Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin.
Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin.
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DOI：
10.1093/nar/gku860
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发表时间：
2014-10
影响因子：
14.9
通讯作者：
Chowdhury S
中科院分区：
文献类型：
--
作者：
Thakur RK;Yadav VK;Kumar A;Singh A;Pal K;Hoeppner L;Saha D;Purohit G;Basundra R;Kar A;Halder R;Kumar P;Baral A;Kumar MJ;Baldi A;Vincenzi B;Lorenzon L;Banerjee R;Kumar P;Shridhar V;Mukhopadhyay D;Chowdhury S
肿瘤转移是指肿瘤从其起源部位扩散到远处器官，并导致大多数癌症死亡。尽管到目前为止已经鉴定了>30种负性调节转移的转移抑制基因（MSG），但是对两个问题知之甚少：第一，哪些MSG对抗肿瘤类型中的转移，以及第二，MSG的哪些分子功能控制转移。在本文中，肺癌患者中的肿瘤转录组（n = 382）、存活数据（n = 530）和淋巴结转移（n = 100）的综合分析将非转移性2（NME 2）鉴定为来自>30种转移抑制因子的库的关键MSG。随后，我们使用染色质免疫沉淀与启动子微阵列（ChIP芯片）和转录组分析生成了NME 2的启动子范围结合图。我们发现了参与粘着斑信号传导的NME 2的新靶点。重要的是，我们检测到NME 2在黏着斑因子黏着斑蛋白启动子中的结合。NME 2的表达减少导致黏着斑蛋白的转录增强。相比之下，NME 1，NME 2的同源物，不与黏着斑蛋白启动子结合，也不调节其表达。在斑马鱼和裸鼠肿瘤模型中，发现NME 2耗尽的肺癌细胞的转移增强。NME 2耗尽的细胞的转移潜力在选择性RNA-i介导的黏着斑蛋白沉默后显著降低。总之，我们证明NME 2水平降低导致黏着斑蛋白的转录去抑制并调节肺癌转移。
Tumor metastasis refers to spread of a tumor from site of its origin to distant organs and causes majority of cancer deaths. Although >30 metastasis suppressor genes (MSGs) that negatively regulate metastasis have been identified so far, two issues are poorly understood: first, which MSGs oppose metastasis in a tumor type, and second, which molecular function of MSG controls metastasis. Herein, integrative analyses of tumor-transcriptomes (n = 382), survival data (n = 530) and lymph node metastases (n = 100) in lung cancer patients identified non-metastatic 2 (NME2) as a key MSG from a pool of >30 metastasis suppressors. Subsequently, we generated a promoter-wide binding map for NME2 using chromatin immunoprecipitation with promoter microarrays (ChIP-chip), and transcriptome profiling. We discovered novel targets of NME2 which are involved in focal adhesion signaling. Importantly, we detected binding of NME2 in promoter of focal adhesion factor, vinculin. Reduced expression of NME2 led to enhanced transcription of vinculin. In comparison, NME1, a close homolog of NME2, did not bind to vinculin promoter nor regulate its expression. In line, enhanced metastasis of NME2-depleted lung cancer cells was found in zebrafish and nude mice tumor models. The metastatic potential of NME2-depleted cells was remarkably diminished upon selective RNA-i-mediated silencing of vinculin. Together, we demonstrate that reduced NME2 levels lead to transcriptional de-repression of vinculin and regulate lung cancer metastasis.
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影响因子：
8.8
作者：
Higashiyama, M;Doi, O;Yokouchi, H;Kodama, K;Nakamori, S;Tateishi, R;Kimura, N
通讯作者：
Kimura, N
影响因子：
8
作者：
Gross, C.;Dubois-Pot, H.;Wasylyk, B.
通讯作者：
Wasylyk, B.
影响因子：
3
作者：
Postel, EH;Berberich, SJ;Kaetzel, DM
通讯作者：
Kaetzel, DM
DOI：
10.1016/s0022-5223(00)70017-1
发表时间：
2000-04-01
影响因子：
6
作者：
Ohta, Y;Nozawa, H;Watanabe, Y
通讯作者：
Watanabe, Y
影响因子：
14.9
作者：
Kar A;Saha D;Purohit G;Singh A;Kumar P;Yadav VK;Kumar P;Thakur RK;Chowdhury S
通讯作者：
Chowdhury S