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Long non‐coding RNA HOTTIP is frequently up‐regulated in hepatocellular carcinoma and is targeted by tumour suppressive miR‐125b
Author(s) -
Tsang Felice H.C.,
Au Sandy L.K.,
Wei Lai,
Fan Dorothy N.Y.,
Lee Joyce M.F.,
Wong Carmen C.L.,
Ng Irene O.L.,
Wong ChunMing
Publication year - 2015
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12746
Subject(s) - competing endogenous rna , hccs , ectopic expression , cancer research , hepatocellular carcinoma , long non coding rna , luciferase , biology , microrna , carcinogenesis , cell growth , gene , rna , transfection , genetics
Background & Aims Hepatocellular carcinoma ( HCC ) is one of the most common human cancers. Recently, emerging evidence has suggested the role of long non‐coding RNA s (lnc RNA s) in human carcinogenesis. In this study, we aimed to investigate the expression and functional implications of lnc RNA s in human HCC . Methods Eighty‐eight well‐annotated lnc RNA s were profiled in primary HCC by quantitative RT ‐ PCR . Functional relevance of lnc RNA s was elucidated in HCC cell lines and nude mice models. The regulatory relationship between mi RNA and lnc RNA was predicted in silico and further validated by luciferase reporter assay and expression analysis. Results In our profiling study, HOTTIP was identified as the most significantly up‐regulated lnc RNA in human HCC s, even in early stage of HCC formation. Functionally, knock‐down of HOTTIP attenuated HCC cell proliferation in vitro and markedly abrogated tumourigenicity in vivo . In addition, knock‐down of HOTTIP also inhibited migratory ability of HCC cells and significantly abrogated lung metastasis in orthotopic implantation model in nude mice. HOTTIP is an antisense lnc RNA mapped to the distal end of the HOXA gene cluster. Knock‐down of HOTTIP significantly suppressed the expression of a number of HOXA genes. Furthermore, we identified miR‐125b as a post‐transcriptional regulator of HOTTIP . Ectopic expression of miR‐125b reduced HOTTIP ‐coupled luciferase activity and suppressed the endogenous level of HOTTIP . Moreover, in human HCC s, HOTTIP expression negatively correlated with that of miR‐125b. Conclusions HOTTIP is a novel oncogenic lnc RNA , which negatively regulated by miR‐125b. Overexpression of HOTTIP contributes to hepatocarcinogenesis by regulating the expression of its neighbouring protein‐coding genes.