Fang Ting-Ting, Sun Xiao-Jing, Chen Jie, Zhao Yan, Sun Rui-Xia, Ren Ning, Liu Bin-Bin
Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Xuhui, Shanghai, P.R. China E-mail :
Asian Pac J Cancer Prev. 2014;15(23):10513-24. doi: 10.7314/apjcp.2014.15.23.10513.
Metastasis is a major reason for poor prognosis in patients with cancer, including hepatocellular carcinoma (HCC). A salient feature is the ability of cancer cells to colonize different organs. Long non-coding RNAs (lncRNAs) play important roles in numerous cellular processes, including metastasis.
In this study, the lncRNA expression profiles of two HCC cell lines, one with high potential for metastasis to the lung (HCCLM3) and the other to lymph nodes (HCCLYM-H2) were assessed using the Arraystar Human LncRNA Array v2.0, which contains 33,045 lncRNAs and 30,215 mRNAs. Coding-non-coding gene co-expression (CNC) networks were constructed and gene set enrichment analysis (GSEA) was performed to identify lncRNAs with potential functions in organ-specific metastasis. Levels of two representative lncRNAs and one representative mRNA, RP5-1014O16.1, lincRNA-TSPAN8 and TSPAN8, were further detected in HCC cell lines with differing metastasis potential by qRT-PCR.
Using microarray data, we identified 1,482 lncRNAs and 1,629 mRNAs that were differentially expressed (≥1.5 fold-change) between the two HCC cell lines. The most upregulated lncRNAs in H2 were RP11-672F9.1, RP5-1014O16.1, and RP11-501G6.1, while the most downregulated ones were lincRNA-TSPAN8, lincRNA-CALCA, C14orf132, NCRNA00173, and CR613944. The most upregulated mRNAs in H2 were C15orf48, PSG2, and PSG8, while the most downregulated ones were CALCB, CD81, CD24, TSPAN8, and SOST. Among them, lincRNA-TSPAN8 and TSPAN8 were found highly expressed in high lung metastatic potential HCC cells, while lowly expressed in no or low lung metastatic potential HCC cells. RP5- 1014O16.1 was highly expressed in high lymphatic metastatic potential HCC cell lines, while lowly expressed in no lymphatic metastatic potential HCC cell lines.
We provide the first detailed description of lncRNA expression profiles related to organ-specific metastasis in HCC. We demonstrated that a large number of lncRNAs may play important roles in driving HCC cells to metastasize to different sites; these lncRNAs may provide novel molecular biomarkers and offer a new basis for combating metastasis in HCC cases.
转移是包括肝细胞癌（HCC）在内的癌症患者预后不良的主要原因。一个显著特征是癌细胞能够在不同器官中定植。长链非编码RNA（lncRNA）在包括转移在内的众多细胞过程中发挥重要作用。
在本研究中，使用包含33,045个lncRNA和30,215个mRNA的Arraystar人类lncRNA阵列v2.0评估了两种HCC细胞系的lncRNA表达谱，一种具有高肺转移潜能（HCCLM3），另一种具有高淋巴结转移潜能（HCCLYM-H2）。构建了编码-非编码基因共表达（CNC）网络并进行了基因集富集分析（GSEA），以鉴定在器官特异性转移中具有潜在功能的lncRNA。通过qRT-PCR进一步检测了具有不同转移潜能的HCC细胞系中两种代表性lncRNA和一种代表性mRNA（RP5-1014O16.1、lincRNA-TSPAN8和TSPAN8）的水平。
利用微阵列数据，我们鉴定出两种HCC细胞系之间差异表达（≥1.5倍变化）的1,482个lncRNA和1,629个mRNA。H2中上调最多的lncRNA是RP11-672F9.1、RP5-1014O16.1和RP11-501G6.1，而下调最多的是lincRNA-TSPAN8、lincRNA-CALCA、C14orf132、NCRNA00173和CR613944。H2中上调最多的mRNA是C15orf48、PSG2和PSG8，而下调最多的是CALCB、CD81、CD24、TSPAN8和SOST。其中，lincRNA-TSPAN8和TSPAN8在高肺转移潜能的HCC细胞中高表达，而在无或低肺转移潜能的HCC细胞中低表达。RP5-1014O16.1在高淋巴转移潜能的HCC细胞系中高表达，而在无淋巴转移潜能的HCC细胞系中低表达。
我们首次详细描述了与HCC器官特异性转移相关的lncRNA表达谱。我们证明了大量lncRNA可能在驱动HCC细胞转移到不同部位中发挥重要作用；这些lncRNA可能提供新的分子生物标志物，并为对抗HCC病例中的转移提供新的依据。
