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• W4386449420 abstract "Background & AimsIntrahepatic cholangiocarcinoma (iCCA) is a deadly cancer worldwide with an increasing incidence and limited therapeutic options. Therefore, there is an urgent need to open the field to new concepts for identifying clinically relevant therapeutic targets and biomarkers. Here, we explored the role and the clinical relevance of circular RNA circLTBP2 in iCCA.MethodsTGFβ-regulated circRNAs were identified by dedicated microarrays in human HuCCT1 iCCA cell line and their clinical relevance was evaluated in independent cohorts of patients. Gain and loss of function of circLTBP2 combined with functional tests was performed in vitro and in vivo in mice. RNA pulldown, miRNA-seq, RNA-IP were performed to explore the sponging activity of circLTBP2.ResultsCircLTBP2 (has_circ_0032603) was identified as a novel TGFβ-induced circRNA in several CCA cell lines. CircLTBP2 promotes tumor cell proliferation, migration and resistance to gemcitabine-induced apoptosis in vitro and tumor growth in vivo. Mechanistically, circLTBP2 acts as a competitive RNA regulating notably the activity of the tumor suppressor microRNA miR-338-3p, leading to the overexpression of its pro-metastatic targets. The restoration of miR-338-3p levels in iCCA cells reversed the pro-tumorigenic effects driven by circLTBP2, including the resistance to gemcitabine-induced apoptosis. In addition, circLTBP2 expression predicted a reduced survival, as detected in tumor tissues but also in serum extracellular vesicles isolated from patients with iCCA.ConclusionsCircLTBP2 is a novel effector of the pro-tumorigenic arm of TGFβ and a clinically relevant biomarker easily detected from liquid biopsies in iCCA.Lay summaryIntrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with limited therapeutic options. Opening the field to new concepts is urgently needed to improve the survival of patients. Here, we evaluated the role and the clinical relevance of circular RNA. We report that TGFβ-induced circLTBP2 contributes to CCA carcinogenesis and may constitute a clinically relevant prognostic biomarker detected in liquid biopsies." @default.
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• W4386449420 date "2023-09-01" @default.
• W4386449420 modified "2023-10-06" @default.
• W4386449420 title "TGFβ-induced circLTBP2 predicts a poor prognosis in intrahepatic cholangiocarcinoma and mediates gemcitabine resistance by sponging miR-338-3p" @default.
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• W4386449420 doi "https://doi.org/10.1016/j.jhepr.2023.100900" @default.
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