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

• Published in: BMC cancer Vol. 12; no. 1; p. 205
• Main Authors: Shimura, Takaya, Yoshida, Michihiro, Fukuda, Shinji, Ebi, Masahide, Hirata, Yoshikazu, Mizoshita, Tsutomu, Tanida, Satoshi, Kataoka, Hiromi, Kamiya, Takeshi, Higashiyama, Shigeki, Joh, Takashi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.05.2012; BioMed Central; BMC
• Subjects: Active Transport, Cell Nucleus; Adult; Aged; Aged, 80 and over; Analysis; Anticoagulants (Medicine); Cancer; Cancer invasion; Cancer therapies; Care and treatment; Cell Line, Tumor; Cell Movement; Cell Nucleus - metabolism; Cell Proliferation; Cytoplasm; EGFR; Epidermal growth factor; Female; Gastric cancer; HB-EGF; Heparin-binding EGF-like Growth Factor; Humans; Infections; Intercellular Signaling Peptides and Proteins - metabolism; Leukemia; Ligands; Lymphoma; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Patient outcomes; Plasma; Proteins; Stomach cancer; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Wound Healing
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-12-205

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. 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. 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. 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.