Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss.
Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss.
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DOI：
10.1101/gad.270959.115
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发表时间：
2016-01-01
影响因子：
10.5
通讯作者：
Spector DL
中科院分区：
文献类型：
--
作者：
Arun G;Diermeier S;Akerman M;Chang KC;Wilkinson JE;Hearn S;Kim Y;MacLeod AR;Krainer AR;Norton L;Brogi E;Egeblad M;Spector DL
在这项研究中，Arun等人表明，在管腔型B乳腺癌小鼠模型（MMTV-PyMT）中Malat 1 lncRNA的缺失导致肿瘤细胞增殖显著减少，诱导原发性乳腺肿瘤从高度未分化癌分化为囊性肿瘤，并减少肿瘤转移。这些发现首次证明了Malat 1在调节乳腺癌发病机制中的关键过程中的功能作用。全基因组分析已经鉴定出数千种长非编码RNA（lncRNA）。Malat 1（转移相关肺腺癌转录物1）是最丰富的lncRNA之一，其表达在许多癌症中发生改变。在这里，我们报告了在MMTV（小鼠乳腺肿瘤病毒）-PyMT小鼠乳腺癌模型中使用反义寡核苷酸（ASO）的Malat 1的遗传丢失或系统性敲低导致肿瘤生长较慢，伴有显著分化为囊性肿瘤和转移减少。此外，Malat 1缺失导致MMTV-PyMT-和Her 2/neu-扩增的肿瘤类器官中分支形态发生减少，细胞粘附增加和迁移丧失。在分子水平上，Malat 1敲低导致基因表达的改变和参与分化和促肿瘤信号通路的基因剪接模式的变化。总之，这些数据首次证明了Malat 1在调节乳腺癌发病机制中的关键过程中的功能作用。因此，Malat 1代表了一个令人兴奋的治疗靶点，Malat 1 ASO代表了抑制乳腺癌进展的潜在疗法。
In this study, Arun et al. show that loss of Malat1 lncRNA in a mouse model of luminal B breast cancer (MMTV-PyMT) results in a marked reduction in tumor cell proliferation, induces the differentiation of primary mammary tumors from highly undifferentiated carcinomas to cystic tumors, and reduces tumor metastasis. The findings demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasis-associated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. Furthermore, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMT- and Her2/neu-amplified tumor organoids, increased cell adhesion, and loss of migration. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Together, these data demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Thus, Malat1 represents an exciting therapeutic target, and Malat1 ASOs represent a potential therapy for inhibiting breast cancer progression.