Downregulation of ribophorin II suppresses tumor growth, migration, and invasion of nasopharyngeal carcinoma

OncoTargets and Therapy, Jun 2018

Downregulation of ribophorin II suppresses tumor growth, migration, and invasion of nasopharyngeal carcinoma Feilong Hong, Yong Li, Haifeng Ni, Jing Li Department of Otolaryngology, Hangzhou First People’s Hospital, Hangzhou, China Background: It has been reported that ribophorin II (RPN2) expression is increased in many cancers, but the role of RPN2 in nasopharyngeal carcinoma (NPC) remains unclear. Patients and methods: This study found that the expression of RPN2 is increased dramatically in NPC tissues of patients compared with that in the adjacent normal tissues. This study attempted at understanding the effect of siRNA-RPN2 treatment on the migration and invasion of NPC cell lines CNE2 and HNE1. Results: RT-PCR and Western blotting showed that RPN2 was highly expressed in CNE2 and HNE1 cells. siRNA-RPN2 treatment significantly inhibited cell viability at 24 and 48 h compared with the control group. Results of the transwell assay showed that, compared to the control groups, migration and invasion of the cells treated with siRNA-RPN2 decreased markedly. In addition, compared to the control groups, caspase-3, caspase-9, and E-cadherin expression levels increased and MMP 2 expression decreased significantly in the siRNA-RPN2-treated group. Phosphorylation of AKT and PI3K was also inhibited after siRNA-RPN2 treatment. Conclusion: siRNA-RPN2 can effectively inhibit the invasion and migration of human NPC cells via AKT/PI3K signaling. This can serve as a novel strategy for NPC treatment. Keywords: siRNA-RPN2, nasopharyngeal carcinoma, migration, invasion, MMP2, MMP9

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Downregulation of ribophorin II suppresses tumor growth, migration, and invasion of nasopharyngeal carcinoma

OncoTargets and Therapy Downregulation of ribophorin ii suppresses tumor growth, migration, and invasion of nasopharyngeal carcinoma Feilong hong Yong li haifeng n i Jing li 0 0 Department of Otolaryngology, hangzhou First People's hospital , hangzhou, china 8 1 0 2 - l u J - 3 1 n o 4 1 2 . 6 1 . 4 5 2 . 1 5 y b / m o c . s s rvpee l.yno PowerdbyTCPDF(ww.tcpdf.org) Background: It has been reported that ribophorin II (RPN2) expression is increased in many cancers, but the role of RPN2 in nasopharyngeal carcinoma (NPC) remains unclear. Patients and methods: This study found that the expression of RPN2 is increased dramatically in NPC tissues of patients compared with that in the adjacent normal tissues. This study attempted at understanding the effect of siRNA-RPN2 treatment on the migration and invasion of NPC cell lines CNE2 and HNE1. Results: RT-PCR and Western blotting showed that RPN2 was highly expressed in CNE2 and HNE1 cells. siRNA-RPN2 treatment significantly inhibited cell viability at 24 and 48 h compared with the control group. Results of the transwell assay showed that, compared to the control groups, migration and invasion of the cells treated with siRNA-RPN2 decreased markedly. In addition, compared to the control groups, caspase-3, caspase-9, and E-cadherin expression levels increased and MMP 2 expression decreased significantly in the siRNA-RPN2-treated group. Phosphorylation of AKT and PI3K was also inhibited after siRNA-RPN2 treatment. Conclusion: siRNA-RPN2 can effectively inhibit the invasion and migration of human NPC cells via AKT/PI3K signaling. This can serve as a novel strategy for NPC treatment. - patients, while RPN2 silencing suppresses cell proliferation and invasiveness.8 The correlation between RPN2 and NPC has not been reported. In this study, we first observed that the expression of RPN2 was significantly higher in the NPC tissue than in the peritumor tissue. Thus, it would be interesting to determine whether RPN2 plays a role in the development and metastasis of NPC. In the present study, we attempted to explore the effect(s) of siRNA-RPN2 silencing on the migration and invasion of NPC cells which expressed RPN2. Moreover, the underlying mechanisms involved were also investigated to provide novel insights into potential NPC therapeutic strategies. 8 1 0 2 l u J 3 1 n o 4 1 2 . 6 .154 Patients and methods .512 Patients and tissue samples /yb Written informed consent was obtained from all participants .com before the study. Sixty-eight patients with NPC admitted rvpee l.yno ttohisthsetuHdayn,gaznhdoouuFrisrtsutdPyewopalse’aspHproosvpeidtablywtehree ienndreoplleenddefonrt s s immunohistochemistry After being dewaxed in xylene and rehydrated through graded alcohol to distilled water, NPC specimen sections were immersed in 3% hydrogen peroxide for 15 min at room temperature to prevent endogenous peroxidase activity. Next, the sections were boiled in the antigen retrieval solution (citrate, pH=6) for 4 min in a pressure cooker for antigen retrieval. After being cooled for 2 h to 26°C, the sections were incubated with diluted rabbit anti-RPN2 antibody (1:200; Proteintech Group, Wuhan, China) overnight at 4°C. The next day, after rinsing thrice with phosphate buffered saline with Tween 20 (PBST), the sections were incubated with the secondary antibody for 30 min at 37°C. Next, the sections were rinsed with PBST three times, and 3,3-diaminobenzidine staining was performed for 2 min for targeted protein identification. The sections were counterstained with hematoxylin to stain the nucleus. After rinsing for 2 h under flowing water and dehydrating at 37°C, the specimen sections were mounted using Neutral Balsam for preservation. submit your manuscript | www.dovepress.com Dovepress cell culture Human NPC cells, namely CNE2, CNE2, HNE1, SUNE-1, and 5-8F cells, were obtained from the Shanghai Cell Bank (Chinese Academy of Sciences, Shanghai, China) and cultured in RPMI 1640 medium (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) containing 10% fetal bovine serum and 1% penicillin/streptomycin (Invitrogen, Thermo Fisher Scientific) at 37°C in 5% CO2. sirna transfection siRNA-RPN2 was designed and synthesized by Genepharma (Shanghai, China). The interference sequence is 5′-GCA GAGCAGAGCAGTAGATTGGCAA-3′. The NPC cells, CNE2 and HNE1, were selected for transfection. After transfection, RPN2 expression was confirmed using reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. For siRNA transfection, the cells were seeded onto 12-well tissue culture plates at a density of 6×104 cells/ well. When the cells were 70% confluent, they were transfected with the RPN2 siRNA (siRPN2) or control siRNA (siNC), according to the manufacturer’s instructions. After 48 h, the transfected cells were collected and processed for the subsequent experiments. cell viability assay The effect of siRNA-RPN2 treatment on CNE2 and HNE1 cell viability was evaluated using the cell counting kit-8 (CCK-8) assay. Briefly, 0, 12-, 24-, 48-, and 72-h post-transfection, the cells were seeded at a density of 4×103 cells/well in 96-cell plates and incubated for the indicated time periods. Next, 20 μL CCK-8 was added to each well and the cells were incubated for 1 h. The OD values were recorded using a microplate reader (Thermo Fisher Scientific) at 450 nm. cell cycle assay After transfection for 48 h, the cells were harvested, washed with PBS, and fixed with 70% ethanol at 4°C overnight. Next, the cells were washed with PBS and resuspended in the RNase A–propidium iodide solution (100 mg/mL RNase A and 5 μg/mL propidium iodide). The cells were incubated at room temperature for 1 h. Stained cells were analyzed using the FACScan flow cytometer (BD Biosciences, Mountain View, CA, USA). cell apoptosis assay Cell apoptosis was detected using the annexin V/PI fluorescence-activated cell sorting (FACS) assay, as described .dow lsue w a /w no :/s rs ttp pe h ro from F d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O previously. Briefly, the cells (3×105 cells/well) were harvested and washed in cold PBS. After fixing with 70% ethanol, the cells were treated with RNase (5 mmol/L) and incubated for 10–15 min in the dark at 37°C. Subsequently, they were stained with 195 μL Annexin V and 5 μL PI. The fluorescence intensities were determined using fluorescence-activated cell sorting (FACS) to analyze the percentage of apoptotic cells. cell migration and invasion assays The cell migration assay was performed using a 24-well transwell chamber with a pore size of 8 μm (Sigma-Aldrich, Munich, Germany). Then, 5×104 siRNA-RPN2-transfected cells, mock cells, and non-transfected cells were resuspended in a serum-free medium and transferred to the upper chamber. The lower chamber was filled with a medium containing 10% fetal bovine serum. After 24-h cultivation, the number of cells stained by 0.1% crystal violet was counted visually under a microscope (OLYMPUS, Hamburg, Germany). The cell invasion assay was performed using the same procedure, except that the upper chamber was coated with matrigel. Results from three independent experiments were averaged and reported. Quantitative reverse transcription (qr T)-Pcr Total RNA was extracted from transfected cells, mock cells, and non-transfected cells and reverse transcribed to cDNA using the First Strand cDNA Synthesis kit (Sigma-Aldrich), according to the manufacturer’s protocol. The PCR cycling conditions were as follows: 95°C for 10 min, followed by 40 cycles of denaturation at 95°C for 15 s and annealing/extension at 60°C for 45 s. The ABI 7300 thermocycler (Applied Biosystems, Foster City, CA, USA) and SYBR Premix Ex Taq kit (Takara, Beijing, China) were used. Western blot analysis The concentration of proteins extracted from cell samples was determined using the BCA assay (Beyotime). Next, the proteins were subjected to SDS-polyacrylamide gel electrophoresis and electroblotted onto polyvinylidene fluoride membranes. Following blocking with 5% non-fat dry milk in PBS for 1 h, the blotting membranes were probed overnight at 4°C with the following antibodies individually: anticaspase-3, anti-caspase-9, anti-E-cadherin, anti-MMP2, antiMMP9, anti-PI3K, anti-AKT, anti-p-PI3K, and anti-p-AKT antibodies. The polyvinylidene fluoride membrane was exposed to an X-ray film, and immunoreactive bands were detected by reaction with the ECL detection system reagents (Amersham, Arlington Heights, IL, USA). Xenograft model experiments All experimental protocols involving animals were approved by the institutional animal care and use committee of the Hangzhou First People’s Hospital and performed following the Guide for the Care and Use of Laboratory Animals issued by Institute of Laboratory Animal Resources. Fourweek-old male severe combined immunodeficiency (SCID) mice were purchased from Beijing HFK Bioscience Co. Ltd. (Beijing, China). Cells transfected with siRNA-RPN2 (Genecopeia, Rockville, MD, USA) were injected into the mice subcutaneously (1×106 cells per mouse). Tumor growth in the mice was monitored every 7 days. All mice were euthanized after 40 days, following which, the tumor nodules in the mice were removed. Tumor sizes were measured using a caliper, and tumor volume was calculated using the following equation: tumor volume (mm3) = length (mm) × width (mm)2/2. statistical analysis All results represent the mean±SD of three independent experiments. Statistical analysis was performed using the SPSS 13.0 statistical package, and data were subjected to one-way analysis of variance (ANOVA), followed by Dunnett’s test. A P-value0.05 was considered to be statistically significant. Results high expression of rPn2 in tumor tissue To verify the biological role of RPN2 in NPC, the expression levels of RPN2 in tissues of NPC patients were evaluated using RT-PCR and IHC. As shown in Figure 1A, the mRNA expression of RPN2 was higher in the NPC tissues than in the adjacent normal tissues (P0.01). IHC analysis also showed that the expression of RPN2 was higher in the NPC tissues than in the adjacent normal tissues (Figure 1B). These results indicated that RPN2 overexpression may result in the initiation and/or progression of NPC. sirPn2 inhibits cell proliferation of nPc cell lines RPN2 mRNA was silenced in CNE2 and HNE1 cell lines, as described previously. The interference efficient was then identified using RT-PCR and Western blotting. Transfection with siRNA-RPN2 resulted in a marked decrease in RPN2 mRNA and protein levels in the siRNA-RPN2 group, compared to the control group and mock group, which confirmed that siRNA-RPN2 was effective in silencing RPN2 expression (Figure 1C and D). The effect of siRNA-RPN2 treatment on cell viability measured using the CCK-8 assay is shown in Figure 1E and F. Compared to the control and mock cell groups, cell viability significantly (P0.05) decreased in the siRNARPN2 group 24-, 48-, and 72-h post-transfection. Decrease in rPn2 expression induces cell cycle arrest and apoptosis To explore the potential mechanism(s) by which RPN2 suppresses NPC cell growth, we evaluated the cell cycle distribution of siRNA-RPN2 transfected cells and siRNA-NC cells using flow cytometry. It was observed that knockdown of RPN2 in the CNE2 and HNE1 cells resulted in an increase in the number of cells in the G0–G1 phase (CNE2, 61.1%±1.1%; HNE1, 59.4%±2.34%) and a decrease in those in the S phase (CNE2, 28.9%±2.32%; HNE1, 29.65%±1.32%), as compared to the siRNA-NC-transfected cells (CNE2: G0–G1, 33.25%±2.09%; S, 55.14%±1.72%; HNE1: G0–G1, 31.18%±1.57%; S, 57.22%±1.67%) (Figure 2A). Additionally, results from the annexin V/PI assay showed that, compared to siRNA-NC-transfected cells (CNE2, 9.77%±1.24%; HNE1, 8.74%±1.14%), the CNE2 and HNE1 cells transfected with A) and cell apoptosis (B) of cne2 submit your manuscript | www.dovepress.com Dovepress 3489 siRNA-RPN2 (CNE2, 33.5%±2.76%; HNE1, 28.7%±1.89%) showed increased apoptosis (Figure 2B). Taken together, these data suggested that RPN2 promotes cell proliferation and suppresses apoptosis in NPC cells in vitro. sirna-rPn2 inhibits tumor growth in vivo 8 We investigated the effects of siRNA-RPN2 treatment on -012 repressing tumor growth in vivo. NPC cells transfected l-Ju with siRNA-RPN2 or a negative control were subcutanen13 ously injected into SCID mice. After 40 days, the mice were 1o4 euthanized, and RPN2 expression levels in their tissues .612 were measured. The expression of RPN2 was observed to .54 be lower in the group treated with siRNA-RPN2 than in the .125 siNC group. Tumors with lower RPN2 expression showed /yb slower growth and were smaller in size than control tumors .com (Figure 3). The average tumor weight was approximately ss 2.3-fold lower in the miR-148a-overexpressing tumors than rvpee l.yno in the negative controls. These results suggested that siRNARPN2 treatment may inhibit NPC cell growth in vivo. effects of sirna-rPn2 treatment on nPc cell migration and invasion Cell invasion and migration are crucial factors for cancer metastasis.10 The transwell assay was employed to investigate the effect of siRNA-RPN2 treatment on the migration and invasion of CNE2 and HNE1 cells. As shown in Figure 4A and B, transfection with siRNA-RPN2 resulted in significant lowering of the migration ability of CNE2 and HNE1 cells. Similarly, the transwell invasion assay demonstrated that the invasion abilities of CNE2 and HNE1 cells transfected with siRNA-RPN2 were notably lower than those of the control and mock cells (Figure 4C and D). These results indicated that siRNA-RPN2 treatment significantly inhibited the migration and invasion of CNE2 and HNE1 cells. sirna-rPn2 regulates the expression of caspase-3, caspase-9, e-cadherin, and MMP2 Caspase-3, caspase-9, E-cadherin, and MMP2 expressions were monitored by Western blot analysis. Results showed that, compared to the siNC group, the siRNA-RPN2-treated group showed a significant increase in the expression of caspase-3, caspase-9, and E-cadherin in both the CNE2 and HNE1 cells (P0.05, Figure 5A and B). MMP2 expression decreased significantly in NPC cells following siRNA-RPN2 treatment (P0.05, Figure 5C and D). Therefore, inhibition of cell invasion and migration mediated by E-cadherin and MMP2 may play an important role in inhibiting NPC metastasis. sirna-rPn2 suppressed the phosphorylation of Pi3K/aKT signaling The phosphorylation of PI3K/AKT signaling plays a crucial role in NPC occurrence and pathogenesis. Therefore, we sciD mice. representative submit your manuscript | www.dovepress.com Dovepress 3491 analyzed the effect of siRNA-RPN2 treatment on phosphorylation of PI3K and AKT. We demonstrated that, compared to the siNC and control groups, the siRNA-RPN2-treated group showed significantly higher inhibition of AKT and PI3K phosphorylation in the CNE2 and HNE1 cells (P0.05, Figure 5B). Discussion Abnormal expression of RPN2 has been reported in breast cancer, non-small cell lung cancer, gastric cancer, colorectal cancer, and prostatic carcinoma.11–13 In the present study, we observed a marked increase in RPN2 expression in NPC tissues. The subsequent experiments were designed to explore the effect of siRNA-RPN2 treatment on tumor migration and invasion in NPC. CNE2 and HNE1 were selected for further investigation and validating the high expression of RPN2. siRNA-RPN2 treatment effectively inhibited cell proliferation (in vivo and in vitro), and suppressed the invasion and migration of CNE2 and HNE1 cells. siRNA-RPN2 treatment also effectively induced cell apoptosis, and cell cycle arrest in the G1 phase. The critical role of siRNA-RPN2 in NPC cell growth, invasion, and migration encouraged us to explore the potential mechanism(s) responsible for the aforementioned observations by measuring the changes in expression of relevant genes and proteins. Zhang et al10 reported that RPN2 regulated colorectal cell proliferation through mediating the glycosylation of EGFR. Fujita et al8 demonstrated that RPN2 promoted cell proliferation and inhibited cell apoptosis by regulation of Bax/Bcl-2 in non-small cell lung cancer. In this study, we identified the 3492 submit your manuscript | www.dovepress.com Dovepress 8 1 0 2 l u J 3 1 n o 4 1 2 . 6 1 . 4 5 2 . 1 5 y b / m o c . s s rvpee l.yno .dow lsue w a /w no / :s rs ttp pe h ro expression of caspase-3/-9. Caspase-3 and caspase-9 are known to participate in mitochondrial apoptosis, which mediates the apoptotic cascade reaction.14–16 Caspase-3 is a downstream target in the mitochondrial apoptosis pathway. Activated caspase-8 can lead to the release of caspase-9 and then give rise to the activation of caspase-3, and ultimately to induce apoptosis.16 Therefore, we detected the caspase3/-9 expressions after cells transfected with RPN2 siRNA. E-cadherin expression is known to decrease in several carcinoma cells. Further, the extracellular matrix also gets destroyed, which results in tumor migration and invasion.17,18 Tumor cell invasion and metastasis are characteristic features of malignant phenotypes and require regulated expression of MMPs. Among all MMPs, MMP2 has been suggested to have well-characterized roles in cancer cell invasion and metastasis.19,20 We also provided evidence suggesting that the mechanism underlying the aforementioned effects was related to the inhibition of expression of MMP2, which is known to play a major role in tumor invasion and metastasis by proteolyzing the extracellular matrix.21,22 These results indicated that the inhibition of cell proliferation, invasion, and migration in response to siRNA-RPN2 treatment may be mediated via the regulation of caspase-3, caspase-9, E-cadherin, and MMP2. PI3K/AKT signaling plays crucial roles in cell proliferation, migration, and invasion of human NPC.23,24 Our study showed that the phosphorylation of PI3K and AKT was blocked by siRNA-RPN2. Conclusion Our study showed that RPN2 was highly expressed in human NPC tissues. Additionally, the mRNA and protein levels of RPN2 were upregulated in the NPC cell lines, namely CNE2 and HNE1. Furthermore, siRNA-RPN2 can markedly inhibit the invasion and migration of NPC cells by regulating caspase-3, caspase-9, E-cadherin, and MMP2 expression, and PI3K/AKT signaling. RPN2, therefore, may serve as a biomarker for the diagnosis and prognosis of NPC. Finally, targeting the PI3K/AKT signaling pathway may be an effective therapeutic strategy for treating NPC. Disclosure The authors report no conflicts of interest in this work. submit your manuscript | www.dovepress.com Dovepress 3493 8 1 0 2 l u J 3 1 n o 4 1 2 . 6 1 . 4 5 2 . 1 5 y b / m o c . s s Publish your work in this journal OncoTargets and Therapy is an international, peer-reviewed, open access journal focusing on the pathological basis of all cancers, potential targets for therapy and treatment protocols employed to improve the management of cancer patients. The journal also focuses on the impact of management programs and new therapeutic agents and protocols on 1. Fountzilas G , Psyrri A , Giannoulatou E , et al. 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Feilong Hong, Yong Li, Haifeng Ni, Jing Li. Downregulation of ribophorin II suppresses tumor growth, migration, and invasion of nasopharyngeal carcinoma, OncoTargets and Therapy, 2018, 3485-3494, DOI: 10.2147/OTT.S158355