Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers.
Gut
; 66(7): 1268-1277, 2017 07.
Article
in En
| MEDLINE
| ID: mdl-27618837
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/ß-catenin pathway in liver cancer.DESIGN:
Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/ß-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/ß-catenin dependent HCC from normal liver and from ß-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 ß-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 ß-catenin. uc.158- was increased in TAA rat CCA and reduced after treatment with Wnt/ß-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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bile Duct Neoplasms
/
Conserved Sequence
/
Cholangiocarcinoma
/
Carcinoma, Hepatocellular
/
RNA, Untranslated
/
Wnt Signaling Pathway
/
Liver Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Gut
Year:
2017
Document type:
Article
Affiliation country:
Reino Unido