氏名

ナカヤマ ジュン

中山 淳

職名

助教

所属

(先進理工学部)

連絡先

メールアドレス

メールアドレス
jnakayama@aoni.waseda.jp

URL等

WebページURL

https://researchmap.jp/jnakayama/

研究者番号
30801237

学歴・学位

学位

博士(理学) 早稲田大学

所属学協会

日本癌学会

日本がん転移学会

日本がん分子標的治療学会

日本分子生物学会

Metastasis Research Society

論文

Comparative analysis of gene regulatory networks of highly metastatic breast cancer cells established by orthotopic transplantation and intra-circulation injection

Nakayama, Jun; Ito, Emi; Fujimoto, Jiro; Fujimoto, Jiro; Watanabe, Shinya; Watanabe, Shinya; Semba, Kentaro; Semba, Kentaro

International Journal of Oncology査読有り50(2)p.497 - 5042017年02月-2017年02月 

PubMedDOIScopus

詳細

ISSN:10196439

概要:Metastasis signature genes in breast cancer have been studied comparing transcriptomic profiles of highly metastatic cancer cell lines established by intra-circulation injection with that of their parental cell line. However, this method is not suitable to analyze the initial steps of metastasis including invasion into local tissues and the circulatory system. To characterize the molecular mechanisms of early metastasis, we established highly metastatic MDA-MB-231 cell lines that metastasized to lung by the two animal transplantation models: the orthotopic transplantation method, which mimics all steps of metastasis, or intra-circulation injection method. We then performed data-mining and network analysis of gene expression profiles of metastatic cell lines established by each transplantation method. Transcriptome analysis of seven metastatic cell lines revealed novel lung metastasis signature genes, including known metastasis promoting genes and signature genes. In the OXconc (orthotopic xenograft concentration) signature, 'chemotaxis' and 'cell adhesion' terms were enriched. In the TVIconc (tail vein injection concentration) signature, 'antigen recognition' and 'cell adhesion' were enriched. Furthermore, network analysis of the metastasis signature genes highlighted hub genes in the gene regulatory network. Our findings show that expression profiles of highly metastatic cell lines were different between the orthotopic transplantation and intra-circulation injection method. It also indicates that some metastatic signature genes have been missed in previous studies. Characterization of metastasis genes using the orthotopic transplantation method will be helpful in understanding the multi-step mechanisms of metastasis. Signature genes in OXconc may have the potential to become prognostic markers.

Endosomal phosphatidylserine is critical for the YAP signalling pathway in proliferating cells

Matsudaira, Tatsuyuki; Mukai, Kojiro; Noguchi, Taishin; Hasegawa, Junya; Hatta, Tomohisa; Iemura, Shun Ichiro; Natsume, Tohru; Miyamura, Norio; Nishina, Hiroshi; Nakayama, Jun; Semba, Kentaro; Tomita, Takuya; Murata, Shigeo; Arai, Hiroyuki; Arai, Hiroyuki; Arai, Hiroyuki; Taguchi, Tomohiko; Taguchi, Tomohiko

Nature Communications査読有り8(1)2017年12月-2017年12月 

DOIScopus

詳細

概要:© 2017 The Author(s). Yes-associated protein (YAP) is a recently discovered growth-promoting transcription coactivator that has been shown to regulate the malignancy of various cancers. How YAP is regulated is not fully understood. Here, we show that one of the factors regulating YAP is phosphatidylserine (PS) in recycling endosomes (REs). We use proximity biotinylation to find proteins proximal to PS. Among these proteins are YAP and multiple proteins related to YAP signalling. Knockdown of ATP8A1 (an RE PS-flippase) or evectin-2 (an RE-resident protein) and masking of PS in the cytoplasmic leaflet of membranes, all suppress nuclear localization of YAP and YAP-dependent transcription. ATP8A1 knockdown increases the phosphorylated (activated) form of Lats1 that phosphorylates and inactivates YAP, whereas evectin-2 knockdown reduces the ubiquitination and increased the level of Lats1. The proliferation of YAP-dependent metastatic cancer cells is suppressed by knockdown of ATP8A1 or evectin-2. These results suggest a link between a membrane phospholipid and cell proliferation.

Cullin‐3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2‐positive breast cancer cells

Murakami, Akari; Maekawa, Masashi; Kawai, Katsuhisa; Nakayama, Jun; Araki, Nobukazu; Semba, Kentaro; Taguchi, Tomohiko; Kamei, Yoshiaki; Takada, Yasutsugu; Higashiyama, Shigeki

Cancer Science査読有り110p.650 - 6612019年02月-2019年02月 

PubMedDOIlinkScopus

詳細

ISSN:13479032

概要:Rho GTPase Rac1 is a central regulator of F‐actin organization and signal transduction to control plasma membrane dynamics and cell proliferation. Dysregulated Rac1 activity is often observed in various cancers including breast cancer and is suggested to be critical for malignancy. Here, we showed that the ubiquitin E3 ligase complex Cullin‐3 (CUL3)/KCTD10 is essential for epidermal growth factor (EGF)‐induced/human epidermal growth factor receptor 2 (HER2)‐dependent Rac1 activation in HER2‐positive breast cancer cells. EGF‐induced dorsal membrane ruffle formation and cell proliferation that depends on both Rac1 and HER2 were suppressed in CUL3‐ or KCTD10‐depleted cells. Mechanistically, CUL3/KCTD10 ubiquitinated RhoB for degradation, another Rho GTPase that inhibits Rac1 activation at the plasma membrane by suppressing endosome‐to‐plasma membrane traffic of Rac1. In HER2‐positive breast cancers, high expression of Rac1 mRNA significantly correlated with poor prognosis of the patients. This study shows that this novel molecular axis (CUL3/KCTD10/RhoB) positively regulates the activity of Rac1 in HER2‐positive breast cancers, and our findings may lead to new treatment options for HER2‐ and Rac1‐positive breast cancers.

外部研究資金

科学研究費採択状況

研究種別:若手研究

ERBB2アンプリコンが制御する乳癌多臓器転移の分子機序解明

2018年04月-2021年03月

配分額:¥4160000

研究種別:

ERBB2アンプリコンが制御する乳癌多臓器転移の分子機序解明

2018年-0月-2021年-0月

配分額:¥4160000

学内研究制度

特定課題研究

Multi-Organ Metastasis誘導遺伝子HNF1Bの分子機序解明

2017年度

研究成果概要:がんの遠隔転移においては、転移先臓器ごとに特徴的な転移制御遺伝子の発現変化が重要であることが明らかとなっている。我々はこれまでに、乳がんERBB2遺伝子増幅領域(17q12.21)に存在するHNF1Bが、乳がんの多臓器転移(Mul...がんの遠隔転移においては、転移先臓器ごとに特徴的な転移制御遺伝子の発現変化が重要であることが明らかとなっている。我々はこれまでに、乳がんERBB2遺伝子増幅領域(17q12.21)に存在するHNF1Bが、乳がんの多臓器転移(Multi-OrganMetastasis:MOM)を亢進する遺伝子であることを見出した。また、このHNF1Bは恒常的なSTAT3のリン酸化を引き起こすことから、本研究ではHNF1B-STAT3と転移の関係性について評価を行った。この活性化STAT3はJAK阻害剤であるRuxolitinibによって抑制できるため、HNF1B-ERBB2発現NMuMG細胞をヌードマウスに移植し、Ruxolitinib投与群と未投与群における転移巣の比較解析を行った。

現在担当している科目

科目名開講学部・研究科開講年度学期
生命医科学ゼミナールI先進理工学部2019春学期
生命医科学ゼミナールI  【前年度成績S評価者用】先進理工学部2019春学期