MiR-223 promotes the cisplatin resistance of human gastric cancer cells via regulating cell cycle by targeting FBXW7
© Zhou et al.; licensee BioMed Central. 2015
Received: 5 January 2015
Accepted: 12 March 2015
Published: 26 March 2015
Increasing evidence showed that miRNAs serve as modulators of human cancer, either as oncogene or tumor suppressors. Cisplatin resistance is the most common cause of chemotherapy failure in gastric cancer (GC). However, the roles of miRNAs in cisplatin resistance of GC remain largely unknown. The aim of the study was to identify a novel miRNA/gene pathway that regulates the sensitivity of GC cells to cisplatin.
In this study, we chose miR-223 by qRT-PCR analysis, the most significantly up-regulated miRNA in GC, to investigate its formation of DDP-resistant phenotype of GC cells and possible molecular mechanisms.
We found that miR-223 was most significantly up-regulated miRNA in DDP-resistant GC cells compared with parental GC cells. Besides, its expression was also significantly up-regulated in GC tissues. FBXW7 was identified as the direct and functional target gene of miR-223. Overexpression of FBXW7 could mimic the effect of miR-223 down-regulation and silencing of FBXW7 could partially reverse the effect of miR-223 down-regulation on DDP resistance of DDP-resistant GC cells. Besides, miR-223 and FBXW7 could affect the G1/S transition of cell cycle by altering some certain cell cycle regulators. Furthermore, miR-223 was found to be significantly up-regulated in H. pylori infected tissues and cells, suggesting that H. pylori infection may lead to GC development and DDP resistance.
Our findings revealed the roles of miR-223/FBXW7 signaling in the DDP resistance of GC cells and targeting it will be a potential strategic approach for reversing the DDP resistance in human GC.
Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide . With an overall 5-year survival rate of only 20%, it becomes a major cause of both morbidity and mortality, where even resectable disease has a 50-90% risk of recurrence and death . However, therapies often fail due to cancer cell multidrug resistance (MDR), which tends to develop after the initial rounds of treatment or before treatment begins (intrinsic MDR) . The molecular mechanism underlying single or multidrug resistance to chemotherapeutic agents is complex and involves increases in drug efflux, insensitivity to drug-induced apoptosis and the enhancement of drug detoxification . Although great efforts have been made to understand the mechanism underlying multidrug resistance, the current knowledge remains limited .
MicroRNAs (miRNAs) are a large class of endogenous non-coding RNAs, 21–23 nucleotides in length that regulate about 30% of human gene expression . MiRNAs can function post-transcriptionally through imperfect base pairing with specific sequences in the 3’ untranslated regions (UTRs) of target mRNAs, leading to transcript degradation or translational inhibition . Increasing evidence has shown that miRNAs have critical roles in the control of various human biological processes, such as development, angiogenesis, apoptosis and differentiation . Increasing researches have shown the existence and importance of miRNAs in the evolution of anticancer drug resistance and miRNAs expression profiling can be correlated with the development of drug resistance, suggesting that the miRNAs-mediated form of drug resistance adds another molecular mechanism of drug resistance . A couple of recent studies have reported the role of miRNAs in modulating GC or other tumor chemoresistance. Zhang et al. showed that miR-106a could promote chemoresistance of cisplatin resistant human GC cells by targeting RUNX3 . Shang et al. showed that miR-508-5p could reverse chemoresistance of GC cells by targeting ABCB1 and ZNRD1 . Zhou et al. identified that miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level . These studies provided initial clues for miRNAs in regulating GC chemoresistance.
In the present study, we demonstrated that miR-223 could promote DDP resistance of GC cells via regulating G1/S cell cycle transition and apoptosis by targeting FBXW7. Thus, this report identifies novel signaling pathways and molecules as potential therapeutic targets for the treatment of DDP-resistant human GCs.
Materials and methods
Patients and samples
A total of 50 pairs of tumor and adjacent tissues were collected from GC patients who performed gastrectomy prior to any treatment at the First Affiliated Hospital of Nanjing Medical University during October 2013 and September 2014. The basic characteristics of the enrolled patients were listed in Additional file 1: Table S1. For the use of materials for research purposes, written informed consent was obtained from each patient. The consent procedure and study protocol were approved by the Medical Institutional Ethical Committee of first affiliated hospital of Nanjing Medical University.
Cell culture and transfection
SGC-7901 and BGC-823 and their respective resistance cells were purchased from Shanghai Institute of Cell Biology (Shanghai, China). All cell lines were cultured in RPMI 1640 (GIBCO, Rockville, MD, USA) medium supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 mg/ml streptomycin in humidified air at 37°C with 5% CO2. MiR-223 mimic or inhibitor or siRNA-FBXW7 and their negative controls were obtained from GenePharma (Shanghai, China). The open reading frame of FBXW7 that was generated by PCR was then inserted into the pcDNA 3.1 expression vector, which was named pcDNA-FBXW7. The recombinant vector was confirmed by the digestion analysis of restriction endonuclease and DNA sequencing. For ectopic expression of miR-223, miR-223 mimic or miR-NC vectors were purchased from GenePharm. The transfection was performed using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) according to the instructions.
Quantitative real-time PCR
Total RNA was isolated using TRIzol reagent. The specific RT primers used were: miR-223:5’-GTCGTATCCAGTGCGTGTCGTGGAGTCGGCAATTGCACTGGATACGACAACTCA-3’ and U6:5’-CGCTTCACGAATTTGCGTGTCA-3’. RT was performed using PrimeScript™ RT reagent Kit (Takara, Otsu, Japan) according to the manufacturer’s instructions. PCR primers used were: miR-223 sense, 5’-CCGCTCGAGGAGCTTCCAGCTGAGCACTGGG-3’ and antisense, 5’-CGACGCGTTATTGCGCCCCCATCAGCACT-3’; U6 sense, 5’-CTCGCTTCGGCAGCACA-3’ and antisense, 5’-AACGCTTCACGAATTTGCGT-3’; FBXW7 Forward, 5’-GTCCCGAGAAGCGGTTTGATA-3’; Reverse, 5’-TGCTCAGGCACGTCAGAAAAG-3’; GAPDH sense, 5’-GCACCGTCAAGGCTGAGAAC-3’ and antisense, 5’-TGGTGAAGACGCCAGTGGA-3’. QRT-PCR was performed using SYBR Premix ExTaq (TaKaRa, Dalian, China) according to the manufacturer’s protocol.
Western blot assay
The cells were lysed using the mammalian protein extraction reagent RIPA (Beyotime, Beijing, China). Approximately a 50 μg protein extraction was separated by 10% SDS-PAGE, transferred to 0.22 mm nitrocellulose (NC) membrane (Sigma), and incubated with specific antibodies. Autoradiograms were quantified by densitometry using Quantity One software (Bio-Rad, CA, USA). β-actin (diluted 1:1000) antibody was used as a control and rabbit anti-FBXW7 (1:1000 dilution), p14 (1:100 dilution), p16 (1:100 dilution), p21 (1:150 dilution), p27 (1:50 dilution), CDK2 (1:200 dilution), CDK4 (1:100 dilution), CDK6 (1:100 dilution), c-myc (1:150 dilution), CCND1 (1:100 dilution), CCND2 (1:150 dilution), CCND3 (1:100 dilution), CCNE1 (1:150 dilution), CCNE2 (1:50 dilution) were provided by Cell Signaling Technology (MA, USA).
In vitro chemosensitivity assay
The in vitro chemosensitivity assay was determined by MTT assay. Briefly, cells were seeded into 96-well plates (3.5 × 103 cells/well) and allowed to attach overnight. Cells were then treated with various concentrations of DDP. At 24 h, cell vitality was assessed using 0.5 mg/mL MTT (Sigma, MO, USA) solution. Approximately 4 h later, the medium was replaced with 150 μl dimethyl sulfoxide (DMSO, Sigma, MO, USA) and vortexed for 10 min. The absorbance at 490 nm (A490) of each well was read using a spectrophotometer. Each experiment was performed in triplicate.
Colony formation assay
Cells were trypsinized to single cell suspensions and were seeded 6-well plates at 500/well. After 14 days culture in RPMI 1640 medium with FBS, the colonies were stained with crystal violet solution and the number of colonies was counted. Each experiment was performed in triplicate.
Luciferase reporter assay
A FBXW7-3’UTR luciferase reporter was created. Briefly, the 3’UTR sequence of FBXW7 predicted to interact with miR-223 was amplified and cloned into the EcoRI and XhoI sites of pGL3-luc vector (Promega, Madison, WI, USA). The site-directed mutagenesis of the miR-223 target-site was carried out using Invitrogen (Californlia, USA). The constructs were sequenced and named pGL3-luc-FBXW7/3’-UTR-wt or pGL3-luc-FBXW7/3’-UTR-mut. For reporter assays, SGC-7901 cells were cultured in 24-well plates and each transfected with 100 ng of pGL3-luc-FBXW7/3’UTR-wt or pGL3-luc-FBXW7/3’UTR-mut and miR-223 mimics or inhibitor using Lipofectamine 2000 (Invitrogen, USA). 48 hours after transfection, cells were harvested and assayed with Dual-Luciferase Reporter Assay kit (Promega, USA) according to the manufacturer’s instructions.
Flow cytometric analysis of cell cycle and apoptosis
For apoptosis analysis, cells were treated with various concentrations of DDP for 24 h, harvested and fixed with 2.5% (v/v) glutaraldehyde for 30 min. The rate of apoptosis was determined using Annexin V-FITC and PI staining by flow cytometry. For cell cycle analysis, cells were treated with various concentrations of DDP for 24 h, washed with ice-cold PBS and fixed with 70% (v/v) ethanol overnight at −20°C. Fixed cells were rehydrated in PBS for 10 min and subjected to PI/RNase staining followed by flow cytometric analysis using a FACScan instrument (Becton Dickinson, Mountain view, CA, US) and CellQuest software (Becton Dickinson, San Jose, CA, US).
All experimental data were expressed as the Mean ± S.D. The significance of differences of clinical data according to miR-223 expression was determined by Student’s t-test. All analyses were performed with SPSS 17.0 (SPSS Inc, Chicago, IL, USA) for Windows. The significance level was set at P < 0.05.
MiR-223 is up-regulated in tumor tissues and DDP-resistant GC cells
Effect of miR-223 expression on sensitivity of GC cells to cisplatin in vitro
FBXW7 was a functional target of miR-223
MiR-223 and FBXW7 regulate the expression of G1/S transition in DDP-resistant GC cells
Expression of miR-223 was negatively correlated with FBXW7 expression in cells and tissues
Cisplatin (DDP), a DNA damaging chemical, has been for many years used as a systematic chemotherapeutic agent for several human tumor types, including GC. It could increase cell death and apoptosis, arresting cells in G0/G1 phase . Unfortunately, intrinsic or acquired tumor cell resistance to DDP severely limits its therapeutic efficacy. Multiple mechanisms have been proposed for the development of DDP resistance in GC, including the reduced intracellular accumulation of the drug, increased levels of glutathione and anti-apoptotic proteins, and decreased pro-apoptotic proteins . Growing evidence has shown that miRNAs have regulatory roles in the pathogenesis of malignant tumors, through the suppression of genes involved in cell growth, differentiation, development, apoptosis, metastasis and chemo- or radio-resistance. It is likely, therefore, that they can also modulate sensitivity and resistance to anticancer drugs in substantial ways. However, the mechanisms responsible for chemotherapy resistance by miRNAs in GC have not been clearly identified.
MiR-223 has been known to be up-regulated in many human cancers, including colorectal cancer , lung cancer  and GC . Specially, miR-223 was reported to be involved in trastuzumab induced resistance of GC ; however, it is still unclear whether miR-223 play a role in DDP induced resistance. The prognostic values of miR-223 in human cancers are also investigated . These experimental data, taken together, support an important role of altered miR-223 during tumor progression and metastasis. Additionally, miR-223 was reported to be significantly up-regulated in H. pylori infected gastric tissues through miRNA array profiling. We found in the present study that H. pylori positive patients had a significantly higher proportion of miR-223 over-expression. In this study, we will investigate the emerging roles of miR-223 in DDP resistance of human GC cells. By loss-of-function studies, down-regulation of miR-223 could reverse the in vitro DDP resistance of DDP-resistant GC cells by affecting G1/S cell cycle transition and inducing apoptosis enhancement. Meanwhile, parental GC cell line transfecting with miR-223 mimic was established for gain-of-function studies. We showed that up-regulation of miR-223 could reduce the sensitivity of parental GC cells to DDP in vitro. Likewise, we also found that up-regulation of miR-223 could affect G1/S transition and reduce the DDP-induced apoptosis in parental GC cells. Importantly, to further explore the molecular mechanisms by which miR-223 exerts its function, the determination of its functional target gene is essential. Analyses using the TargetScan, PicTar and miRanda algorithms’ databases revealed that more than 100 genes were predicted to be the potential targets of miR-223. According to the functions of these genes and the effect of miR-223 on GC cells, FBXW7 was chosen as the interesting gene in further study. Our data clearly suggest that miR-223 promotes the DDP resistance of GC cells by directly targeting FBXW7. This conclusion is based on several pieces of evidence. First, miR-223 inhibitor significantly up-regulates the expression of FBXW7 mRNA and protein in 7901/DDP cells, whereas miR-223 mimic significantly down-regulates the expression of FBXW7 mRNA and protein in 7901 cells. Second, the luciferase activity assay indicated that miR-223 could bind the 3’-UTR of the FBXW7 transcript. Third, overexpression of FBXW7 could mimic the effect of miR-223 inhibitor in 7901/DDP cells, whereas silencing of FBXW7 could partially reverse the effect of miR-223 inhibitor in 7901 cells. Fourth, down-regulation of FBXW7 could mimic the effect of miR-223 mimic in 7901 cells, whereas up-regulation of FBXW7 could partially reverse the effect of miR-223 mimic in 7901/DDP cells. Finally, FBXW7 was negatively correlated with miR-223 in GC tissues. These data suggest that miR-223 targets FBXW7 and down-regulates its expression in GC.
FBXW7, also known as F-box and WD repeat domain-containing 7, has been found to be involved in numerous cellular processes including cell proliferation, apoptosis, cell cycle, differentiation and its expression change is related to tumor prognosis [29,30]. FBXW7 has been identified as a p53 target gene. In support of this notion, Fbxw7 was dramatically up-regulated by infection with adenovirus-mediated transfer of wild-type p53 into the p53-deficient cells . It is considered as a p53-dependent tumor suppressor protein and leads to ubiquitination-mediated suppression of several oncoproteins including c-Myc, cyclin E, Notch, c-Jun and others [32,33]. In our study, however, we did not find c-myc protein change after FBXW7 transfection. C-myc mRNA was inhibited after FBXW7 overexpression and increased after FBXW7 knock down. This is probably due to the post-transcriptional regulation of the genes. MicroRNAs (miRNAs) including miR-27 , miR-25  and miR-223  have been reported to be involved in regulating the expression of FBXW7. Wang et al. reported that FBXW7 is a potential miR-27a target. Consistently, there is an inverse correlation between miR-27a expression and FBXW7 levels in human tumor samples. Lerner et al. further discovered that miR-27a suppresses FBXW7 during specific cell cycle phases . Wertz et al. reported that FBXW7 inactivation and increased Mcl-1 levels promoted resistance to anti-tubulin chemotherapeutic agents and accelerated tumorigenesis. This group also reported that inhibition of Mcl-1 in FBXW7 null cells restored their sensitivity to taxol- and vincristine-induced cell death . Collectively, these provided stronger evidence that the formation of DDP resistant phenotype of GC cells was mediated via FBXW7 inactivation.
In summary, our data establish a functional link that miR-223 and FBXW7 in GC, and show that miR-223 could promote DDP resistance in GC cells via regulating cell cycle and apoptosis by targeting FBXW7. Thus, in the future, miR-223/FBXW7 signature might predict the responses of GC patients to DDP-based chemotherapy and represent potential targets for therapeutic intervention.
This work was supported by National Natural Science Foundation of China (No. 81270476 and 81470830), the Priority Academic Program Development of Jiangsu Higher Education Institutions (JX10231801) and Jiangsu postgraduate scientific research and innovation projects (CXZZ13_0574).
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