A novel transforming growth factor beta‐induced long noncoding RNA promotes an inflammatory microenvironment in human intrahepatic cholangiocarcinoma

Abstract

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 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 TGFβ and in resected human iCCA. Conclusion: We identify a novel TGFβ‐induced long noncoding RNA up‐regulated in human iCCA and associated with an inflammatory microenvironment. (Hepatology Communications 2018;2:254‐269)

Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances

“…In addition to its effects on promoting α‐SMA+CAF expansion, TGF‐β1 is a known inducer of ECM proteins, notably collagen type 1, Postn, and Tnc, which are highly germane to supporting and sustaining the desmoplastic microenvironment of iCCA. Of further note, a TGF‐β‐induced circular isoform of long noncoding RNA was recently demonstrated to be highly up‐regulated in human iCCA and to promote an inflammatory microenvironment in human iCCA, associated with an overexpression of proinflammatory cytokines …”

“…Of further note, a TGF-β-induced circular isoform of long noncoding RNA was recently demonstrated to be highly up-regulated in human iCCA and to promote an inflammatory microenvironment in human iCCA, associated with an overexpression of proinflammatory cytokines. (19) Like TGF-β, PDGF-D, an isoform belonging to the PDGF family, is also considered a key driver of the desmoplastic reaction, particularly in relation to its effects on α-SMA+CAF recruitment. In a compelling study by Cadamuro et al, (20) these authors have proposed a model in which PDGF-D, selectively overexpressed in CCA cells through a hypoxia-mediated mechanism, is released into the tumor cell environment, where it binds to and activates its cognate receptor PDGF receptor beta (PDGFRβ) present on fibroblastic cells.…”

Circular RNA SMARCA5 correlates with favorable clinical tumor features and prognosis, and increases chemotherapy sensitivity in intrahepatic cholangiocarcinoma

“…CircRNAs have been identified to be expressed stably in various cells, and they are reported to be involved in various physiological development, including serving as microRNA sponges, interacting with proteins, regulating transcription and splicing, and participating in translation . Until now, there are only preliminary investigations focusing on the role of circRNAs in cancers .…”

Functions and roles of long noncoding RNA in cholangiocarcinoma

“…| 17119 differentially expressed (CRNDE; Xia et al, 2018), cancer susceptibility candidate 15 (CASC15; Merdrignac et al, 2018), and highly upregulated in liver cancer (HULC; Wang et al, 2016) are overexpressed in CCA and contribute to malignant phenotypes of CCA cells. These results illustrate that they perform regulatory roles in the pathological process and molecular mechanism of CCA.…”