Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

Pietro Carotenuto; Matteo Fassan; Rosantony Pandolfo; Andrea Lampis; Caterina Vicentini; Luciano Cascione; Viola Paulus-Hock; Luke Boulter; Rachel Guest; Luca Quagliata; Jens Claus Hahne; Rachel Ridgway; Tam Jamieson; Dimitris Athineos; Angelo Veronese; Rosa Visone; Claudio Murgia; Giulia Ferrari; Vincenza Guzzardo; Thomas Ronald Jeffry Evans; Martin MacLeod; Gui Ji Feng; Trevor Dale; Massimo Negrini; Stuart J. Forbes; Luigi Terracciano; Aldo Scarpa; Tushar Patel; Nicola Valeri; Paul Workman; Owen Sansom; Chiara Braconi

doi:10.1136/gutjnl-2016-312278

Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

Pietro Carotenuto, Matteo Fassan, Rosantony Pandolfo, Andrea Lampis, Caterina Vicentini, Luciano Cascione, Viola Paulus-Hock, Luke Boulter, Rachel Guest, Luca Quagliata, Jens Claus Hahne, Rachel Ridgway, Tam Jamieson, Dimitris Athineos, Angelo Veronese, Rosa Visone, Claudio Murgia, Giulia Ferrari, Vincenza Guzzardo, Thomas Ronald Jeffry EvansMartin MacLeod, Gui Ji Feng, Trevor Dale, Massimo Negrini, Stuart J. Forbes, Luigi Terracciano, Aldo Scarpa, Tushar Patel, Nicola Valeri, Paul Workman, Owen Sansom, Chiara Braconi

Gastroenterology and Hepatology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1268-1277
Number of pages	10
Journal	Gut
Volume	66
Issue number	7
DOIs	https://doi.org/10.1136/gutjnl-2016-312278
State	Published - Jul 1 2017

Keywords

BILARY DUCT CARCINOMA
CHOLANGIOCARCINOMA
HEPATOCELLULAR CARCINOMA
RNA EXPRESSION

ASJC Scopus subject areas

Gastroenterology

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10.1136/gutjnl-2016-312278

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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., ... Braconi, C. (2017). Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut, 66(7), 1268-1277. https://doi.org/10.1136/gutjnl-2016-312278

Carotenuto, P, Fassan, M, Pandolfo, R, Lampis, A, Vicentini, C, Cascione, L, Paulus-Hock, V, Boulter, L, Guest, R, Quagliata, L, Hahne, JC, Ridgway, R, Jamieson, T, Athineos, D, Veronese, A, Visone, R, Murgia, C, Ferrari, G, Guzzardo, V, Evans, TRJ, MacLeod, M, Feng, GJ, Dale, T, Negrini, M, Forbes, SJ, Terracciano, L, Scarpa, A, Patel, T, Valeri, N, Workman, P, Sansom, O & Braconi, C 2017, 'Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers', Gut, vol. 66, no. 7, pp. 1268-1277. https://doi.org/10.1136/gutjnl-2016-312278

@article{3e88d357523b4f60bcd74c7a5246d9f8,

title = "Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers",

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.",

keywords = "BILARY DUCT CARCINOMA, CHOLANGIOCARCINOMA, HEPATOCELLULAR CARCINOMA, RNA EXPRESSION",

author = "Pietro Carotenuto and Matteo Fassan and Rosantony Pandolfo and Andrea Lampis and Caterina Vicentini and Luciano Cascione and Viola Paulus-Hock and Luke Boulter and Rachel Guest and Luca Quagliata and Hahne, {Jens Claus} and Rachel Ridgway and Tam Jamieson and Dimitris Athineos and Angelo Veronese and Rosa Visone and Claudio Murgia and Giulia Ferrari and Vincenza Guzzardo and Evans, {Thomas Ronald Jeffry} and Martin MacLeod and Feng, {Gui Ji} and Trevor Dale and Massimo Negrini and Forbes, {Stuart J.} and Luigi Terracciano and Aldo Scarpa and Tushar Patel and Nicola Valeri and Paul Workman and Owen Sansom and Chiara Braconi",

note = "Publisher Copyright: {\textcopyright} 2017 Published by the BMJ Publishing Group Limited.",

year = "2017",

month = jul,

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doi = "10.1136/gutjnl-2016-312278",

language = "English (US)",

volume = "66",

pages = "1268--1277",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "7",

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TY - JOUR

T1 - Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

AU - Carotenuto, Pietro

AU - Fassan, Matteo

AU - Pandolfo, Rosantony

AU - Lampis, Andrea

AU - Vicentini, Caterina

AU - Cascione, Luciano

AU - Paulus-Hock, Viola

AU - Boulter, Luke

AU - Guest, Rachel

AU - Quagliata, Luca

AU - Hahne, Jens Claus

AU - Ridgway, Rachel

AU - Jamieson, Tam

AU - Athineos, Dimitris

AU - Veronese, Angelo

AU - Visone, Rosa

AU - Murgia, Claudio

AU - Ferrari, Giulia

AU - Guzzardo, Vincenza

AU - Evans, Thomas Ronald Jeffry

AU - MacLeod, Martin

AU - Feng, Gui Ji

AU - Dale, Trevor

AU - Negrini, Massimo

AU - Forbes, Stuart J.

AU - Terracciano, Luigi

AU - Scarpa, Aldo

AU - Patel, Tushar

AU - Valeri, Nicola

AU - Workman, Paul

AU - Sansom, Owen

AU - Braconi, Chiara

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

KW - BILARY DUCT CARCINOMA

KW - CHOLANGIOCARCINOMA

KW - HEPATOCELLULAR CARCINOMA

KW - RNA EXPRESSION

UR - http://www.scopus.com/inward/record.url?scp=84987816193&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84987816193&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2016-312278

DO - 10.1136/gutjnl-2016-312278

M3 - Article

C2 - 27618837

AN - SCOPUS:84987816193

SN - 0017-5749

VL - 66

SP - 1268

EP - 1277

JO - Gut

JF - Gut

IS - 7

ER -

Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

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