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

doi:10.1038/ncomms1892

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 journal › Article › peer-review

295 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 language	English
Article number	883
Journal	Nature communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1892
Publication status	Published - 2012
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

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10.1038/ncomms1892

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Yae, T., Tsuchihashi, K., Ishimoto, T., Motohara, T., Yoshikawa, M., Yoshida, G. J., 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, 3, Article 883. https://doi.org/10.1038/ncomms1892

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title = "Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell",

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.",

author = "Toshifumi Yae and Kenji Tsuchihashi and Takatsugu Ishimoto and Takeshi Motohara and Momoko Yoshikawa and Yoshida, {Go J.} and Takeyuki Wada and Takashi Masuko and Kaoru Mogushi and Hiroshi Tanaka and Tsuyoshi Osawa and Yasuharu Kanki and Takashi Minami and Hiroyuki Aburatani and Mitsuyo Ohmura and Akiko Kubo and Makoto Suematsu and Kazuhisa Takahashi and Hideyuki Saya and Osamu Nagano",

year = "2012",

doi = "10.1038/ncomms1892",

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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

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T1 - Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell

AU - Yae, Toshifumi

AU - Tsuchihashi, Kenji

AU - Ishimoto, Takatsugu

AU - Motohara, Takeshi

AU - Yoshikawa, Momoko

AU - Yoshida, Go J.

AU - Wada, Takeyuki

AU - Masuko, Takashi

AU - Mogushi, Kaoru

AU - Tanaka, Hiroshi

AU - Osawa, Tsuyoshi

AU - Kanki, Yasuharu

AU - Minami, Takashi

AU - Aburatani, Hiroyuki

AU - Ohmura, Mitsuyo

AU - Kubo, Akiko

AU - Suematsu, Makoto

AU - Takahashi, Kazuhisa

AU - Saya, Hideyuki

AU - Nagano, Osamu

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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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JO - Nature communications

JF - Nature communications

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

Abstract

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