Li Yue, Wu Zhenzhen, Yuan Jia, Sun Li, Lin Li, Huang Na, Bin Jianping, Liao Yulin, Liao Wangjun
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Cancer Lett. 2017 Jun 1;395:31-44. doi: 10.1016/j.canlet.2017.02.035. Epub 2017 Mar 6.
MALAT1 is an oncogenic long non-coding RNA that has been found to promote the proliferation of many malignant cell types and non-malignant human umbilical vein endothelial cells (HUVECs). However, the functions of MALAT1 in vasculogenic mimicry (VM) and angiogenesis and the potential mechanisms responsible have not yet been investigated in any malignancy. Here, in situ hybridization and CD31/periodic acid-Schiff double staining of 150 gastric cancer (GC) clinical specimens revealed that MALAT1 expression was tightly associated with densities of VM and endothelial vessels. MALAT1 knockdown markedly reduced GC cell migration, invasion, tumorigenicity, metastasis, and VM, while restricting HUVEC angiogenesis and increasing vascular permeability. Moreover, MALAT1 was found to regulate expression of VE-cadherin, β-catenin, MMPs 2 and 9, MT1-MMP, p-ERK, p-FAK, and p-paxillin, which have been established as classical markers of VM and angiogenesis and components of associated signaling pathways. Consistent with this, the p-ERK inhibitors U0126 and PD98059 both effectively blocked GC cell VM. In conclusion, MALAT1 can promote tumorigenicity and metastasis in GC by facilitating VM and angiogenesis via the VE-cadherin/β-catenin complex and ERK/MMP and FAK/paxillin signaling pathways.
MALAT1是一种致癌性长链非编码RNA，已发现它可促进多种恶性细胞类型以及非恶性人脐静脉内皮细胞（HUVECs）的增殖。然而，MALAT1在血管生成拟态（VM）和血管生成中的功能以及潜在机制在任何恶性肿瘤中均未得到研究。在此，对150例胃癌（GC）临床标本进行原位杂交和CD31/过碘酸希夫双重染色，结果显示MALAT1表达与VM和内皮血管密度密切相关。敲低MALAT1可显著降低GC细胞的迁移、侵袭、致瘤性、转移和VM，同时抑制HUVEC血管生成并增加血管通透性。此外，发现MALAT1可调节VE-钙黏蛋白、β-连环蛋白、基质金属蛋白酶2和9、MT1-MMP、p-ERK、p-FAK和p-桩蛋白的表达，这些已被确立为VM和血管生成的经典标志物以及相关信号通路的组成部分。与此一致的是，p-ERK抑制剂U0126和PD98059均能有效阻断GC细胞的VM。总之，MALAT1可通过VE-钙黏蛋白/β-连环蛋白复合物以及ERK/MMP和FAK/桩蛋白信号通路促进VM和血管生成，从而促进GC的致瘤性和转移。
