miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells

PLOS ONE, Dec 2019

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 miR-23a bound to the IRF1 mRNA 3′UTR directly and specifically. The ectopic expression of IRF1 markedly promoted paclitaxel-induced 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 up-regulated 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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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. - . 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)


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Xue Liu, Jing Ru, Jian Zhang, Li-hua Zhu, Min Liu, Xin Li, Hua Tang. miR-23a Targets Interferon Regulatory Factor 1 and Modulates Cellular Proliferation and Paclitaxel-Induced Apoptosis in Gastric Adenocarcinoma Cells, PLOS ONE, 2013, Volume 8, Issue 6, DOI: 10.1371/journal.pone.0064707