Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell.
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.
Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Toshifumi
T
Yae
Kenji
K
Tsuchihashi
Takatsugu
T
Ishimoto
Takeshi
T
Motohara
Momoko
M
Yoshikawa
Go J
GJ
Yoshida
Takeyuki
T
Wada
Takashi
T
Masuko
Kaoru
K
Mogushi
Hiroshi
H
Tanaka
Tsuyoshi
T
Osawa
Yasuharu
Y
Kanki
Takashi
T
Minami
Hiroyuki
H
Aburatani
Mitsuyo
M
Ohmura
Akiko
A
Kubo
Makoto
M
Suematsu
Kazuhisa
K
Takahashi
Hideyuki
H
Saya
Osamu
O
Nagano
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000150:complications* / Q000235:genetics*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005260:Female; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000235:genetics*; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins