タナカ　ノリナ   TANAKA Norina   田中　紀奈    所属   医学部 医学科（東京女子医科大学病院）    職種   助教
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	SLAMF3-Mediated Signaling via ERK Pathway Activation Promotes Aggressive Phenotypic Behaviors in Multiple Myeloma.
掲載誌名	正式名：Molecular cancer research 略　 称：Mol Cancer Res ISSNコード：15573125/15417786
掲載区分	国外
巻・号・頁	18(4),pp.632-643
著者・共著者	Ishibashi Mariko†, Takahashi Risa, Tsubota Asako, Sasaki Makoto, Handa Hiroshi, Imai Yoichi, Tanaka Norina, Tsukune Yutaka, Tanosaki Sakae, Ito Shigeki, Asayama Toshio, Sunakawa Mika, Kaito Yuta, Kuribayashi-Hamada Yasuko, Onodera Asaka, Moriya Keiichi, Komatsu Norio, Tanaka Junji, Odajima Takeshi, Sugimori Hiroki, Inokuchi Koiti, Tamura Hideto*
発行年月	2020/04
概要	The signaling lymphocytic activation molecule family 3 (SLAMF3) is a member of the immunoglobulin superfamily expressed on T, B, and natural killer cells and modulates the activation and cytotoxicity of these cells. SLAMF3 is also expressed on plasma cells from patients with multiple myeloma (MM), although its role in MM pathogenesis remains unclear. This study found that SLAMF3 is highly and constitutively expressed on MM cells regardless of disease stage and that SLAMF3 knockdown/knockout suppresses proliferative potential and increases drug-induced apoptosis with decreased levels of phosphorylated ERK protein in MM cells. SLAMF3-overexpressing MM cells promote aggressive myeloma behavior in comparison with cytoplasmic domain-truncated SLAMF3 (ΔSLAMF3) cells. SLAMF3 interacts directly with adaptor proteins SH2 domain-containing phosphatase 2 (SHP2) and growth factor receptor bound 2 (GRB2), which also interact with each other. SLAMF3 knockdown, knockout, ΔSLAMF3, and SHP2 inhibitor-treated MM cells decreased phosphorylated ERK protein levels. Finally, serum soluble SLAMF3 (sSLAMF3) levels were markedly increased in advanced MM. Patients with high levels of sSLAMF3 progressed to the advanced stage significantly more often and had shorter progression-free survival times than those with low levels. This study revealed that SLAMF3 molecules consistently expressed on MM cells transmit MAPK/ERK signals mediated via the complex of SHP2 and GRB2 by self-ligand interaction between MM cells and induce a high malignant potential in MM. Furthermore, high levels of serum sSLAMF3 may reflect MM disease progression and be a useful prognostic factor. IMPLICATIONS: SLAMF3 may be a new therapeutic target for immunotherapy and novel agents such as small-molecule inhibitors.
DOI	10.1158/1541-7786.MCR-19-0391
PMID	31974290