Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
Cancer Res. 2019 Oct 15;79(20):5131-5139. doi: 10.1158/0008-5472.CAN-19-0255. Epub 2019 Jul 23.
Next-generation sequencing has uncovered thousands of long noncoding RNAs (lncRNA). Many are reported to be aberrantly expressed in various cancers, including hepatocellular carcinoma (HCC), and play key roles in tumorigenesis. This review provides an in-depth discussion of the oncogenic mechanisms reported to be associated with deregulated HCC-associated lncRNAs. Transcriptional expression of lncRNAs in HCC is modulated through transcription factors, or epigenetically by aberrant histone acetylation or DNA methylation, and posttranscriptionally by lncRNA transcript stability modulated by miRNAs and RNA-binding proteins. Seventy-four deregulated lncRNAs have been identified in HCC, of which, 52 are upregulated. This review maps the oncogenic roles of these deregulated lncRNAs by integrating diverse datasets including clinicopathologic features, affected cancer phenotypes, associated miRNA and/or protein-interacting partners as well as modulated gene/protein expression. Notably, 63 deregulated lncRNAs are significantly associated with clinicopathologic features of HCC. Twenty-three deregulated lncRNAs associated with both tumor and metastatic clinical features were also tumorigenic and prometastatic in experimental models of HCC, and eight of these mapped to known cancer pathways. Fifty-two upregulated lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer, whereas 22 downregulated lncRNAs have tumor-suppressive properties. Aberrantly expressed lncRNAs in HCC exert pleiotropic effects on miRNAs, mRNAs, and proteins. They affect multiple cancer phenotypes by altering miRNA and mRNA expression and stability, as well as through effects on protein expression, degradation, structure, or interactions with transcriptional regulators. Hence, these insights reveal novel lncRNAs as potential biomarkers and may enable the design of precision therapy for HCC.
下一代测序技术已经发现了数千种长非编码 RNA(lncRNA)。许多报道称,这些 lncRNA 在各种癌症中异常表达,包括肝细胞癌(HCC),并在肿瘤发生中发挥关键作用。这篇综述深入讨论了与失调的 HCC 相关 lncRNA 相关的致癌机制。HCC 中 lncRNA 的转录表达通过转录因子调节,或通过异常的组蛋白乙酰化或 DNA 甲基化以及通过 miRNA 和 RNA 结合蛋白调节的 lncRNA 转录本稳定性进行表观遗传调节。在 HCC 中已经鉴定出 74 种失调的 lncRNA,其中 52 种上调。通过整合包括临床病理特征、受影响的癌症表型、相关 miRNA 和/或蛋白相互作用伙伴以及调节的基因/蛋白表达在内的多种数据集,本综述绘制了这些失调的 lncRNA 的致癌作用图谱。值得注意的是,63 种失调的 lncRNA 与 HCC 的临床病理特征显著相关。与肿瘤和转移性临床特征相关的 23 种失调的 lncRNA 在 HCC 的实验模型中也是致瘤和促转移的,其中 8 种与已知的癌症途径有关。52 种上调的 lncRNA 具有致癌特性,与癌症的显著标志有关,而 22 种下调的 lncRNA 具有肿瘤抑制特性。HCC 中异常表达的 lncRNA 对 miRNA、mRNA 和蛋白质产生多效性影响。它们通过改变 miRNA 和 mRNA 的表达和稳定性,以及通过对蛋白质表达、降解、结构或与转录调节剂的相互作用的影响,影响多种癌症表型。因此,这些见解揭示了新的 lncRNA 作为潜在的生物标志物,并可能为 HCC 的精准治疗设计提供依据。
Cancer Res. 2019-7-23
Biochim Biophys Acta Mol Basis Dis. 2017-4-18
Int J Mol Sci. 2018-2-28
Cancer Lett. 2013-10-30
Noncoding RNA Res. 2024-12-14
MedComm (2020). 2024-10-2