LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription
LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription
复制标题
LINC02273通过表观遗传增加AGR2转录来驱动乳腺癌转移
DOI：
10.1186/s12943-019-1115-y
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发表时间：
2019-12-19
期刊：
影响因子：
37.3
通讯作者：
Wu, Jiong
中科院分区：
文献类型：
--
作者：
Xiu, Bingqiu;Chi, Yayun;Wu, Jiong
背景大多数乳腺癌患者死于转移而非原发肿瘤，然而对癌症转移的分子机制仍知之甚少。长链非编码RNA（lncRNA）已被证明可以调节癌症的发生和发展。然而，lncRNAs的驱动转移在癌症患者和他们的潜在mechanism.MethodslncRNAs的转移淋巴结中高表达的微阵列鉴定仍然在很大程度上未知。生存分析采用Kaplan-Meier法。进行细胞增殖、迁移和侵袭测定以确认LINC 02273的表型。采用尾静脉模型和乳腺脂肪垫模型进行体内研究。RNA pull-down和RIP分析用于确认hnRNPL和LINC 02273的相互作用。通过RNA纯化随后测序（ChIRP-seq）、RNA-seq、ChIP-seq和荧光素酶报告基因测定的染色质分离揭示了hnRNPL-LINC 02273调节AGR 2。反义寡核苷酸用于在体内treatment.ResultsWe确定了一种新的长非编码RNA LINC 02273，其表达在转移性病变相比，原发性肿瘤，匹配的肿瘤样本的遗传筛选显着升高。增加LINC 02273在体外和体内促进乳腺癌转移。我们进一步表明，LINC 02273是稳定的hnRNPL，蛋白质增加转移病灶，在乳腺癌细胞。从机制上讲，hnRNPL-LINC 02273形成了一种复合物，该复合物激活了AGR 2转录并促进了癌症转移。将hnRNPL-LINC 02273复合物募集到AGR 2启动子区域通过增加局部H3 K4 me 3和H3 K27 ac水平来表观遗传上调AGR 2。AGR 2和LINC 02273的组合是预测乳腺癌患者生存的独立预后因素。此外，我们的数据显示，LINC 02273靶向的反义寡核苷酸（阿索）实质上抑制乳腺癌transferationinvivo.ConclusionsOur研究结果揭示了LINC 02273-hnRNPL-AGR 2轴在乳腺癌转移中的关键作用，并提供潜在的新的治疗靶点转移性乳腺癌的干预。
BackgroundThe majority of breast cancer patients die of metastasis rather than primary tumors, whereas the molecular mechanisms orchestrating cancer metastasis remains poorly understood. Long noncoding RNAs (lncRNA) have been shown to regulate cancer occurrence and progression. However, the lncRNAs that drive metastasis in cancer patients and their underlying mechanisms are still largely unknown.MethodslncRNAs highly expressed in metastatic lymph nodes were identified by microarray. Survival analysis were made by Kaplan-Meier method. Cell proliferation, migration, and invasion assay was performed to confirm the phenotype of LINC02273. Tail vein model and mammary fat pad model were used for in vivo study. RNA pull-down and RIP assay were used to confirm the interaction of hnRNPL and LINC02273. Chromatin isolation by RNA purification followed by sequencing (ChIRP-seq), RNA-seq, ChIP-seq, and luciferase reporter assay reveal hnRNPL-LINC02273 regulates AGR2. Antisense oligonucleotides were used for in vivo treatment.ResultsWe identified a novel long noncoding RNA LINC02273, whose expression was significantly elevated in metastatic lesions compared to the primary tumors, by genetic screen of matched tumor samples. Increased LINC02273 promoted breast cancer metastasis in vitro and in vivo. We further showed that LINC02273 was stabilized by hnRNPL, a protein increased in metastatic lesions, in breast cancer cells. Mechanistically, hnRNPL-LINC02273 formed a complex which activated AGR2 transcription and promoted cancer metastasis. The recruitment of hnRNPL-LINC02273 complex to AGR2 promoter region epigenetically upregulated AGR2 by augmenting local H3K4me3 and H3K27ac levels. Combination of AGR2 and LINC02273 was an independent prognostic factor for predicting breast cancer patient survival. Moreover, our data revealed that LINC02273-targeting antisense oligonucleotides (ASO) substantially inhibited breast cancer metastasis in vivo.ConclusionsOur findings uncover a key role of LINC02273-hnRNPL-AGR2 axis in breast cancer metastasis and provide potential novel therapeutic targets for metastatic breast cancer intervention.