A Novel Transforming Growth Factor Beta-Induced Long Noncoding RNA Promotes an Inflammatory Microenvironment in Human Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a deadly liver primary cancer associated with poor prognosis and limited therapeutic opportunities. Active transforming growth factor beta (TGF beta) signaling is a hallmark of the iCCA microenvironment. However, the impact of TGF beta on the transcriptome of iCCA tumor cells has been poorly investigated. Here, we have identified a specific TGFb signature of genes commonly deregulated in iCCA cell lines, namely HuCCT1 and Huh28. Novel coding and noncoding TGF beta targets were identified, including a TGF beta-induced long noncoding RNA (TLINC), formerly known as cancer susceptibility candidate 15 (CASC15). TLINC is a general target induced by TGF beta 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 proin-flammatory cytokines, including interleukin 8, both in vitro 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 TGFb and in resected human iCCA. Conclusion: We identify a novel TGF beta-induced long noncoding RNA up-regulated in human iCCA and associated with an inflammatory microenvironment.