LncGPR107 drives the self-renewal of liver tumor initiating cells and liver tumorigenesis through GPR107-dependent manner.
LncGPR107 drives the self-renewal of liver tumor initiating cells and liver tumorigenesis through GPR107-dependent manner.
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LncGPR107通过GPR107依赖性方式驱动肝肿瘤起始细胞的自我更新和肝肿瘤发生
DOI：
10.1186/s13046-018-0794-3
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发表时间：
2018-06-20
期刊：
影响因子：
--
通讯作者：
Jiang X
中科院分区：
文献类型：
--
作者：
Huang G;Jiang H;Lin Y;Xia W;Luo Y;Wu Y;Cai W;Zhou X;Jiang X
肝肿瘤起始细胞（TIC）具有自我更新和分化的特性，是肿瘤发生、转移和耐药的原因。G蛋白偶联受体（GPCR）是许多生理和病理过程中的关键调节剂。然而，它们在肝脏TIC中的作用尚不清楚。使用在线可用数据集进行无偏倚筛选。肝TIC通过具有表面标志物CD 133的FACS分选，或通过六钩蚴形成富集。TIC自我更新通过六钩蚴形成和肿瘤起始测定来检查。进行功能丧失和功能获得测定以检查lncRNA的作用。采用RNA pulldown、RNA免疫沉淀、ChIP、western blot和双荧光原位杂交等方法探讨lncRNA的分子机制。我们对肝癌中的GPCR表达进行了无偏筛选，发现GPR 107是肝癌和肝TIC中最高表达的GPCR。GPR 107对肝脏TIC的自我更新至关重要。GPR 107的表达受一个长的非编码RNA lncGPR 107的调控。LncGPR 107在肝癌和肝TIC中也高度表达。LncGPR 107通过GPR 107驱动肝脏TIC的自我更新。此外，lncGPR 107募集SRCAP复合物到GPR 107启动子以驱动其转录激活。LncGPR 107缺失抑制SRCAP复合物和GPR 107启动子的结合以及随后的GPR 107表达。此外，LncGPR 107-SRCAP-GPR 107可以靶向肝脏TIC消除。GPR 107是肝癌和肝TIC中最高表达的GPCR。LncGPR 107通过募集SRCAP重塑复合物到GPR 107启动子上，顺式参与GPR 107的转录调控。这项工作揭示了GPCR信号在肝脏TIC自我更新中的重要作用，并为肝脏TIC和GPCR调控增加了新的层面。
With self-renewal and differentiation properties, liver tumor initiating cells (TICs) are the reasons for tumor initiation, metastasis and drug resistance. G protein coupled receptors (GPCR) are critical modulators in many physiological and pathological processes. While, their roles in liver TICs are unknown. An unbiased screening was performed using online-available data dataset. Liver TICs were sorted by FACS with surface marker CD133, or enriched by oncosphere formation. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH were used explore the molecular mechanism of lncRNA. We performed an unbiased screening for GPCR expression in liver cancers, and found GPR107 was the most highly expressed GPCR in liver cancer and liver TICs. GPR107 was essential for the self-renewal of liver TICs. The expression of GPR107 was regulated by a long noncoding RNA lncGPR107. LncGPR107 was also highly expressed in liver cancers and liver TICs. LncGPR107 drove the self-renewal of liver TICs through GPR107. Moreover, lncGPR107 recruited SRCAP complex to GPR107 promoter to drive its transcriptional activation. LncGPR107 depletion inhibited the binding of SRCAP complex and GPR107 promoter and subsequent GPR107 expression. Moreover, LncGPR107-SRCAP-GPR107 can be targeted for liver TIC elimination. GPR107 was the most highly expressed GPCR in liver cancer and liver TICs. LncGPR107 participated in the transcriptional regulation of GPR107 in cis, through recruiting SRCAP remodeling complex to GPR107 promoter. This work revealed the important role of GPCR signaling in liver TIC self-renewal and added a new layer for liver TIC and GPCR regulation.
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