Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion.
Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion.
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DOI：
10.1186/1471-2407-12-205
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发表时间：
2012-05-30
期刊：
影响因子：
3.8
通讯作者：
Joh T
中科院分区：
文献类型：
--
作者：
Shimura T;Yoshida M;Fukuda S;Ebi M;Hirata Y;Mizoshita T;Tanida S;Kataoka H;Kamiya T;Higashiyama S;Joh T
膜锚定的肝素结合表皮生长因子样生长因子（proHB-EGF）产生可溶性HB-EGF，其是表皮生长因子受体（EGFR）配体，以及胞外域脱落后HB-EGF的羧基末端片段（HB-EGF-CTF）。我们以前报道过HB-EGF-CTF和具有proHB-EGF胞浆区的未脱落proHB-EGF（HB-EGF-C）在脱落刺激后从质膜转运到细胞核并调节细胞周期。然而，核输出HB-EGF-C在人类胃癌中的意义尚不清楚。我们研究了96例胃癌患者行胃切除术后HB-EGF-C细胞内定位与临床预后的关系。此外，我们建立了稳定的胃癌细胞系过表达野生型HB-EGF（wt-HB-EGF）和突变型HB-EGF（HB-EGF-mC），这阻止了脱落后HB-EGF-C核转位。采用transwell侵袭实验和创伤愈合实验研究了这2种胃癌细胞系之间的细胞运动性。96例胃癌组织中HB-EGF-C免疫反应阳性率为19.8%（19/96），阳性率为26.0%（25/96）。HB-EGF-C在pT 3/4期肿瘤中的阳性表达率明显高于pT 1/2期肿瘤（T1/2 vs.T3/4：11.1%vs.36.4%，P < 0.01）。与对照细胞相比，表达wt-HB-EGF和HB-EGF-mC的细胞的生长显著增加，但表达HB-EGF-mC的细胞的生长与表达wt-HB-EGF的细胞相比显著降低。表达wt-HB-EGF的胃癌细胞的侵袭能力明显增强，而表达HB-EGF-mC的胃癌细胞的侵袭能力较对照组略有增强。此外，wt-HB-EGF过表达增加了伤口愈合的有效性，但对表达HB-EGF-mC的细胞没有显著影响。HB-EGF作为EGFR配体的功能和HB-EGF-C核转位的新信号均诱导胃癌生长，而HB-EGF-C核转位在胃癌侵袭中独立起关键作用。提示HB-EGF-C核转位可能在胃癌侵袭中起重要作用。HB-EGF-C核转位可能为胃癌的治疗提供一个新的分子靶点。
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.
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DOI：
10.1006/bbrc.1994.2131
发表时间：
1994-08-15
影响因子：
3.1
作者：
KOBRIN, MS;FUNATOMI, H;KORC, M
通讯作者：
KORC, M
影响因子：
29.4
作者：
INUI, Y;HIGASHIYAMA, S;MATSUZAWA, Y
通讯作者：
MATSUZAWA, Y
影响因子：
4.8
作者：
Kinugasa, Yumi;Hieda, Miki;Higashiyama, Shigeki
通讯作者：
Higashiyama, Shigeki
影响因子：
6.4
作者：
Murayama, Y;Miyagawa, J;Matsuzawa, Y
通讯作者：
Matsuzawa, Y
DOI：
10.1073/pnas.90.9.3889
发表时间：
1993-05-01
影响因子：
11.1
作者：
MARIKOVSKY, M;BREUING, K;KLAGSBRUN, M
通讯作者：
KLAGSBRUN, M