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BMC Cancer. 2012; 12: 205.
Published online May 30, 2012. doi:  10.1186/1471-2407-12-205
PMCID: PMC3414754
Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion
Takaya Shimura,corresponding author1 Michihiro Yoshida,1 Shinji Fukuda,2 Masahide Ebi,1 Yoshikazu Hirata,1 Tsutomu Mizoshita,1 Satoshi Tanida,1 Hiromi Kataoka,1 Takeshi Kamiya,1 Shigeki Higashiyama,2,3 and Takashi Joh1
1Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
2Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
3Department of Cell Growth and Tumor Regulation, Proteo-Medicine Research Center, Ehime University, Shitsukawa, Toon, Ehime, 791-0295, Japan
corresponding authorCorresponding author.
Takaya Shimura: tshimura/at/med.nagoya-cu.ac.jp; Michihiro Yoshida: mityoshi/at/med.nagoya-cu.ac.jp; Shinji Fukuda: sfukuda/at/m.ehime-u.ac.jp; Masahide Ebi: ebissen/at/yahoo.co.jp; Yoshikazu Hirata: yhirata/at/med.nagoya-cu.ac.jp; Tsutomu Mizoshita: tmizoshi/at/med.nagoya-cu.ac.jp; Satoshi Tanida: stanida/at/med.nagoya-cu.ac.jp; Hiromi Kataoka: hkataoka/at/med.nagoya-cu.ac.jp; Takeshi Kamiya: kamitake/at/med.nagoya-cu.ac.jp; Shigeki Higashiyama: shigeki/at/m.ehime-u.ac.jp; Takashi Joh: tjoh/at/med.nagoya-cu.ac.jp
Received December 17, 2011; Accepted May 30, 2012.
Abstract
Background
Membrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields soluble HB-EGF, which is an epidermal growth factor receptor (EGFR) ligand, and a carboxy-terminal fragment of HB-EGF (HB-EGF-CTF) after ectodomain shedding. We previously reported that HB-EGF-CTF and unshed proHB-EGF which has the cytoplasmic domain of proHB-EGF (HB-EGF-C), translocate from the plasma membrane to the nucleus and regulate cell cycle after shedding stimuli. However, the significance of nuclear exported HB-EGF-C in human gastric cancer is unclear.
Methods
We investigated the relationship between intracellular localization of HB-EGF-C and clinical outcome in 96 gastric cancer patients treated with gastrectomy. Moreover, we established stable gastric cancer cell lines overexpressing wild-type HB-EGF (wt-HB-EGF) and mutated HB-EGF (HB-EGF-mC), which prevented HB-EGF-C nuclear translocation after shedding. Cell motility between these 2 gastric cancer cell lines was investigated using a transwell invasion assay and a wound healing assay.
Results
Of the 96 gastric cancer cases, HB-EGF-C immunoreactivity was detected in both the nucleus and cytoplasm in 19 cases (19.8 %) and in the cytoplasm only in 25 cases (26.0 %). The nuclear immunoreactivity of HB-EGF-C was significantly increased in stage pT3/4 tumors compared with pT1/2 tumors (T1/2 vs. T3/4: 11.1 % vs. 36.4 %, P < 0.01). The growth of wt-HB-EGF- and HB-EGF-mC-expressing cells significantly increased compared with control cells, but the growth of HB-EGF-mC-expressing cells was significantly decreased compared with wt-HB-EGF-expressing cells. Gastric cancer cell invasion obviously increased in wt-HB-EGF-expressing cells, but invasion in HB-EGF-mC-expressing cells showed a slight increase compared with control cells. Moreover, wt-HB-EGF overexpression increased the effectiveness of wound healing, but had no significant effect in HB-EGF-mC-expressing cells.
Conclusions
Both the function of HB-EGF as an EGFR ligand and a novel signal for HB-EGF-C nuclear translocation induce gastric cancer growth, whereas HB-EGF-C nuclear translocation independently plays a critical role in gastric cancer invasion. The present study demonstrated that HB-EGF-C nuclear translocation might be crucial in gastric cancer invasion. HB-EGF-C nuclear translocation may offer a prognostic marker and a new molecular target for gastric cancer therapy.
Keywords: EGFR, Gastric cancer, HB-EGF, Cancer invasion
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