Genome-wide screening identifies oncofetal lncRNA Ptn-dt promoting the proliferation of hepatocellular carcinoma cells by regulating the Ptn receptor
Genome-wide screening identifies oncofetal lncRNA Ptn-dt promoting the proliferation of hepatocellular carcinoma cells by regulating the Ptn receptor
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DOI：
10.1038/s41388-018-0643-z
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发表时间：
2019-05-02
期刊：
影响因子：
8
通讯作者：
Wang, Fang
中科院分区：
文献类型：
--
作者：
Huang, Jin-Feng;Jiang, Hong-Yue;Wang, Fang
癌胚基因是指在胎儿和肿瘤组织中大量表达，但在成人组织中表达下调或未检测到的基因，可作为肿瘤标志物用于癌症的诊断和治疗。同时，已知长链非编码RNA（lncRNA）在肝细胞癌（HCC）的发病机制中起关键作用，包括肿瘤的生长、增殖、转移、侵袭和复发。我们使用基因芯片进行了全基因组筛选，以检测胎肝、成人肝和小鼠肝癌组织中的lncRNA表达谱，以鉴定HCC中的癌胚lncRNA。从微阵列数据分析，我们确定lncRNA Ptn-dt作为一个可能的癌胚基因。体内外实验结果均证实Ptn-dt过表达明显促进小鼠肝癌细胞的增殖。RNA pulldown实验表明Ptn-dt能与HuR蛋白相互作用。有趣的是，miR-96也与HuR结合以维持其稳定性。lncRNA Ptn-dt的过表达导致miR-96的下调，这可能是Ptn-dt与HuR相互作用的结果。同时，已有研究报道Ptn可通过间变性淋巴瘤激酶（Alk）信号通路促进肿瘤生长和血管畸形。我们的研究发现，Ptn-dt过表达可通过与HuR相互作用抑制miR-96的表达，促进Alk的表达，从而增强Ptn的生物学功能。综上所述，我们发现了一个新的癌胚lncRNA Ptn-dt，它可以通过调节HuR/miR-96/Alk通路和Ptn-Alk轴来促进肝癌细胞的增殖。
Oncofetal genes are genes that express abundantly in both fetal and tumor tissues yet downregulated or undetected in adult tissues, and can be used as tumor markers for cancer diagnosis and treatment. Meanwhile, long noncoding RNAs (lncRNAs) are known to play crucial roles in the pathogenesis of hepatocellular carcinoma (HCC), including tumor growth, proliferation, metastasis, invasion, and recurrence. We performed a genome-wide screening using microarrays to detect the lncRNA expression profiles in fetal livers, adult livers, and liver cancer tissues from mice to identify oncofetal lncRNAs in HCC. From the microarray data analysis, we identified lncRNA Ptn-dt as a possible oncofetal gene. Both in vitro and in vivo experiments results confirmed that overexpression of Ptn-dt significantly promoted the proliferation of mouse HCC cells. RNA pulldown assay showed that Ptn-dt could interact with the HuR protein. Interestingly, miR-96 binds with HuR to maintain its stability as well. Overexpression of lncRNA Ptn-dt led to the downregulation of miR-96, which might be due to the interaction between Ptn-dt and HuR. Meanwhile, previous studies have reported that Ptn can promote tumor growth and vascular abnormalization via anaplastic lymphoma kinase (Alk) signaling. In our study, we found that overexpression of Ptn-dt could promote the expression of Alk through repressing miR-96 via interacting with HuR, thus enhancing the biologic function of Ptn. In summary, a new oncofetal lncRNA Ptn-dt is identified, and it can promote the proliferation of HCC cells by regulating the HuR/miR-96/Alk pathway and Ptn-Alk axis.