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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 (TGF?) signaling is a hallmark of the iCCA microenvironment. However, the impact of TGF? on the transcriptome of iCCA tumor cells has been poorly investigated. Here, we have identified a specific TGF? signature of genes commonly deregulated in iCCA cell lines, namely HuCCT1 and Huh28. Novel coding and noncoding TGF? targets were identified, including a TGF?-induced long noncoding RNA (TLINC), formerly known as cancer susceptibility candidate 15 (CASC15). TLINC is a general target induced by TGF? 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 TGF? and in resected human iCCA. Conclusion: We identify a novel TGF?-induced long noncoding RNA up-regulated in human iCCA and associated with an inflammatory microenvironment. (Hepatology Communications 2018;2:254-269).

SUBMITTER: Merdrignac A

PROVIDER: S-EPMC5831019 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Merdrignac Aude A Angenard Gaëlle G Allain Coralie C Petitjean Kilian K Bergeat Damien D Bellaud Pascale P Fautrel Allain A Turlin Bruno B Clément Bruno B Dooley Steven S Sulpice Laurent L Boudjema Karim K Coulouarn Cédric C

Hepatology communications 20180130 3

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 t ...[more]

PMID: 29507901

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Project description:Purpose: Our research developed immune-related long noncoding RNAs (lncRNAs) for risk stratification in cervical cancer (CC) and explored factors of prognosis, inflammatory microenvironment infiltrates, and chemotherapeutic therapies. Methods: The RNA-seq data and clinical information of CC were collected from the TCGA TARGET GTEx database and the TCGA database. lncRNAs and immune-related signatures were obtained from the GENCODE database and the ImPort database, respectively. We screened out immune-related lncRNA signatures through univariate Cox, LASSO, and multivariate Cox regression methods. We established an immune-related risk model of hub immune-related lncRNAs to evaluate whether the risk score was an independent prognostic predictor. The xCell and CIBERSORTx algorithms were employed to appraise the value of risk scores which are in competition with tumor-infiltrating immune cell abundances. The estimation of tumor immunotherapy response through the TIDE algorithm and prediction of innovative recommended medications on the target to immune-related risk model were also performed on the basis of the IC50 predictor. Results: We successfully established six immune-related lncRNAs (AC006126.4, EGFR-AS1, RP4-647J21.1, LINC00925, EMX2OS, and BZRAP1-AS1) to carry out prognostic prediction of CC. The immune-related risk model was constructed in which we observed that high-risk groups were strongly linked with poor survival outcomes. Risk scores varied with clinicopathological parameters and the tumor stage and were an independent hazard factor that affect prognosis of CC. The xCell algorithm revealed that hub immune-related signatures were relevant to immune cells, especially mast cells, DCs, megakaryocytes, memory B cells, NK cells, and Th1 cells. The CIBERSORTx algorithm revealed an inflammatory microenvironment where naive B cells (p < 0.01), activated dendritic cells (p < 0.05), activated mast cells (p < 0.0001), CD8+ T cells (p < 0.001), and regulatory T cells (p < 0.01) were significantly lower in the high-risk group, while macrophages M0 (p < 0.001), macrophages M2 (p < 0.05), resting mast cells (p < 0.0001), and neutrophils (p < 0.01) were highly conferred. The result of TIDE indicated that the number of immunotherapy responders in the low-risk group (124/137) increased significantly (p = 0.00000022) compared to the high-risk group (94/137), suggesting that the immunotherapy response of CC patients was completely negatively correlated with the risk scores. Last, we compared differential IC50 predictive values in high- and low-risk groups, and 12 compounds were identified as future treatments for CC patients. Conclusion: In this study, six immune-related lncRNAs were suggested to predict the outcome of CC, which is beneficial to the formulation of immunotherapy.

Dataset Information

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

Publications

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

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