Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell

Toshifumi Yae, Kenji Tsuchihashi, Takatsugu Ishimoto, Takeshi Motohara, Momoko Yoshikawa, Go J. Yoshida, Takeyuki Wada, Takashi Masuko, Kaoru Mogushi, Hiroshi Tanaka, Tsuyoshi Osawa, Yasuharu Kanki, Takashi Minami, Hiroyuki Aburatani, Mitsuyo Ohmura, Akiko Kubo, Makoto Suematsu, Kazuhisa Takahashi, Hideyuki Saya () and Osamu Nagano ()
Additional contact information
Toshifumi Yae: Institute for Advanced Medical Research, School of Medicine, Keio University
Kenji Tsuchihashi: Institute for Advanced Medical Research, School of Medicine, Keio University
Takatsugu Ishimoto: Institute for Advanced Medical Research, School of Medicine, Keio University
Takeshi Motohara: Institute for Advanced Medical Research, School of Medicine, Keio University
Momoko Yoshikawa: Institute for Advanced Medical Research, School of Medicine, Keio University
Go J. Yoshida: Institute for Advanced Medical Research, School of Medicine, Keio University
Takeyuki Wada: Institute for Advanced Medical Research, School of Medicine, Keio University
Takashi Masuko: Cell Biology Laboratory, School of Pharmacy, Kinki University
Kaoru Mogushi: Medical Research Institute, Tokyo Medical and Dental University
Hiroshi Tanaka: Medical Research Institute, Tokyo Medical and Dental University
Tsuyoshi Osawa: Lab for Vascular Biology, RCAST, The University of Tokyo
Yasuharu Kanki: Lab for Vascular Biology, RCAST, The University of Tokyo
Takashi Minami: Lab for Vascular Biology, RCAST, The University of Tokyo
Hiroyuki Aburatani: RCAST, The University of Tokyo
Mitsuyo Ohmura: School of Medicine, Keio University
Akiko Kubo: School of Medicine, Keio University
Makoto Suematsu: School of Medicine, Keio University
Kazuhisa Takahashi: Juntendo University, School of Medicine
Hideyuki Saya: Institute for Advanced Medical Research, School of Medicine, Keio University
Osamu Nagano: Institute for Advanced Medical Research, School of Medicine, Keio University

Nature Communications, 2012, vol. 3, issue 1, 1-9

Abstract: Abstract In cancer metastasis, various environmental stressors attack the disseminating cells. The successful colonization of cancer cells in secondary sites therefore requires the ability of the cells to avoid the consequences of such exposure to the stressors. Here we show that orthotopic transplantation of a CD44 variant isoform-expressing (CD44v+) subpopulation of 4T1 breast cancer cells, but not that of a CD44v− subpopulation, in mice results in efficient lung metastasis accompanied by expansion of stem-like cancer cells. Such metastasis is dependent on the activity of the cystine transporter xCT, and the stability of this protein is controlled by CD44v. We find that epithelial splicing regulatory protein 1 regulates the expression of CD44v, and knockdown of epithelial splicing regulatory protein 1 in CD44v+ cells results in an isoform switch from CD44v to CD44 standard (CD44s), leading to reduced cell surface expression of xCT and suppression of lung colonization. The epithelial splicing regulatory protein 1-CD44v-xCT axis is thus a potential therapeutic target for the prevention of metastasis.

Date: 2012
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DOI: 10.1038/ncomms1892

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