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生化学(堺単位)腫瘍生化学グループ

-腫瘍の悪性化に関わる活性化シグナルの解明-
腫瘍に転移・浸潤や薬剤耐性などの悪性形質をもたらすシグナル経路の活性化の解明を進めています。
教授: 堺 隆一
助教: 白木原 琢哉
技術員:日景 祥子
博士課程(血液内科):宮田 知美

腫瘍の悪性化に関わるチロシンリン酸化蛋白質群の解析
腫瘍の悪性化に際して活性化したシグナル経路をチロシンリン酸化の変化を指標に分離・同定する手法で、これまでに数多くのチロシン リン酸化蛋白質の腫瘍における機能を明らかにしてきた。特にSrcファミリーキナーゼの基質であるp130Cas、CDCP1、Ossaなどについては、それぞれ全く異なったメカニズムで転移や浸潤をに関わることを示すことができた。これらのチロシンキナーゼ基質分子群の相互作用の解析やシグナル阻害分子による治療モデルの樹立などについて研究を進めている。

腫瘍の発生・進展におけるALKキナーゼの役割の解析
腫瘍の発生・進展におけるALKキナーゼの役割の解析神経芽腫細胞でALK(anaplastic lymphoma kinase)が活性化していることを2002年に見出して以来、神経芽腫におけるALK活性化シグナルの媒介分子と役割の解析を行ってきている。神経 特異的なShcファミリーであるShcCはALKのがん化シグナルを伝え、ALKが活性化していない細胞でも神経芽腫の分化抑制に働いている。またALKの分解に関わるFlotillin-1タンパク質はALKの量的制御により神経芽腫の悪性化に関わっている。ALKの活性化シグナルを媒介する分子群の解明により、神経芽腫およびALKの関わる他の腫瘍におけるALKシグナルの役割を明らかにすることを目標としている。

最近の主要論文
Yamaguchi H, Ito Y, Miura N, Nagamura Y, Nakabo A, Fukami K, Honda K, Sakai R:Actinin-1 and actinin-4 play essential but distinct roles in invadopodia formation by carcinoma cells. Eur J of Biochem, 96:685-694,2017. 

Nakashima K, Uekita T, Yano S, Kikuchi JI, Nakanishi R, Sakamoto N, Fukumoto K, Nomoto A, Kawamoto K, Shibahara T, Yamaguchi H, Sakai R:Novel small molecule inhibiting CDCP1-PKCδ pathway reduces tumor metastasis and proliferation. Cancer Sci. 108 : 1049-1057,2017. 

Ueno H, Tomiyama A, Yamaguchi H, Uekita T, Shirakihara T, Nakashima K, Otani N, Wada K, Sakai R, Arai H, Mori K:Augmentation of invadopodia formation in temozolomide- resistant or adopted glioma is regulated by c-Jun terminal kinase-paxillin axis. Biochem Biophys Res Commun. 468:240-247,2015. 

Yamaguchi H, Sakai R:Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion. Cancers (Basel)14:2054-2062,2015

Uekita T, Fujii S, Miyazawa Y, Iwakawa R, Narisawa-Saito M, Nakashima K, Tsuta K, Tsuda H, Kiyono T, Yokota J, Sakai R:Oncogenic Ras/ERK signaling activates CDCP1 to promote tumor invasion and metastasis. Mol Cancer Res, 12:1449-1459,2014.

Tomiyama A, Uekita T, Kamata R, Sasaki K, Takita J, Ohira M, Nakagawara A, Kitanaka C, Mori K, Yamaguchi H, Sakai R:Flotillin-1 regulates oncogenic signaling in neuroblastoma cells by regulating ALK membrane association. Cancer Res, 74:3790-3801,2014.

Yamaguchi H, Takanashi M, Yoshida N, Ito Y, Kamata R, Fukami K, Yanagihara K, Sakai R:Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and FGFR inhibitors. Cancer Sci, 105:528-536,2014.

Yamaguchi H, Yoshida N, Takanashi M, Ito Y, Fukami K, Yanagihara K, Yashiro M, Sakai R:Stromal fibroblasts mediate extracellular matrix remodeling and invasion of scirrhous gastric carcinoma cells. PlosOne, 9:e85485(1-12),2014.

Uekita T, Fujii S, Miyazawa Y, Hashiguchi A, Abe H, Sakamoto M, Sakai R:Suppression of autophagy by CUB domain-containing protein 1 signaling is essential for anchorage-independent survival of lung cancer cells. Cancer Sci, 104:865-870,2013.

Shirakihara T, Kawasaki T, Fukagawa A, Semba K, Sakai R, Miyazono K, Miyazawa K, Saitoh M:Identification of integrin α3 as a molecular marker of cells undergoing epithelial-mesenchymal transition and of cancer cells with aggressive phenotypes. Cancer Sci, 104:1189-1197,2013.

Miyazawa Y, Uekita T, Ito Y, Seiki M, Yamaguchi H, Sakai R:CDCP1 regulates the function of MT1-MMP and invadopodia-mediated invasion of cancer cells. Mol Cancer Res, 11:628-633,2013.

Uekita T, Sakai R:Roles of CUB domain-containing protein 1 signaling in cancer invasion and metastasis. Cancer Sci, 102:1943-1948,2011.

Yamaguchi H, Yoshida S, Muroi E, Yoshida N, Kawamura M, Kouchi Z, Nakamura Y, Sakai R, Fukami K:Phosphoinositide 3-kinase signaling pathway mediated by p110a regulates invadopodia formation. J Cell Biol, 193:1275-1288,2011.

Yagi R, Tanaka M, Sasaki K, Kamata R, Nakanishi Y, Kanai Y, Sakai, R:ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion. Oncogene, 30:1413-1421,2011.

Miyazawa Y, Uekita T, Hiraoka N, Fujii S, Kosuge T, Kanai Y, Nojima Y, Sakai R:CUB domain containing protein 1, a prognostic factor for human pancreatic cancers, promotes cell migration and extracellular matrix degradation. Cancer Res, 70:5136-5146,2010.

Tanaka M, Kamata R, Yanagihara K, Sakai R:Suppression of gastric cancer dissemination by ephrin-B1-derived peptide. Cancer Sci, 101:87-93,2010.

Miyake I, Ohira M, Nakagawara A, Sakai R:Distinct role of ShcC docking protein in the differentiation of neuroblastoma. Oncogene, 28:662-673,2009.

Tanaka M, Sasaki K, Kamata R, Hoshino Y, Yanagihara K, Sakai R:A novel RNA-binding protein, Ossa/C9orf10 regulates activity of Src kinases to protect cells from oxidative stress-induced apoptosis. Mol Cell Biol, 29:402-413,2009.

Jia L, Uekita T, Sakai R:Hyperphosphorylated cortactin in cancer cells plays an inhibitory role in cell motility by regulating tyrosine phosphorylation of p130Cas. Mol Cancer Res, 6:654-662,2008.

Uekita T, Tanaka M, Takigahira M, Miyazawa Y, Nakanishi Y, Kanai Y, Yanagihara K, Sakai R:CUB-domain containing protein 1 regulates peritoneal dissemination of gastric scirrhous carcinoma. Am J Pathol, 172:1729-1739,2008.

Uekita T, Jia L, Narisawa-Saito M, Yokota J, Kiyono T, Sakai R:CUB domain-containing protein 1 is a novel regulator of anoikis resistance in lung adenocarcinoma Mol Cell Biol, 27:7649-7660,2007.

Tanaka M, Kamata R, Takigahira M, Yanagihara K, Sakai R:Phosphorylation of ephrin-B1 regulates dissemination of gastric scirrhous carcinoma. Am J Pathol, 171:68-78,2007.

Tanaka M, Sasaki K, Kamata R, Sakai R:Carboxyl terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cells. J Cell Sci, 120:2179-2189,2007.

Huang J, Sakai R, Furuichi T:The docking protein Cas links tyrosine phosphorylation signaling to elongation of cerebellar granule cell axons. Mol Biol Cell, 17:3187-3196,2006.

Sawada Y, Tamada M, Dubrin-Thaler B, Cherniavskaya O, Sakai R, Tanaka S, Sheetz MP:Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell,127:1015-1026,2006.

お問い合わせ
北里大学医学部 生化学(堺単位)腫瘍生化学グループ
〒252-0374 神奈川県相模原市南区北里1-15-1
E-mail:rsakai@kitasato-u.ac.jp