Merdrignac Aude, Angenard Gaëlle, Allain Coralie, Petitjean Kilian, Bergeat Damien, Bellaud Pascale, Fautrel Allain, Turlin Bruno, Clément Bruno, Dooley Steven, Sulpice Laurent, Boudjema Karim, Coulouarn Cédric
Institut National de la Santé et de la Recherche Médicale, INRA, Université de Rennes, CHU Rennes, UMR 1241, Nutrition Metabolisms and Cancer, Service de Chirurgie Hépatobiliaire et Digestive, Biosit, Biogenouest, Core Facility H2P2 and CRB Santé Rennes France.
Department of Medicine II, Medical Faculty Mannheim Heidelberg University Mannheim Germany.
Hepatol Commun. 2018 Jan 30;2(3):254-269. doi: 10.1002/hep4.1142. eCollection 2018 Mar.
Intrahepatic cholangiocarcinoma (iCCA) is a deadly liver primary cancer associated with poor prognosis and limited therapeutic opportunities. Active transforming growth factor beta (TGFβ) signaling is a hallmark of the iCCA microenvironment. However, the impact of TGFβ on the transcriptome of iCCA tumor cells has been poorly investigated. Here, we have identified a specific TGFβ signature of genes commonly deregulated in iCCA cell lines, namely HuCCT1 and Huh28. Novel coding and noncoding TGFβ targets were identified, including a TGFβ-induced long noncoding RNA (TLINC), formerly known as cancer susceptibility candidate 15 (CASC15). TLINC is a general target induced by TGFβ in hepatic and nonhepatic cell types. In iCCA cell lines, the expression of a long and short TLINC isoform was associated with an epithelial or mesenchymal phenotype, respectively. Both isoforms were detected in the nucleus and cytoplasm. The long isoform of TLINC was associated with a migratory phenotype in iCCA cell lines and with the induction of proinflammatory cytokines, including interleukin 8, both and in resected human iCCA. TLINC was also identified as a tumor marker expressed in both epithelial and stroma cells. In nontumor livers, TLINC was only expressed in specific portal areas with signs of ductular reaction and inflammation. Finally, we provide experimental evidence of circular isoforms of TLINC, both in iCCA cells treated with TGFβ and in resected human iCCA. : We identify a novel TGFβ-induced long noncoding RNA up-regulated in human iCCA and associated with an inflammatory microenvironment. ( 2018;2:254-269).
肝内胆管癌（iCCA）是一种致命的原发性肝癌，预后较差且治疗机会有限。活跃的转化生长因子β（TGFβ）信号传导是iCCA微环境的一个标志。然而，TGFβ对iCCA肿瘤细胞转录组的影响尚未得到充分研究。在这里，我们在iCCA细胞系（即HuCCT1和Huh28）中鉴定出了一组通常失调的特定TGFβ基因特征。我们鉴定出了新的编码和非编码TGFβ靶标，包括一种TGFβ诱导的长链非编码RNA（TLINC），以前称为癌症易感性候选基因15（CASC15）。TLINC是TGFβ在肝和非肝细胞类型中诱导产生的一个普遍靶标。在iCCA细胞系中，长链和短链TLINC异构体的表达分别与上皮或间充质表型相关。两种异构体都在细胞核和细胞质中被检测到。TLINC的长链异构体与iCCA细胞系中的迁移表型以及促炎细胞因子（包括白细胞介素8）的诱导相关，在切除的人iCCA中也是如此。TLINC还被鉴定为在上皮细胞和基质细胞中均表达的肿瘤标志物。在非肿瘤肝脏中，TLINC仅在具有小胆管反应和炎症迹象的特定门静脉区域表达。最后，我们提供了在TGFβ处理的iCCA细胞和切除的人iCCA中均存在TLINC环状异构体的实验证据。我们鉴定出一种在人iCCA中上调的新型TGFβ诱导长链非编码RNA，其与炎症微环境相关。（2018；2：254 - 269）
