Metastasis-associated in colon cancer-1 promotes vasculogenic mimicry in gastric cancer by upregulating TWIST1/2.
Metastasis-associated in colon cancer-1 promotes vasculogenic mimicry in gastric cancer by upregulating TWIST1/2.
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结肠癌转移相关-1通过上调TWIST1/2促进胃癌血管生成拟态
DOI：
10.18632/oncotarget.3416
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发表时间：
2015-05-10
期刊：
影响因子：
--
通讯作者：
Liao W
中科院分区：
文献类型：
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作者：
Wang L;Lin L;Chen X;Sun L;Liao Y;Huang N;Liao W
血管生成拟态（VM）是一种与上皮-间质转化（EMT）、TWIST 1激活和肿瘤进展密切相关的血液供应模式。我们先前报道了结肠癌转移相关蛋白1（MACC 1）诱导EMT并与胃癌（GC）患者的不良预后相关，但MACC 1是否促进VM并调节GC中的TWIST信号通路仍不清楚。在这项研究中，我们研究了MACC 1的表达和VM的88例IV期胃癌患者的免疫组化，还研究了TWIST 1和TWIST 2在MACC 1诱导的VM中的作用，通过使用裸鼠与GC异种移植瘤和GC细胞系。我们发现死于胃癌的患者肿瘤中VM密度显著增加，并且与MACC 1免疫反应性呈正相关（p < 0.05）。MACC 1和VM双阳性患者的3年生存率仅为8.6%，而MACC 1和VM均阴性患者的3年生存率为41.7%。此外，与匹配的邻近非肿瘤组织相比，MACC 1、TWIST 1和TWIST 2的核表达在GC组织中上调（p < 0.05）。MACC 1的过表达增加了TWIST 1/2的表达，并在裸鼠的GC异种移植物和GC细胞系中诱导了典型的VM。MACC 1增强TWIST 1/2启动子活性并促进VM，而TWIST 1或TWIST 2的沉默抑制VM。肝细胞生长因子（HGF）增加了MACC 1，TWIST 1和TWIST 2的核转位，而c-Met抑制剂降低了这些作用。这些发现表明MACC 1通过调节HGF/c-Met-TWIST 1/2信号通路促进GC中的VM，这意味着MACC 1和该通路是GC潜在的新治疗靶点。
Vasculogenic mimicry (VM) is a blood supply modality that is strongly associated with the epithelial-mesenchymal transition (EMT), TWIST1 activation and tumor progression. We previously reported that metastasis-associated in colon cancer-1 (MACC1) induced the EMT and was associated with a poor prognosis of patients with gastric cancer (GC), but it remains unknown whether MACC1 promotes VM and regulates the TWIST signaling pathway in GC. In this study, we investigated MACC1 expression and VM by immunohistochemistry in 88 patients with stage IV GC, and also investigated the role of TWIST1 and TWIST2 in MACC1-induced VM by using nude mice with GC xenografts and GC cell lines. We found that the VM density was significantly increased in the tumors of patients who died of GC and was positively correlated with MACC1 immunoreactivity (p < 0.05). The 3-year survival rate was only 8.6% in patients whose tumors showed double positive staining for MACC1 and VM, whereas it was 41.7% in patients whose tumors were negative for both MACC1 and VM. Moreover, nuclear expression of MACC1, TWIST1, and TWIST2 was upregulated in GC tissues compared with matched adjacent non-tumorous tissues (p < 0.05). Overexpression of MACC1 increased TWIST1/2 expression and induced typical VM in the GC xenografts of nude mice and in GC cell lines. MACC1 enhanced TWIST1/2 promoter activity and facilitated VM, while silencing of TWIST1 or TWIST2 inhibited VM. Hepatocyte growth factor (HGF) increased the nuclear translocation of MACC1, TWIST1, and TWIST2, while a c-Met inhibitor reduced these effects. These findings indicate that MACC1 promotes VM in GC by regulating the HGF/c-Met-TWIST1/2 signaling pathway, which means that MACC1 and this pathway are potential new therapeutic targets for GC.
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影响因子：
6.6
作者：
Juneja, Manisha;Ilm, Katharina;Stein, Ulrike
通讯作者：
Stein, Ulrike
影响因子：
12.8
作者：
Merindol, N.;Riquet, A.;Szablewski, V.;Eliaou, J-F;Puisieux, A.;Bonnefoy, N.
通讯作者：
Bonnefoy, N.
影响因子：
50.3
作者：
Ansieau, Stephane;Bastid, Jeremy;Puisieux, Alain
通讯作者：
Puisieux, Alain
影响因子：
64.8
作者：
Ricci-Vitiani, Lucia;Pallini, Roberto;De Maria, Ruggero
通讯作者：
De Maria, Ruggero
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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