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, Osamu Nagano

Research output: Contribution to journalArticle

186 Citations (Scopus)

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.

Original languageEnglish
Article number883
JournalNature Communications
Volume3
DOIs
Publication statusPublished - 2012

Fingerprint

splicing
Alternative Splicing
metastasis
lungs
cancer
Cells
Protein Splicing
proteins
Lung
Messenger RNA
cells
Neoplasm Metastasis
Neoplasms
Protein Isoforms
Proteins
transplantation
transporter
Cystine
stems
breast

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. / Yae, Toshifumi; Tsuchihashi, Kenji; Ishimoto, Takatsugu; Motohara, Takeshi; Yoshikawa, Momoko; Yoshida, Go J.; Wada, Takeyuki; Masuko, Takashi; Mogushi, Kaoru; Tanaka, Hiroshi; Osawa, Tsuyoshi; Kanki, Yasuharu; Minami, Takashi; Aburatani, Hiroyuki; Ohmura, Mitsuyo; Kubo, Akiko; Suematsu, Makoto; Takahashi, Kazuhisa; Saya, Hideyuki; Nagano, Osamu.

In: Nature Communications, Vol. 3, 883, 2012.

Research output: Contribution to journalArticle

Yae, T, Tsuchihashi, K, Ishimoto, T, Motohara, T, Yoshikawa, M, Yoshida, GJ, Wada, T, Masuko, T, Mogushi, K, Tanaka, H, Osawa, T, Kanki, Y, Minami, T, Aburatani, H, Ohmura, M, Kubo, A, Suematsu, M, Takahashi, K, Saya, H & Nagano, O 2012, 'Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell', Nature Communications, vol. 3, 883. https://doi.org/10.1038/ncomms1892
Yae, Toshifumi ; Tsuchihashi, Kenji ; Ishimoto, Takatsugu ; Motohara, Takeshi ; Yoshikawa, Momoko ; Yoshida, Go J. ; Wada, Takeyuki ; Masuko, Takashi ; Mogushi, Kaoru ; Tanaka, Hiroshi ; Osawa, Tsuyoshi ; Kanki, Yasuharu ; Minami, Takashi ; Aburatani, Hiroyuki ; Ohmura, Mitsuyo ; Kubo, Akiko ; Suematsu, Makoto ; Takahashi, Kazuhisa ; Saya, Hideyuki ; Nagano, Osamu. / Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. In: Nature Communications. 2012 ; Vol. 3.
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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.",
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