长链非编码 RNA HOTAIR 过表达诱导 c-Met 信号下调促进肝癌细胞的混合上皮/间充质表型。
lncRNA HOTAIR overexpression induced downregulation of c-Met signaling promotes hybrid epithelial/mesenchymal phenotype in hepatocellular carcinoma cells.
机构信息
Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.
Department of Medical Biology and Genetics, Graduate School of Health Sciences, Dokuz Eylul University, 35340, Balcova, Izmir, Turkey.
出版信息
Cell Commun Signal. 2020 Jul 11;18(1):110. doi: 10.1186/s12964-020-00602-0.
BACKGROUND
Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are both reversible processes, and regulation of phenotypical transition is very important for progression of several cancers including hepatocellular carcinoma (HCC). Recently, it is defined that cancer cells can attain a hybrid epithelial/mesenchymal (hybrid E/M) phenotype. Cells with hybrid E/M phenotype comprise mixed epithelial and mesenchymal properties, they can be more resistant to therapeutics and also more capable of initiating metastatic lesions. However, the mechanisms regulating hybrid E/M in HCC are not well described yet. In this study, we investigated the role of the potential crosstalk between lncRNA HOTAIR and c-Met receptor tyrosine kinase, which are two essential regulators of EMT and MET, in acquiring of hybrid E/M phenotype in HCC.
METHODS
Expression of c-Met and lncRNA HOTAIR were defined in HCC cell lines and patient tissues through HCC progression. lncRNA HOTAIR was overexpressed in SNU-449 cells and its effects on c-Met signaling were analyzed. c-Met was overexpressed in SNU-398 cells and its effect on HOTAIR expression was analyzed. Biological significance of HOTAIR/c-Met interplay was defined in means of adhesion, proliferation, motility behavior, invasion, spheroid formation and metastatic ability. Effect of ectopic lncRNA HOTAIR expression on phenotype was defined with investigation of molecular epithelial and mesenchymal traits.
RESULTS
In vitro and in vivo experiments verified the pivotal role of lncRNA HOTAIR in acquisition of hybrid E/M phenotype through modulating expression and activation of c-Met and its membrane co-localizing partner Caveolin-1, and membrane organization to cope with the rate limiting steps of metastasis such as survival in adhesion independent microenvironment, escaping from anoikis and resisting to fluidic shear stress (FSS) in HCC.
CONCLUSIONS
Our work provides the first evidence suggesting a role for lncRNA HOTAIR in the modulation of c-Met to promote hybrid E/M phenotype. The balance between lncRNA HOTAIR and c-Met might be critical for cell fate decision and metastatic potential of HCC cells. Video Abstract.
背景
上皮-间质转化（EMT）和间质-上皮转化（MET）都是可逆的过程，表型转化的调节对于包括肝细胞癌（HCC）在内的几种癌症的进展非常重要。最近，人们定义癌细胞可以获得混合上皮/间质（混合 E/M）表型。具有混合 E/M 表型的细胞具有混合的上皮和间质特性，它们可以对治疗更具抵抗力，并且更有能力引发转移性病变。然而，HCC 中调节混合 E/M 的机制尚未得到很好的描述。在这项研究中，我们研究了长链非编码 RNA HOTAIR 和 c-Met 受体酪氨酸激酶之间潜在的串扰在 HCC 中获得混合 E/M 表型中的作用，这两种物质都是 EMT 和 MET 的两个重要调节因子。
方法
通过 HCC 进展，在 HCC 细胞系和患者组织中定义了 c-Met 和长链非编码 RNA HOTAIR 的表达。在 SNU-449 细胞中过表达长链非编码 RNA HOTAIR，并分析其对 c-Met 信号的影响。在 SNU-398 细胞中过表达 c-Met，并分析其对 HOTAIR 表达的影响。通过粘附、增殖、运动行为、侵袭、球体形成和转移能力来定义 HOTAIR/c-Met 相互作用的生物学意义。通过研究分子上皮和间充质特征来定义异位长链非编码 RNA HOTAIR 表达对表型的影响。
结果
体内外实验验证了长链非编码 RNA HOTAIR 通过调节 c-Met 及其膜共定位伴侣 Cav-1 的表达和激活，以及膜组织来应对转移的限速步骤，如在无粘附微环境中存活、逃避细胞凋亡和抵抗流体剪切力（FSS），在获得混合 E/M 表型中发挥关键作用。
结论
我们的工作首次证明了长链非编码 RNA HOTAIR 在调节 c-Met 以促进混合 E/M 表型中的作用。长链非编码 RNA HOTAIR 和 c-Met 之间的平衡对于 HCC 细胞的命运决定和转移潜力可能至关重要。视频摘要。
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