Assistant Professor(without tenure)
（School of Advanced Science and Engineering）
Doctor of Science, Ph.D. Waseda University
Murakami, Akari; Maekawa, Masashi; Kawai, Katsuhisa; Nakayama, Jun; Araki, Nobukazu; Semba, Kentaro; Taguchi, Tomohiko; Kamei, Yoshiaki; Takada, Yasutsugu; Higashiyama, Shigeki
Cancer Science Peer Review Yes 110p.650 - 6612019/02-2019/02
Outline：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.
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 Peer Review Yes 8(1) 2017/12-2017/12
Outline：© 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.
Nakayama, Jun; Ito, Emi; Fujimoto, Jiro; Fujimoto, Jiro; Watanabe, Shinya; Watanabe, Shinya; Semba, Kentaro; Semba, Kentaro
International Journal of Oncology Peer Review Yes 50(2) p.497 - 5042017/02-2017/02
Outline：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.
Research Classification：Multi-Organ Metastasis of Breast Cancer Regulated by ERBB2-Amplicon
Research Results Outline：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-OrganM...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。
|Life Science and Medical Bio-science Seminar I||School of Advanced Science and Engineering||2019||spring semester|
|Life Science and Medical Bio-science Seminar I [S Grade]||School of Advanced Science and Engineering||2019||spring semester|