Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells

Kana Tominaga, Hiroshi Minato, Takahiko Murayama, Asako Sasahara, Tatsunori Nishimura, Etsuko Kiyokawa, Hajime Kanauchi, Seiichiro Shimizu, Ayaka Sato, Kotoe Nishioka, Ei ichi Tsuji, Masao Yano, Toshihisa Ogawa, Hideshi Ishii, Masaki Mori, Koichi Akashi, Koji Okamoto, Masahiko Tanabe, Kei ichiro Tada, Arinobu TojoNoriko Gotoh

研究成果: ジャーナルへの寄稿記事

1 引用 (Scopus)

抄録

Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

元の言語英語
ページ(範囲)625-630
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
116
発行部数2
DOI
出版物ステータス出版済み - 1 8 2019

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Semaphorins
Neoplastic Stem Cells
Cell Division
Neuropilin-1
Breast Neoplasms
Stem Cell Niche
Neoplasms
Asymmetric Cell Division
Mixed Function Oxygenases
Transducers
Breast
Stem Cells
Cytokines

All Science Journal Classification (ASJC) codes

  • General

これを引用

Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells. / Tominaga, Kana; Minato, Hiroshi; Murayama, Takahiko; Sasahara, Asako; Nishimura, Tatsunori; Kiyokawa, Etsuko; Kanauchi, Hajime; Shimizu, Seiichiro; Sato, Ayaka; Nishioka, Kotoe; Tsuji, Ei ichi; Yano, Masao; Ogawa, Toshihisa; Ishii, Hideshi; Mori, Masaki; Akashi, Koichi; Okamoto, Koji; Tanabe, Masahiko; Tada, Kei ichiro; Tojo, Arinobu; Gotoh, Noriko.

:: Proceedings of the National Academy of Sciences of the United States of America, 巻 116, 番号 2, 08.01.2019, p. 625-630.

研究成果: ジャーナルへの寄稿記事

Tominaga, K, Minato, H, Murayama, T, Sasahara, A, Nishimura, T, Kiyokawa, E, Kanauchi, H, Shimizu, S, Sato, A, Nishioka, K, Tsuji, EI, Yano, M, Ogawa, T, Ishii, H, Mori, M, Akashi, K, Okamoto, K, Tanabe, M, Tada, KI, Tojo, A & Gotoh, N 2019, 'Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells', Proceedings of the National Academy of Sciences of the United States of America, 巻. 116, 番号 2, pp. 625-630. https://doi.org/10.1073/pnas.1806851116
Tominaga, Kana ; Minato, Hiroshi ; Murayama, Takahiko ; Sasahara, Asako ; Nishimura, Tatsunori ; Kiyokawa, Etsuko ; Kanauchi, Hajime ; Shimizu, Seiichiro ; Sato, Ayaka ; Nishioka, Kotoe ; Tsuji, Ei ichi ; Yano, Masao ; Ogawa, Toshihisa ; Ishii, Hideshi ; Mori, Masaki ; Akashi, Koichi ; Okamoto, Koji ; Tanabe, Masahiko ; Tada, Kei ichiro ; Tojo, Arinobu ; Gotoh, Noriko. / Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells. :: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; 巻 116, 番号 2. pp. 625-630.
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abstract = "Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.",
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T1 - Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells

AU - Tominaga, Kana

AU - Minato, Hiroshi

AU - Murayama, Takahiko

AU - Sasahara, Asako

AU - Nishimura, Tatsunori

AU - Kiyokawa, Etsuko

AU - Kanauchi, Hajime

AU - Shimizu, Seiichiro

AU - Sato, Ayaka

AU - Nishioka, Kotoe

AU - Tsuji, Ei ichi

AU - Yano, Masao

AU - Ogawa, Toshihisa

AU - Ishii, Hideshi

AU - Mori, Masaki

AU - Akashi, Koichi

AU - Okamoto, Koji

AU - Tanabe, Masahiko

AU - Tada, Kei ichiro

AU - Tojo, Arinobu

AU - Gotoh, Noriko

PY - 2019/1/8

Y1 - 2019/1/8

N2 - Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

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