Objective: Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/β-catenin pathway in liver cancer. Design: Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/β-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation. Results: Overexpression of the T-UCR uc.158-could differentiate Wnt/β-catenin dependent HCC from normal liver and from β-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158-was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of β-catenin altered uc.158-expression in human malignant hepatocytes. uc.158-expression was increased in CTNNB1-mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of β-catenin. uc.158-was increased in TAA rat CCA and reduced after treatment with Wnt/β-catenin inhibitors. uc.158-expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158-reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158-sequence. Modulation of uc.158-changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158-inhibitor and anti-miR-193b rescued the effect of uc.158-inhibition on cell viability. Conclusions: We showed that uc.158-is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics.

Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers / Carotenuto, P.; Fassan, M.; Pandolfo, R.; Lampis, A.; Vicentini, C.; Cascione, L.; Paulus-Hock, V.; Boulter, L.; Guest, R.; Quagliata, L.; Hahne, J. C.; Ridgway, R.; Jamieson, T.; Athineos, D.; Veronese, A.; Visone, R.; Murgia, C.; Ferrari, G.; Guzzardo, V.; Evans, T. R. J.; Macleod, M.; Feng, G. J.; Dale, T.; Negrini, M.; Forbes, S. J.; Terracciano, L.; Scarpa, A.; Patel, T.; Valeri, N.; Workman, P.; Sansom, O.; Braconi, C.. - In: GUT. - ISSN 0017-5749. - 66:7(2017), pp. 1268-1277. [10.1136/gutjnl-2016-312278]

Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

Carotenuto P.
Primo
;
Quagliata L.;
2017

Abstract

Objective: Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/β-catenin pathway in liver cancer. Design: Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/β-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation. Results: Overexpression of the T-UCR uc.158-could differentiate Wnt/β-catenin dependent HCC from normal liver and from β-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158-was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of β-catenin altered uc.158-expression in human malignant hepatocytes. uc.158-expression was increased in CTNNB1-mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of β-catenin. uc.158-was increased in TAA rat CCA and reduced after treatment with Wnt/β-catenin inhibitors. uc.158-expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158-reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158-sequence. Modulation of uc.158-changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158-inhibitor and anti-miR-193b rescued the effect of uc.158-inhibition on cell viability. Conclusions: We showed that uc.158-is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics.
2017
GUT
Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers / Carotenuto, P.; Fassan, M.; Pandolfo, R.; Lampis, A.; Vicentini, C.; Cascione, L.; Paulus-Hock, V.; Boulter, L.; Guest, R.; Quagliata, L.; Hahne, J. C.; Ridgway, R.; Jamieson, T.; Athineos, D.; Veronese, A.; Visone, R.; Murgia, C.; Ferrari, G.; Guzzardo, V.; Evans, T. R. J.; Macleod, M.; Feng, G. J.; Dale, T.; Negrini, M.; Forbes, S. J.; Terracciano, L.; Scarpa, A.; Patel, T.; Valeri, N.; Workman, P.; Sansom, O.; Braconi, C.. - In: GUT. - ISSN 0017-5749. - 66:7(2017), pp. 1268-1277. [10.1136/gutjnl-2016-312278]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/875762
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