LncRNA SNHG10 Facilitates Hepatocarcinogenesis and Metastasis by Modulating Its Homolog SCARNA13 via a Positive Feedback Loop
LncRNA SNHG10 Facilitates Hepatocarcinogenesis and Metastasis by Modulating Its Homolog SCARNA13 via a Positive Feedback Loop
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LncRNA SNHG10 通过正反馈环调节其同源物 SCARNA13 促进肝癌发生和转移
DOI：
10.1158/0008-5472.can-18-4044
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发表时间：
2019-07-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Hong
中科院分区：
文献类型：
--
作者：
Lan, Tian;Yuan, Kefei;Wu, Hong
了解非编码RNA(NcRNA)在肿瘤发生和转移中的作用将建立识别诊断和治疗靶点的新途径。在这里，我们的目的是鉴定肝细胞癌(HCC)特异性的ncRNA，并研究它们在肝癌发生和转移中的作用。从肺转移产生的异种移植瘤的RNA序列中发现，长非编码RNA小核仁RNA宿主基因10(SNHG10)及其同源基因SCARNA13是肝癌发生和转移的新驱动因素。在肝癌中，SNHG10的表达与SCARNA13的表达呈正相关，且SNHG10或SCARNA13的高表达与总生存期相关。由于SCARNA13在SNHG10过表达和敲除后分别表现出显著的上升和下降，我们推测SNHG10可能是SCARNA13的上游调控因子。SNHG10和SCARNA13协同促进了肝癌细胞的恶性表型，SNHG10作为miR-150-5p的海绵，与RPL4mRNA相互作用，增加c-Myb的表达和活性。上调和过度激活的c-Myb通过调节SNHG10启动子活性，形成正反馈环，持续刺激SCARNA13表达，从而促进SNHG10和SCARNA13的表达。SCARNA13介导SNHG10介导的肝癌细胞增殖、侵袭和迁移，并通过调节SOX9促进肝癌细胞的细胞周期和上皮-间充质转化。总体而言，我们发现在肝癌的发生和转移过程中，SNHG10及其同系物SCARNA13伴随上调的复杂回路。意义：这些发现揭示了非编码RNA在肝细胞癌的发生和转移中的作用。
Understanding the roles of noncoding RNAs (ncRNA) in tumorigenesis and metastasis would establish novel avenues to identify diagnostic and therapeutic targets. Here, we aimed to identify hepatocellular carcinoma (HCC)-specific ncRNA and to investigate their roles in hepatocarcinogenesis and metastasis. RNA-seq of xenografts generated by lung metastasis identified long noncoding RNA small nucleolar RNA host gene 10 (SNHG10) and its homolog SCARNA13 as novel drivers for the development and metastasis of HCC. SNHG10 expression positively correlated with SCARNA13 expression in 64 HCC cases, and high expression of SNHG10 or SCARNA13 was associated with poor overall survival. As SCARNA13 showed significant rise and decline after overexpression and knockdown of SNHG10, respectively, we hypothesized that SNHG10 might act as an upstream regulator of SCARNA13. SNHG10 and SCARNA13 coordinately contributed to the malignant phenotype of HCC cells, where SNHG10 served as a sponge for miR-150-5p and interacted with RPL4 mRNA to increase the expression and activity of c-Myb. Reciprocally, upregulated and hyperactivated c-Myb enhanced SNHG10 and SCARNA13 expression by regulating SNHG10 promoter activity, forming a positive feedback loop and continuously stimulating SCARNA13 expression. SCARNA13 mediated SNHG10-driven HCC cell proliferation, invasion, and migration and facilitated the cell cycle and epithelial-mesenchymal transition of HCC cells by regulating SOX9. Overall, we identified a complex circuitry underlying the concomitant upregulation of SNHG10 and its homolog SCARNA13 in HCC in the process of hepatocarcinogenesis and metastasis.Significance: These findings unveil the role of a noncoding RNA in carcinogenesis and metastasis of hepatocellular carcinoma.