Research.
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| 3.
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後藤, 典子 ; Gotoh, Noriko
概要:
金沢大学がん進展制御研究所<br />がん組織は非常に不均一であるため、細胞群を1細胞に分離して解析することが重要である。本研究では乳がん臨床検体からがん幹細胞を高密度に濃縮できる申請者独自の手法と、転写産物を正確に網羅的に解析する最新の技
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術を用いて、がん幹細胞から分化がん細胞へ至るヒエラルキーの解明を目指した。その結果、分化がん細胞集団に比較し、がん幹細胞集団は、遺伝子発現パターンのばたつきが大きく、がん幹細胞から前駆細胞へ至って遺伝子発現が大きくかわるヒエラルキーの存在が示唆された。その中から、鍵分子候補を同定し、qPCRで発現確認し、がん幹細胞の維持とヒエラルキーの形成に重要な役割を果たすことが示唆された。<br />Cancer tissues are composed of very heterogenous cell populations, including cancer stem cells, progenitor cancer cells and differentiated cancer cells. It is thus important to clarify the characteristics of each cell type at single cell levels. The aim of this study to clarify the molecular mechanisms how cancer stem cells are maintained in the caner stem cell niche by analyzing transcriptome at single cell levels. We have clarified the semaphorin-neuropilin (NP) signal plays critical roles for breast cancer stem cells. We sorted NP-positive and control NP-negative cell population derived from breast cancer patient samples and analyzed transcriptome at single cell levels by using the cutting-edge technologies. We found that NP-positive cell population show strong variance in mRNA expression patterns than NP-negative cell population. These findings suggest that NP-positive cells are composed of more heterogenous cell populations with clear hierarchy than NP-negative cells.<br />研究課題/領域番号:15H04294, 研究期間(年度):2015-04-01 – 2018-03-31
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| 4.
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後藤, 典子 ; Gotoh, Noriko
概要:
金沢大学がん進展制御研究所<br />乳がん臨床検体よりの初代培養細胞を用いて、次世代シークエンサーを用いたエクソーム解析とRNAシークエンス解析を行った。その結果、既知のがん遺伝子、がん抑制遺伝子の変異を確認、さらにがん幹細胞様細胞の新規
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分子標的候補が複数得られた。詳細な機能解析により、がん幹細胞を根治する新規分子標的をさらに絞り込んだ。<br />We performed exome sequence and RNA sequence by using primary cultured cells derived from tumor tissues of breast cancer patients. We analyzed luminal type A, luminal type B and triple negative type breast cancer tissues. We found several novel molecular targets in breast cancer stem-like cells. Functional analysis of these molecules, we identified promising molecular targets of breast cancer stem-like cells.<br />研究課題/領域番号:26640072, 研究期間(年度):2014-04-01 – 2016-03-31
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| 5.
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論文
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後藤, 典子 ; Gotoh, Noriko
概要:
金沢大学がん進展制御研究所<br />増殖因子による幹細胞ならびに癌幹細胞の制御を調べるために、その細胞内シグナル伝達を担うFRS2ファミリー分子、FRS2alphaとFRS2betaのノックアウトマウスならびに変異マウスを作出し、解析を行
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った。その結果、FRS2alphaは、主にFGFシグナルの欠損により、視神経の網膜への投射、内耳の形成ならびに神経の痛み刺激に関わる神経の発達に重要であることがわかった。一方、FRS2betaは、乳癌幹細胞の維持に重要であった。<br />In order to examine the molecular mechanisms how growth factor signaling play roles for maintenance of tissue specific stem cells and cancer stem cells, we made mutant mice of FRS2alpha or FRS2beta, mediators for intracellular signaling through FGF or EGF, respectively. We found that FRS2alpha plays important roles for axon path finding of optic nerves, development of inner ears and sensory neurons. On the other hand, FRS2beta plays important roles for maintenance of breast cancer stem cells.<br />研究課題/領域番号:23390062, 研究期間(年度):2011-04-01 – 2014-03-31
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| 6.
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論文
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後藤, 典子 ; Gotoh, Noriko
概要:
金沢大学がん進展制御研究所 / 東京大学<br />乳癌幹細胞スフェア培養の系で、HER2-NFkBパスウエイもしくはHER2-PI3Kパスウエイを阻害し、詳細な時系列をとってRNAを抽出し、DNAマイクロアレイ解析を行った。得られた分子I
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GF2, AR, GDF15などが癌幹細胞維持に重要な役割を果たしていることを、乳癌臨床検体を用いて確かめた。HER2/ErbB2乳癌自然発症モデルMMTV-ErbB2マウスとFRS2betaノックアウトマウスを交配させたマウスを用いて解析を行い、FRS2betaによってErbBシグナルを効果的に減弱させることにより、癌幹細胞の自己複製能が維持させる仕組みを明らかにした。<br />In order to analyze HER2/ErbB2-PI3K-NFkB pathway in breast cancer stem cells, DNA microarray analysis was performed by using breast cancer cells stimulated with HER2 in the presence or absence of NFkB inhibitor or PI3K inhibitor. We identified several candidate molecular targets in breast cancer stem cells, IGF2, AR, GDF15, for example. We confirmed that these molecules play important roles for stemness of breast cancer cells.We analyzed FRS2beta knockout mice in the background of MMTV-ErbB2 mammary tumor model. We found that FRS2beta play important roles for stemness of mammary tumors through fine-tuning of ErbB2 signaling.<br />研究課題/領域番号:22130009, 研究期間(年度):2010-04-01 – 2015-03-31
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