Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China.
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
Clin Transl Med. 2021 May;11(5):e409. doi: 10.1002/ctm2.409.
Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not known how CNV in lncRNAs affects HCC progression and recurrence. We aimed to identify a CNV-related lncRNA involved in HCC progression and recurrence and illustrate its underlying mechanisms and prognostic value.
We analyzed the whole genome sequencing (WGS) data of matched cancerous and noncancerous liver samples from 49 patients with HCC to identify lncRNAs with CNV. The results were validated in another cohort of 238 paired HCC and nontumor samples by TaqMan copy number assay. We preformed Kaplan-Meier analysis and log-rank test to identify lncRNA CNV with prognostic value. We conducted loss- and gain-of-function studies to explore the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR-seq), quantitative real-time PCR (qRT-PCR), western blot, and dual-luciferase reporter assays. We confirmed the binding mechanism between lncRNA and protein by RNA pull-down, RNA immunoprecipitation, qRT-PCR, and western blot analyses.
Genomic copy numbers of LINC01133 were increased in HCC, which were positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression in HCC cells promoted proliferation and aggressive phenotypes in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. LINC01133 sponged miR-199a-5p, resulting in enhanced expression of SNAI1, which induced epithelial-to-mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate the ANXA2/STAT3 signaling pathway.
LINC01133 promotes HCC progression by sponging miR-199a-5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in patients with HCC.
长非编码 RNA（lncRNA）与癌症的发生和发展密切相关。尽管肝癌（HCC）中基因拷贝数变异（CNV）很常见，但lncRNA 的 CNV 如何影响 HCC 的进展和复发尚不清楚。我们旨在鉴定一种与 HCC 进展和复发相关的 CNV 相关 lncRNA，并阐明其潜在机制和预后价值。
我们分析了 49 例 HCC 患者配对癌组织和非癌组织的全基因组测序（WGS）数据，以鉴定 CNV 的 lncRNA。通过 TaqMan 拷贝数检测在另一个由 238 对 HCC 和非肿瘤样本组成的队列中验证了结果。我们进行了 Kaplan-Meier 分析和对数秩检验，以确定具有预后价值的 lncRNA CNV。我们进行了失活和激活功能研究，以在体外和体内探索 LINC01133 的生物学功能。通过 microRNA 测序（miR-seq）、定量实时 PCR（qRT-PCR）、western blot 和双荧光素酶报告基因检测来阐明竞争内源性 RNA（ceRNA）机制。我们通过 RNA 下拉、RNA 免疫沉淀、qRT-PCR 和 western blot 分析证实了 lncRNA 与蛋白质之间的结合机制。
LINC01133 的基因组拷贝数在 HCC 中增加，与 LINC01133 的高表达呈正相关。LINC01133 拷贝数的增加预示着 HCC 患者的预后不良。在 HCC 细胞中过表达 LINC01133 可促进体外增殖和侵袭表型，并促进体内肿瘤生长和肺转移，而 LINC01133 敲低则产生相反的效果。LINC01133 可吸附 miR-199a-5p，从而增强 SNAI1 的表达，诱导 HCC 细胞发生上皮间质转化（EMT）。此外，LINC01133 与 Annexin A2（ANXA2）相互作用，激活 ANXA2/STAT3 信号通路。
LINC01133 通过吸附 miR-199a-5p 并与 ANXA2 相互作用，促进 HCC 进展。LINC01133 CNV 增益可预测 HCC 患者的不良预后。
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