Long Noncoding RNA JHDM1D-AS1 Promotes Tumor Growth by Regulating Angiogenesis in Response to Nutrient Starvation.
Long Noncoding RNA JHDM1D-AS1 Promotes Tumor Growth by Regulating Angiogenesis in Response to Nutrient Starvation.
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长的非编码RNA JHDM1D-AS1通过调节养分饥饿而调节血管生成来促进肿瘤的生长。
DOI：
10.1128/mcb.00125-17
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发表时间：
2017-09-15
影响因子：
5.3
通讯作者：
Osawa T
中科院分区：
文献类型：
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作者：
Kondo A;Nonaka A;Shimamura T;Yamamoto S;Yoshida T;Kodama T;Aburatani H;Osawa T
长链非编码RNA在肿瘤进展中发挥着关键作用，但它们在营养匮乏的肿瘤微环境中的癌细胞中的作用仍然未知。在这里，我们发现营养饥饿响应性长非编码RNA JHDM1D反义1（JHDM1D-AS1）通过响应营养饥饿调节血管生成来促进肿瘤发生。癌细胞中 JHDM1D-AS1 的表达增加。此外，与正常组织相比，临床肿瘤样本中JHDM1D-AS1的表达增加。 JHDM1D-AS1 在人胰腺癌（PANC-1 和 AsPC-1）细胞中的稳定表达可促进体外细胞生长。值得注意的是，这些表达 JHDM1D-AS1 的细胞显示体内肿瘤生长显着增加，这与 CD31+ 血管形成的增加和 CD11b+ 巨噬细胞谱系细胞向肿瘤组织的浸润增加有关。肿瘤异种移植物的全基因组分析表明，在表达 JHDM1D-AS1 的胰腺癌细胞的肿瘤异种移植物中，肿瘤源性血管生成因子（如 hHGF 和 hFGF1）的基因以及宿主源性炎症反应基因（如 mMmp3、mMmp9、mS100a8 和 mS100a9）的表达增加，导致预后不良。我们的结果提供了证据，表明营养饥饿下 JHDM1D-AS1 表达增加可通过上调血管生成来加速肿瘤生长，从而为改进治疗策略奠定基础。
Long noncoding RNAs play a pivotal role in tumor progression, but their role in cancer cells in the nutrient-starved tumor microenvironment remains unknown. Here, we show that a nutrient starvation-responsive long noncoding RNA, JHDM1D antisense 1 (JHDM1D-AS1), promotes tumorigenesis by regulating angiogenesis in response to nutrient starvation. Expression of JHDM1D-AS1 was increased in cancer cells. In addition, expression of JHDM1D-AS1 was increased in clinical tumor samples compared to that in normal tissue. Stable expression of JHDM1D-AS1 in human pancreatic cancer (PANC-1 and AsPC-1) cells promoted cell growth in vitro. Remarkably, these JHDM1D-AS1-expressing cells showed a significant increase in tumor growth in vivo that was associated with increased formation of CD31+ blood vessels and elevated infiltration of CD11b+ macrophage lineage cells into tumor tissues. Genome-wide analysis of tumor xenografts revealed that expression of genes for tumor-derived angiogenic factors such as hHGF and hFGF1 concomitant with host-derived inflammation-responsive genes such as mMmp3, mMmp9, mS100a8, and mS100a9 was increased in tumor xenografts of JHDM1D-AS1-expressing pancreatic cancer cells, leading to a poor prognosis. Our results provide evidence that increased JHDM1D-AS1 expression under nutrient starvation accelerates tumor growth by upregulating angiogenesis, thus laying the foundation for improved therapeutic strategies.