miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells
et al. (2013) miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-
Induced Apoptosis in Gastric Adenocarcinoma Cells. PLoS ONE 8(6): e64707. doi:10.1371/journal.pone.0064707
miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells
Xue Liu 0
Jing Ru 0
Jian Zhang 0
Li-hua Zhu 0
Min Liu 0
Xin Li 0
Hua Tang 0
Jin Q. Cheng, H.Lee Moffitt Cancer Center & Research Institute, United States of America
0 1 Tianjin Life Science Research Center and Department of Microbiology, School of Basic Medical Sciences, Tianjin Medical University , Tianjin , China , 2 Department of Pathogen Biology and Immunology, College of Basic Medicine, Hebei United University , Tangshan, Hebei Province , China
MicroRNAs are a class of non-coding RNAs that function as key regulators of gene expression at the post-transcriptional level. In our previous research, we found that miR-23a was significantly up-regulated in human gastric adenocarcinoma cells. In the current study, we demonstrate that miR-23a suppresses paclitaxel-induced apoptosis and promotes the cell proliferation and colony formation ability of gastric adenocarcinoma cells. We have identified tumor suppressor interferon regulator factor 1 (IRF1) as a direct target gene of miR-23a. We performed a fluorescent reporter assay to confirm that miR23a bound to the IRF1 mRNA 39UTR directly and specifically. The ectopic expression of IRF1 markedly promoted paclitaxelinduced apoptosis and inhibited cell viability and colony formation ability, whereas the knockdown of IRF1 had the opposite effects. The restoration of IRF1 expression counteracted the effects of miR-23a on the paclitaxel-induced apoptosis and cell proliferation of gastric adenocarcinoma cells. Quantitative real-time PCR showed that miR-23a is frequently upregulated in gastric adenocarcinoma tissues, whereas IRF1 is down-regulated in cancer tissues. Altogether, these results indicate that miR-23a suppresses paclitaxel-induced apoptosis and promotes cell viability and the colony formation ability of gastric adenocarcinoma cells by targeting IRF1 at the post-transcriptional level.
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. These authors contributed equally to this work.
Gastric cancer is a disease that is associated with a poor
prognosis and a high mortality rate [1,2]. Gastric cancer is the
second leading cause of cancer death worldwide after lung cancer
[3]. Approximately 90% of gastric cancers are adenocarcinomas,
which originate from the glandular epithelium of the gastric
mucosa [4]. Previous studies have suggested that gastric
adenocarcinoma is a multifactorial disease [5]. Numerous studies have
also revealed that oncogenes or tumor suppressors may play
important roles in the tumorigenesis and progression of gastric
cancer [6,7]. However, the molecular mechanisms of gastric
cancer development and progression remain unresolved.
miRNAs are a class of small, non-coding RNAs that can
regulate gene expression by either inducing the degradation of
target mRNAs or by impairing the translation of their target
mRNAs. miRNAs can also up-regulate gene expression by
targeting the 59 untranslated region (UTR) of their target genes.
Many studies have revealed that aberrantly expressed miRNAs
participate in tumorigenesis in temporal and spatial manners [8].
Some miRNAs become over-expressed in tumor cells and function
as oncogenes. miR-223 has been shown to stimulate gastric cancer
cell migration and invasion in vitro and in vivo [9]. miR-27a is highly
expressed in gastric adenocarcinoma tissue and promotes cell
growth [10,11]. However, other miRNAs are deleted or reduced
in tumor cells and act as tumor suppressor genes. The
miR200bc/429 cluster, miR-497 and miR-181b, have been shown to
be down-regulated in gastric cancer cell lines [12,13,14], and these
miRNAs have been suggested to play a role in the development of
multidrug resistance by modulating apoptosis through the
regulation of BCL2 [15].
Recently, several reports have demonstrated that miR-23a has
diverse functions in tumor biology. miR-23a, is located in the
miR23a/24/27a cluster and regulates the TGF-b-induced epithelial
mesenchymal transition (EMT) by targeting E-cadherin in lung
cancer cells [16]. The miR-23a cluster is a downstream target of
PU.1 and is involved in antagonizing lymphoid cell fate [17].
miR23a promotes colon carcinoma cell growth, invasion and
metastasis through the inhibition of the MTSS gene [18].
miR23a also targets glutaminase (GLS) mRNA and inhibits the
expression of the GLS protein [19]. The miR-23a/24/27a cluster
appears to function as an antiapoptotic and
proliferationpromoting factor in liver cancer cells [20], and miR-23a has been
shown to be significantly up-regulated in bladder cancers
compared to normal bladder mucosa [21].
miR-23a was also found to act as an oncogene in gastric cancer.
In a previous study that was conducted in our lab [ (...truncated)