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

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)625-630
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
Publication statusPublished - Jan 8 2019

All Science Journal Classification (ASJC) codes

  • General


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