Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells
| Autor: | Ei ichi Tsuji, Keiichiro Tada, Seiichiro Shimizu, Ayaka Sato, Arinobu Tojo, Kana Tominaga, Masaki Mori, Masao Yano, Noriko Gotoh, Toshihisa Ogawa, Hiroshi Minato, Kotoe Nishioka, Hajime Kanauchi, Koichi Akashi, Etsuko Kiyokawa, Tatsunori Nishimura, Hideshi Ishii, Takahiko Murayama, Asako Sasahara, Masahiko Tanabe, Koji Okamoto |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Medical Sciences Population Symmetric cell division Breast Neoplasms semaphorin Mixed Function Oxygenases 03 medical and health sciences Mice 0302 clinical medicine breast cancer Semaphorin Spheroids Cellular Neuropilin 1 medicine Neuropilin Animals Humans education cancer stem cell niche education.field_of_study tumor micoenvironment Multidisciplinary Chemistry Cancer Semaphorin-3A Biological Sciences medicine.disease Cell biology Neoplasm Proteins 030104 developmental biology 030220 oncology & carcinogenesis Gene Knockdown Techniques NUMB Neoplastic Stem Cells neuropilin Collapsin response mediator protein family Cell Division Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Tumors are composed of both cancer stem-like cells (CSCs) and differentiated cancer cells. Each CSC can undergo either a symmetric cell division to produce two CSCs or an asymmetric cell division to produce one CSC and one differentiated cancer cell. It is believed that the rate of symmetric division increases as more CSCs become malignant; however, underlying molecular mechanisms remain elusive. Here we show that stimulation with a cytokine, semaphorin (Sema), activates monooxygenase of MICAL3, a cytoplasmic signal transducer, through the neuropilin (NP) receptor that is specifically expressed on the breast CSC plasma membrane. The activation of MICAL3 induces symmetric division of CSCs. Each molecule in this signaling pathway represents a promising therapeutic target for eliminating CSCs. 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. |
| Databáze: | OpenAIRE |
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