Open AccessNuclear translocation of pro‐amphiregulin induces chemoresistance in gastric cancer
Author(s) -
Yoshida Michihiro,
Shimura Takaya,
Fukuda Shinji,
Mizoshita Tsutomu,
Tanida Satoshi,
Kataoka Hiromi,
Kamiya Takeshi,
Nakazawa Takahiro,
Higashiyama Shigeki,
Joh Takashi
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2012.02204.x
Subject(s) - amphiregulin , cancer , chromosomal translocation , cancer research , nuclear localization sequence , cancer cell , ectodomain , biology , in vivo , nucleus , medicine , pathology , epidermal growth factor receptor , receptor , microbiology and biotechnology , biochemistry , genetics , gene
Amphiregulin ( AR ) is derived from a membrane‐anchored form (pro AR ) by ectodomain shedding, and is a ligand that activates epidermal growth factor receptor ( EGFR ). We have recently shown that pro AR translocates from the plasma membrane to the nucleus after truncation of 11 amino acids at the C ‐terminus, which is independent of the conventional EGFR signaling pathway. Although pro AR immunoreactivity has reportedly been detected in the nucleus of cancer cells, its biological meaning has never been investigated. This study was performed to investigate the roles of pro AR nuclear translocation in human gastric cancer. We constructed pro AR truncated 11 amino acids at the C ‐terminus (pro AR Δ C 11) that spontaneously translocates to the nucleus, and established pro AR Δ C 11‐expression regulatable gastric cancer cells ( MKN 45, MKN 28) using the tet‐off system. Using these cells, we found that pro AR nuclear translocation significantly induced chemoresistance in vitro and in vivo . Analyzing the relationship between immunoreactive localization of pro AR and the clinical outcome for 46 advanced gastric cancer cases treated with chemotherapy, median survival time was 311 days in 16 patients with AR ‐positive staining in the nucleus and 387 days in 30 patients with AR ‐negative staining ( P < 0.05). The present study demonstrates that pro AR nuclear translocation increases resistance to anti‐cancer drugs, which might be associated with poor prognosis in human gastric cancer. ( Cancer Sci 2012; 103: 708–715)