Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells
Huo et al. Molecular Cancer
Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells
Xiaoqi Huo 0
Shuanglin Han 0
Guang Wu 0
Olivier Latchoumanin 0
Gang Zhou 0
Lionel Hebbard
Jacob George 0
Liang Qiao 0
0 Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital , Westmead, NSW 2145 , Australia
Hepatocellular carcinoma (HCC) is one of the most common malignant tumours with a poor prognosis worldwide. While early stage tumours can be treated with curative approaches such as liver transplantation or surgical resection, these are only suitable for a minority of patients. Those with advanced stage disease are only suitable for supportive approaches and most are resistant to the conventional chemotherapy or radiotherapy. Liver cancer stem cells (LCSCs) are a small subset of cancer cells with unlimited differentiation ability and tumour forming potential. In order to develop novel therapeutic approaches for HCC, we need to understand how the cancer develops and why treatment resistance occurs. Using high-throughput sequencing techniques, a large number of dysregulated long noncoding RNAs (lncRNAs) have been identified, and some of which are closely linked to key aspects of liver cancer pathology, progression, outcomes and for the maintenance of cancer stem cell-like properties. In addition, some lncRNAs are potential biomarkers for HCC diagnosis and may serve as the therapeutic targets. This review summarizes data recently reported lncRNAs that might be critical for the maintenance of the biological properties of LCSCs.
Hepatocellular carcinoma (HCC); Liver cancer stem cells (LCSCs); Long non-coding RNAs (lncRNAs)
Background
Although more than 70% of the whole human genome is
transcriptionally very active, only less than 2% of the
transcripts are eventually translated into proteins [
1, 2
].
Long noncoding RNAs (lncRNAs) are a subclass of
functional ncRNAs (tRNA and rRNA are not included in this
review); they are over 200 nucleotides in size and are
incapable of encoding protein [
3, 4
]. lncRNAs may share
some characteristics of mRNAs [
4
]. For instance, lncRNAs
are transcribed by RNA polymerase II; they are 5′ capped,
equipped with 3′ polyA (polyadenylate) tail and consist of
multiple exons [
4, 5
]. Initially, lncRNAs were thought to
be junk or transcriptional noise since they are not well
conserved across species and because expression levels
were relatively lower compared with mRNAs [
5–8
].
However, recent studies suggest that lncRNAs play a key
role in many biological processes such as X chromosome
inactivation, cell cycle regulation, and cardiac
development [
4, 5, 9, 10
]. lncRNAs are also involved in the
development of many diseases. For example, using microarray
analysis, a list of dysregulated (either up-regulated or
down-regulated) lncRNAs have been identified in many
tumour types such as prostate, liver, lung, and breast
cancer [
11–18
]. Broadly, lncRNAs can be classified as either
oncogenic or tumor-suppressive [
19
].
Hepatocellular carcinoma (HCC) is a leading cause of
cancer related death worldwide [
20, 21
], with more than
500,000 new cases reported every year [22]. Early stage
HCC can be effectively treated by liver transplantation or
curative surgery, but for advanced cases, the therapeutic
strategies are limited [
23, 24
]. Tumour recurrence and
disease relapse after therapy, as well as drug resistance are
the critical issues leading to poor prognosis [
24, 25
].
Within the liver tumour bulk, a small group of cells
known as liver cancer stem cells (LCSCs) are considered
to be responsible for the initiation, recurrence and drug
resistance of HCC [
26, 27
]. How LCSCs are regulated at
the molecular level is not well understood. Knowledge of
the key regulators of LCSC behaviour would facilitate the
development of more effective therapeutic approaches IIn
this regard, increasing evidence has shown that lncRNAs
may be involved in the regulation of the biological
function of LCSCs. For example, multiple lncRNAs are
expressed aberrantly in LCSCs compared to non-cancer
stem cells [
28, 29
], while some lncRNAs are required for
the self-renewal and tumour propagation of LCSCs [
30–
32
], or are closely associated with the clinico-pathological
features [
8, 33, 34
]. However, the precise function of
lncRNAs in LCSCs is poorly defined. This review
summarizes current understanding of the lncRNAs and their
implications for HCC and LCSCs.
Origin and classification of lncRNA
Unlike mRNA, lncRNAs are not very well conserved across
species [
8, 35
]. These RNAs may derive from several
sources: (1) insertion of a transposable element; (2)
duplication of noncoding RNA; (3) transformation from a previous
protein coding gene; and (4) chromatin rearrangement
[
36–38
] (Fig. 1). In fact, lncRNAs can be generated either
from prot (...truncated)