The long noncoding RNA lncZic2 drives the self-renewal of liver tumor-initiating cells via the protein kinase C substrates MARCKS and MARCKSL1
The long noncoding RNA lncZic2 drives the self-renewal of liver tumor-initiating cells via the protein kinase C substrates MARCKS and MARCKSL1
复制标题
长非编码 RNA lncZic2 通过蛋白激酶 C 底物 MARCKS 和 MARCKSL1 驱动肝肿瘤起始细胞的自我更新。
DOI：
10.1074/jbc.ra117.001321
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发表时间：
2018-05-25
影响因子：
4.8
通讯作者：
Zhu, Pingping
中科院分区：
文献类型：
--
作者：
Chen, Zhenzhen;Liu, Yating;Zhu, Pingping
肝肿瘤起始细胞（TIC）形成肝细胞肿瘤中的小细胞亚群，并导致肿瘤发生、转移、复发和耐药性。最近，我们发现转录因子ZIC家族成员2（ZIC 2）在肝脏TIC中高度表达，并且是其自我更新所必需的。然而，肝脏TIC自我更新的分子机制仍不清楚。在这里，使用人类肝癌临床样本的表达谱和CRISPR干扰测定，我们鉴定了一种长的非编码RNA（lncRNA）lncZic 2，它位于ZIC 2基因座附近，在肝癌和肝脏TIC中高度表达。我们发现，lncZic 2是所需的自我更新的肝脏TIC在ZIC 2独立的方式。lncZic 2驱动肉豆蔻酰化富含丙氨酸的蛋白激酶C底物（MARCKS）和MARCKS-like 1（MARCKSL 1）的表达，其表达水平在肝肿瘤发生和肝TIC自我更新过程中增加。从机制上讲，lncZic 2与BRM/SWI 2相关基因1（BRG 1）相互作用，并将该转录调节因子募集到MARCKS和MARCKSL 1基因的启动子中，从而激活这些基因的表达。此外，我们注意到lncZic 2和BRG 1的缺失降低了MARCKS和MARCKSL 1的表达，并降低了肝脏TIC水平。总之，lncZic 2是通过转录因子BRG 1上调MARCKS和MARCKSL 1基因表达来实现肝脏TIC自我更新所必需的。我们的研究结果表明，lncZic 2-BRG 1-MARCKS/MARCKSL 1信号级联可能是一个潜在的目标，消除肝脏TIC在肝癌的管理。
Liver tumor-initiating cells (TICs) form small subsets of cells in hepatocellular tumors and account for tumorigenesis, metastasis, recurrence, and drug resistance. Recently, we found that the transcription factor Zic family member 2 (ZIC2) is highly expressed in liver TICs and required for their self-renewal. However, the molecular mechanisms underlying self-renewal of liver TICs remain unclear. Here, using expression profiling and CRISPR-interference assays with clinical samples of human liver cancers, we identified a long noncoding RNA (lncRNA), lncZic2, that is located near the ZIC2 locus and was highly expressed in liver cancer and liver TICs. We found that lncZic2 is required for the self-renewal of liver TICs in a ZIC2-independent manner. lncZic2 drove the expression of myristoylated alanine-rich protein kinase C substrate (MARCKS) and MARCKS-like 1 (MARCKSL1), whose expression levels were increased during liver tumorigenesis and liver TIC self-renewal. Mechanistically, lncZic2 interacted with BRM/SWI2-related gene 1 (BRG1) and recruited this transcriptional regulator to the promoters of the MARCKS and MARCKSL1 gene, which activated expression of these genes. Moreover, we noted that depletion of lncZic2 and BRG1 decreases MARCKS and MARCKSL1 expression and diminishes liver TIC levels. In conclusion, lncZic2 is required for the self-renewal of liver TICs by up-regulating MARCKS and MARCKSL1 gene expression via the transcription factor BRG1. Our findings suggest that the lncZic2-BRG1-MARCKS/MARCKSL1 signaling cascade might be a potential target for eliminating liver TICs in the management of liver cancer.