Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion

BMC Cancer

Research Article

Shinji Fukuda¹  Shigeki Higashiyama²  Yoshikazu Hirata³  Takashi Joh³  Masahide Ebi³  Takaya Shimura³  Michihiro Yoshida³  Tsutomu Mizoshita³  Satoshi Tanida³  Hiromi Kataoka³  Takeshi Kamiya³ 

[1] Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, 791-0295, Shitsukawa, Toon, Ehime, Japan;Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, 791-0295, Shitsukawa, Toon, Ehime, Japan;Department of Cell Growth and Tumor Regulation, Proteo-Medicine Research Center, Ehime University, 791-0295, Shitsukawa, Toon, Ehime, Japan;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, 467-8601, Mizuho-ku, Nagoya, Japan;

关键词: EGFR;    Gastric cancer;    HB-EGF;    Cancer invasion;   

DOI  :  10.1186/1471-2407-12-205

 received in 2011-12-17, accepted in 2012-05-30,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundMembrane-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.MethodsWe 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.ResultsOf 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.ConclusionsBoth 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.

【 授权许可】

CC BY   
© Shimura et al.; licensee BioMed Central Ltd. 2012