Li T, Xie J, Shen C, Cheng D, Shi Y, Wu Z, Deng X, Chen H, Shen B, Peng C, Li H, Zhan Q, Zhu Z
Department of Hepato-Bilio-Pancreatic Surgery, Shanghai Institute of Digestive Surgery, Rui Jin Hospital affiliated with Shanghai Jiaotong University, Shanghai, People's Republic of China.
Oncogene. 2016 Mar 24;35(12):1575-84. doi: 10.1038/onc.2015.223. Epub 2015 Jun 15.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Despite progress in diagnostics and treatment of HCC, its prognosis remains poor. Emerging studies showed that long noncoding RNAs (lncRNAs) have crucial regulatory roles in cancer biology. In the current study, differentially expressed lncRNAs between HCC and paired non-tumor tissues were identified using microarrays. The effects of a specific differentially expressed lncRNA (termed ZEB1-AS1) on tumor progression were investigated in vitro and in vivo. We found that ZEB1-AS1 is frequently upregulated in HCC samples, especially in metastatic tumor tissues. DNA methylation analysis shows a tumor-specific ZEB1-AS1 promoter hypomethylation. Aberrant methylation is tightly correlated with overexpression of ZEB1-AS1 in HCC. Patients with ZEB1-AS1 hypomethylation or with high ZEB1-AS1 expression have poor recurrence-free survival. Functionally, ZEB1-AS1 promotes tumor growth and metastasis, acts as an oncogene in HCC. The ZEB1-AS1 gene is located in physical contiguity with ZEB1 and positively regulates the ZEB1 expression. ZEB1 inhibition partially abrogates ZEB1-AS1-induced epithelial to mesenchymal transition (EMT) and cancer metastasis. Our results provide novel insights into the function of lncRNA-driven hepatocarcinogenesis, highlight the important role of ZEB1-AS1 and ZEB1 in HCC progression, and indicate that ZEB1-AS1 may be served as a valuable prognostic biomarker for HCC.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。尽管在HCC的诊断和治疗方面取得了进展，但其预后仍然很差。新兴研究表明，长链非编码RNA（lncRNAs）在癌症生物学中具有关键的调节作用。在本研究中，使用微阵列鉴定了HCC与配对的非肿瘤组织之间差异表达的lncRNAs。在体外和体内研究了一种特定的差异表达lncRNA（称为ZEB1-AS1）对肿瘤进展的影响。我们发现ZEB1-AS1在HCC样本中经常上调，尤其是在转移性肿瘤组织中。DNA甲基化分析显示肿瘤特异性的ZEB1-AS1启动子低甲基化。异常甲基化与HCC中ZEB1-AS1的过表达密切相关。ZEB1-AS1低甲基化或高表达的患者无复发生存期较差。在功能上，ZEB1-AS1促进肿瘤生长和转移，在HCC中起癌基因的作用。ZEB1-AS1基因与ZEB1在物理上相邻，并正向调节ZEB1的表达。抑制ZEB1可部分消除ZEB1-AS1诱导的上皮-间质转化（EMT）和癌症转移。我们的结果为lncRNA驱动的肝癌发生功能提供了新的见解，突出了ZEB1-AS1和ZEB1在HCC进展中的重要作用，并表明ZEB1-AS1可能作为HCC的一个有价值的预后生物标志物。
