Rationale: Tumor metastasis is the main cause for cancer-related death. However, the driving molecules of metastasis remain largely unknown. Here, we aim to identify long non-coding RNAs (lncRNAs) critical for human hepatocellular carcinoma (HCC) metastasis. Methods: Microarrays were used to screen a comprehensive set of lncRNAs with differential expression profiles in sulfatide-treated cells. Mass spectrometry, protein arrays, and RNA pull-down experiments were used to identify proteins that interacted with lncRNA. Epigenetic analysis was used to study lncRNA-mediated regulation mechanisms. Results: We identified lncRNA AY927503 (AY) as a metastasis-associated molecule that was highly expressed in human hepatocellular carcinoma (HCC) and correlated with metastatic events and poor prognosis in patients with HCC. AY promoted HCC cell migration, stemness, 5-fluorouracil resistance, and metastasis in mice. However, knockdown of integrin αV (ITGAV) abolished AY-stimulated migration, cell viability in HCC cells or tube formation. AY strongly promoted ITGAV transcription and αVβ3 expression by interacting with the ITGAV promoter specifically and stimulating its activity. AY was identified to interact with histone 1FX (H1FX), but deletion of the central domain of AY (AY∆371-522) abolished H1FX binding and ITGAV promoter stimulation. AY significantly enriched H3K4Me3 and acH3K9/14 but reduced H3K27Me3 and H1FX occupancy on the ITGAV promoter, which remodeled chromatin structures for RNA polymerase II recruitment. Knockdown of H1FX abrogated ITGAV transcription stimulated by AY. Conclusions: Our findings suggested that lncRNA AY promoted HCC metastasis via induction of chromatin modification for ITGAV transcription as a pioneer factor and was a potential molecular signature for metastasis or poor prognosis in patients with HCC.

中文翻译：

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LncRNA AY通过刺激ITGAV转录促进肝细胞癌转移。

理由：肿瘤转移是癌症相关死亡的主要原因。然而，转移的驱动分子仍然很大程度上未知。在这里，我们旨在确定对人类肝细胞癌（HCC）转移至关重要的长非编码RNA（lncRNA）。方法：使用微阵列筛选在硫化物处理的细胞中具有差异表达谱的一整套lncRNA。质谱，蛋白质阵列和RNA下拉实验用于鉴定与lncRNA相互作用的蛋白质。表观遗传学分析用于研究lncRNA介导的调控机制。结果：我们鉴定出lncRNA AY927503（AY）是一种与转移相关的分​​子，在人类肝细胞癌（HCC）中高表达，并与HCC患者的转移事件和不良预后相关。AY促进了HCC细胞迁移，小鼠的干，5-氟尿嘧啶耐药性和转移。但是，整合素αV（ITGAV）的敲除废除了AY刺激的迁移，HCC细胞中的细胞活力或管形成。AY通过与ITGAV启动子特异性相互作用并刺激其活性，强烈促进了ITGAV转录和αVβ3表达。AY被确定与组蛋白1FX（H1FX）相互作用，但是AY中央结构域的缺失（AY∆371-522）消除了H1FX的结合和ITGAV启动子的刺激。AY显着丰富了H3K4Me3和acH3K9 / 14，但减少了ITGAV启动子上的H3K27Me3和H1FX占用，从而重新构建了用于RNA聚合酶II募集的染色质结构。击倒H1FX废除了AY刺激的ITGAV转录。结论：