MicroRNA‑210 negatively regulates the radiosensitivity of nasopharyngeal carcinoma cells

  • Authors:
    • Bo‑Yi Li
    • Yi Luo
    • Wen‑Si Zhao
    • Lu Zhang
    • Han‑Jing Zhou
    • Yu‑Chun Zou
    • Tao Zhang
  • View Affiliations

  • Published online on: June 6, 2017     https://doi.org/10.3892/mmr.2017.6694
  • Pages: 1401-1408
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Abstract

Radiotherapy is one of the primary methods of treatment of malignant tumors, however, resistance to radiation is a major problem. The reasons for the radioresistance are still poorly understood. However, it is generally accepted that microRNAs (miRNAs or miRs) can regulate the radiosensitivity of tumors. The present study therefore aimed to identify specific miRNAs and their effects on radioresistant cells. More specifically, the aim was to investigate specific miRNAs and their effects on radioresistant tumor cells. The radioresistant tumor cells (CNE‑2R) were established using a dose gradient method, and the miRNA expression profiles of CNE‑2R cells and the parental cells (CNE‑2) were determined. The expression of miR‑210 in CNE‑2R cells was significantly higher than in CNE‑2 cells. CNE‑2R cells were transfected with LV‑hsa‑miR‑210‑inhibitor, and CNE‑2 cells were transfected with LV‑hsa‑miR‑210. The expression of miR‑210 was confirmed by reverse transcription quantitative‑polymerase chain reaction. The percentages of CNE‑2R‑miR‑210‑inhibitor and CNE‑2 cells in the G2/M phase were higher than in the CNE‑2R and CNE‑2‑miR‑210 cells, and the percentages of cells in S phase were lower than in the CNE‑2R and CNE‑2‑miR‑210 cells. Following 4 Gy of radiation, CNE‑2R‑miR‑210‑inhibitor and CNE‑2 cells, which express low levels of miR‑210, had a higher apoptosis rate than CNE‑2R and CNE‑2‑miR‑210 cells. Following 4, 8 and 12 Gy of radiation, cell viability and survival fraction of CNE‑2R‑miR‑210‑inhibitor cells were lower than those of CNE‑2R and CNE‑2‑miR‑210 cells, and similar to those of CNE‑2 cells. Together, these findings strongly suggest that miR‑210 negatively regulates the radiosensitivity of tumor cells, and may therefore have therapeutic potential for the treatment of radiation resistance.

Introduction

Presently, the primary treatments of cancer include surgery, radiotherapy, chemotherapy and targeted therapy. Radiotherapy is the main treatment used for cancer (1). It is widely used for the treatment of tumors in rectal cancer, non-small cell lung cancer and breast cancer (24).

For example, radiotherapy is the preferred and primary treatment for nasopharyngeal cancer (NPC) (5). Following radiotherapy, the five-year survival percentage for patients with NPC has increased from 50–60% to a current percentage of ~70%. However, following radical radiotherapy, ~20% of NPC patients still have residual tumors (6). Local treatment failure and distant metastasis are the key factors which prevent therapeutic efficacy, and intrinsic or acquired radiation resistance is one of the primary reasons causing the failure of radiotherapy and worse treatment outcomes (7,8).

Thus, it is important to gain further insights into the molecular mechanisms of chemotherapeutic drug resistance, and find novel strategies involving improved therapeutic benefits for cancer patients.

microRNAs (miRNAs) are a class of small RNAs with an approximate length of 19–25 nucleotides, which are endogenous short noncoding RNAs (9). miRNAs bind to the 3′-untranslated region of target mRNAs, followed by degradation of the mRNA or inhibition of its translation. They may also regulate the expression of target genes at the post-transcriptional level (10), and are associated with regulating cell growth, proliferation, differentiation and apoptosis (11). miRNAs are observed in many cancers, and are involved in malignant tumor development and progression (12). Several studies have reported that the expressions of miRNAs are closely associated with the radiosensitivity of tumors, and upregulated or downregulated expression of miRNAs can increase tumor radiosensitivity (13). To address these possibilities, the following study characterized the effects of miRNAs on the radiation resistance of tumor cells, in order to provide a biochemical basis for further studies, which may use this biomarker to predict the radiosensitivity of cancer patients.

Materials and methods

Cells and cell culture

The CNE-2 cell line, which is suspected to be identical to CNE-1 and cross-contaminated with HeLa (cervical carcinoma) as well as an additional unknown cell line (14), was cultured in RPMI 1640 medium (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (Gibco; Thermo Fisher Scientific, Inc.), 1% penicillin-streptomycin (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) and grown at 37°C in an incubator with an atmosphere of 5% CO2.

Development of acquired radioresistant cells

CNE-2 cells were cultured in 25 cm2 culture flasks. The cells were exposed to a series of increasing X-ray doses using a medical electronic linear accelerator (Varian Medical Systems, Palo Alto, CA, USA), in order to establish the radiation resistant tumor cells (CNE-2R). The distance of the source was 100 cm, and the radiation field was 10×10 cm at a dose rate of 300 cGy/min. Cells were irradiated twice with 2 Gy, four times with 4 Gy, and five times with 6 Gy with X-ray radiation over a period of 6 months, so that the CNE-2 cells were exposed to a total dose of 50 Gy. Following several cell passages, the radiation resistant tumor cells were established.

Apoptosis assay

The cells were radiated with 0 and 4 Gy of radiation. Following 12 h, many cells were detached with trypsin without the use of EDTA. Cells were harvested in culture medium and centrifuged for 5 min at 300 × g, and 1×105 cells were treated with 5 µl Annexin V/PE and 10 µl 7-AAD (BD Biosciences, Franklin Lakes, NJ, USA). The cells were gently vortexed and incubated for 15 min at room temperature in the dark. A total of 400 µl 1X binding buffer was added into solution, the cells were analyzed using a Gallios flow cytometer (Beckman Coulter, Inc., Brea, CA, USA).

Cell cycle assay

The cells were digested with trypsin, and were centrifuged for 5 min at 300 × g. Then the cells were resuspended twice with 2 ml PBS, fixed with 1 ml 70% ice cold ethanol, and stored at 4°C overnight. Then 100 µg/ml RNase and 50 µg/ml PI were added, and following incubation in the dark for 30 min, the cell cycle was detected using a Gallios flow cytometer.

Cell viability assay

The cells (5×103) were seeded into 96-well plates. After the cells adhered to the plate, they were irradiated with different doses of X-ray radiation using 0, 4, 8 and 12 Gy, followed by incubation for 24 h. Medium (100 µl) was mixed with 10 µl of CCK-8 solution (Dojindo Molecular Technologies, Inc., Kumamoto, Japan), and a total of 110 µl of the mixed solution was added to each well, followed by incubation of the cells for 2 h. The absorbance at 450 nm of the cells was then read using a microplate reader (Tecan Group Ltd., Männedorf, Switzerland).

Colony formation assay

The surviving cells were characterized using a colony formation assay. Two hundred cells were seeded into six-well plates. After the cells adhered, they were exposed to X-ray radiation with single doses of 0, 4, 8 and 12 Gy, and the cells were incubated for 2 weeks without disturbance. After 2 weeks, there were >50 cells in each colony. The cells were fixed with 4% paraformaldehyde for 30 min and stained with crystal violet solution for 30 min, and the colonies counted. The percentage of cell survival was calculated as follows: The numbers of colonies at × Gy/(the numbers of cells seeded at a × Gy colony forming rate).

MicroRNA microarray analysis

CapitalBio Technology Co., Ltd. (Beijing, China) conducted the present study's Agilent Human miRNA microarrays, which were 8×60 K microarrays used for detecting miRNA expression profiles of the CNE-2 and CNE-2R cells. There were many differential expressions of miRNAs using the microRNA microarray. Among these differential expressions, miR-210 had a significant fold change and a high probe signal, so miR-210 was chosen for further assays. Differences of miR-210 in the CNE-2 and CNE-2R cells were measured by RT-qPCR.

Overexpression of miR-210 in CNE-2 cells and downregulation of miR-210 in CNE-2R cells

CNE-2R cells were transfected with LV-hsa-miR-210-inhibitor, which is a lentivirus inhibiting miR-210 loaded with green fluorescent protein (GFP; GeneChem Co., Ltd., Shanghai, China), and CNE-2 cells were transfected with LV-hsa-miR-210 + GFP, which is a lentivirus expressing miR-210 (GeneChem Co., Ltd.). Following infection with the virus, the infected cells were screened by puromycin for 1 month to establish stable downregulated and upregulated cells. Overexpression of miR-210 in CNE-2 cells resulted in CNE-2-miR-210 cells, and downregulation of miR-210 in CNE-2R cells resulting in CNE-2R-miR-210-inhibitor cells.

RT-qPCR

Total cellular RNA was extracted with TRIzol reagent (Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA), then the RNA samples were used for cDNA synthesis using an All-in-One miRNA First-Strand cDNA Synthesis kit (GeneCopoeia, Inc., Rockville, MD, USA). miR-210 was detected with RT-qPCR by the All-in-One miRNA RT-qPCR kit (GeneCopoeia, Inc.). U6 was used as the control for detection of miR-210. The miR-210 RT-qPCR primer was purchased from GeneCopoeia, Inc. All steps followed the manufacturer's protocols. The results were calculated using the 2−ΔΔCq method (15).

Statistical analysis

SPSS software (version, 19.0; IBM SPSS, Armonk, NY, USA) was used for all the statistical analyses. One-way analysis of variance with Student-Newman-Keuls post hoc tests for multiple comparisons or a Student's t-test were used for the appropriate types of data. P<0.05 was considered to indicate a statistically significant difference.

Results

Radiosensitivity of the CNE-2R cells

To verify whether the radioresistant tumor cells were established, the radiosensitivity of the CNE-2R cells was compared with the parental cells. The percentage of CNE-2 cells in G2/M phase was significantly greater than CNE-2R cells (Fig. 1A; P<0.05). At the same time, determination of cell viabilities indicated that the CNE-2R cells had lower decreases in viability than the CNE-2 cells when irradiated with 4, 8 and 12 Gy of radiation (Fig. 1B; P<0.05). Furthermore, the radiosensitivities of the CNE-2 and CNE-2R cells were compared using the colony formation assay, which reported that the CNE-2R cells had a greater percentage of radioresistant cells than the CNE-2 cells (Fig. 1C). These results demonstrated that the CNE-2R cells were more radioresistant than the CNE-2 cells, and that radioresistant tumor cells were established using the stated protocol.

Expression of miRNAs and RT-qPCR verification between the CNE-2 cells and CNE-2R cells

Microarray analyses were used to compare the patterns of miRNA expression between the acquired radioresistant CNE-2R cells and their parental CNE-2 cells. There were 92 miRNAs with expression changes greater than 2-fold in CNE-2R cells, involving 60 miRNAs that were upregulated and 32 miRNAs that were downregulated (Table I). The expression of miR-210 in CNE-2R cells was 247.25-fold higher than the expression in CNE-2 cells (P=0.0006).

Table I.

Differential expression of miRNAs in CNE-2 and CNE-2R cells.

Table I.

Differential expression of miRNAs in CNE-2 and CNE-2R cells.

No.miRNAFold changea (log2)P-value
  1miR-105-5p28.1790.0032
  2miR-1228-3p98.9610.0172
  3miR-122897.5140.0042
  4miR-130a-3p2.3960.0901
  5miR-149-5p44.5560.0503
  6miR-181d43.6550.0082
  7miR-182-5p35.5250.0260
  8miR-192-5p107.7000.0081
  9miR-194-5p40.4620.0206
10miR-197-3p2.1510.0095
11miR-210247.2500.0006
12miR-212-3p51.6850.0225
13miR-296-5p40.7810.0304
14miR-301b19.5200.0087
15miR-3132112.2600.0059
16miR-3162-3p207.0300.0203
17miR-338-3p4.4610.0048
18miR-340-5p39.5230.0076
19miR-342-3p2.7020.0095
20miR-34a-3p48.2420.0207
21miR-34b-3p41.0550.0190
22miR-3591-3p142.9800.0303
23miR-361-3p95.4040.0040
24miR-365364.1640.0073
25miR-3663-3p157.8200.0206
26miR-3940-5p52.8160.0104
27miR-4254141.5800.0065
28miR-4433-5p106.8400.0081
29miR-444961.0670.0009
30miR-447840.2680.0054
31miR-448465.9650.0070
32miR-451b211.1900.0009
33miR-452-5p153.1600.0013
34miR-454-3p65.3270.0305
35miR-463481.7830.0097
36miR-4649-3p69.2140.0063
37miR-4665-3p85.4700.0130
38miR-4701-5p142.8200.0066
39miR-473031.1100.0411
40miR-4787-5p64.6100.0225
41miR-48481.5680.0020
42miR-5010-3p119.3500.0145
43miR-503-5p67.1020.0176
44miR-51002.1270.0105
45miR-517c-3p62.5760.0067
46miR-52158.8900.0112
47miR-522-3p108.3510.0054
48miR-532-3p65.0690.0092
49miR-57256.2820.0132
50miR-629-3p2.0020.0051
51miR-629-5p53.4440.0066
52miR-6510-5p95.5230.0110
53miR-6512-5p2.1480.0098
54miR-6514-3p118.2510.0109
55miR-6515-3p90.4460.0230
56miR-664b-3p64.3570.0080
57miR-6716-3p32.4620.0102
58miR-766-3p50.1400.0077
59miR-94055.3100.0220
60miR-952.0490.0035
61miR-1224-5p2.1150.0089
62miR-125a-3p3.4130.0113
63miR-1268a3.2350.0248
64miR-1268b2.0050.0016
65miR-12752.8760.0105
66miR-12872.0520.0077
67miR-12904.1050.0080
68miR-135a-3p40.3350.0211
69miR-188-5p2.4680.0370
70miR-21-3p2.5900.0087
71miR-22-5p2.1100.0112
72miR-221-3p2.2930.0099
73miR-221-5p2.1740.0115
74miR-3135b3.4590.0063
75miR-36482.1350.0061
76miR-36563.4380.0124
77miR-3679-5p2.1050.0035
78miR-429886.9300.0039
79miR-44557.3430.0091
80miR-44592.0760.0022
81miR-44662.2090.0231
82miR-44852.0760.0103
83miR-44872.4460.0007
84miR-45323.1760.0176
85miR-46722.5120.0233
86miR-483-5p91.4040.0145
87miR-5001-5p2.0790.0069
88miR-574-5p3.5200.0201
89miR-57876.6420.0088
90miR-60873.0590.0121
91miR-642a-3p2.0420.0084
92miR-663a156.2000.0092

a |Fold change|>2 is listed; fold change equals resistance/parental.

Downregulation of miR-210 in CNE-2R cells and overexpression of miR-210 in CNE-2 cells

In order to determine the relationship between miR-210 and radioresistance, the authors transfected LV-hsa-miR-210 into CNE-2 cells (Fig. 2A), and transfected the LV-hsa-miR-210-inhibitor into CNE-2R cells (Fig. 2B). Following infection for 72 h, 95% of the CNE-2R cells and 95% of the CNE-2 cells expressed green fluorescent protein, as assessed with a fluorescence microscope. Next, the expressions of miR-210 in CNE-2R-miR-210-inhibitor and CNE-2-miR-210 cells were measured by RT-qPCR. The expression of miR-210 in CNE-2-miR-210 cells was significantly greater than CNE-2 cells (Fig. 3A; P<0.05), and the expression of miR-210 was significantly lower in CNE-2R-miR-210-inhibitor cells compared to CNE-2R cells (Fig. 3B; P<0.05). Consistent with these expected results, downregulation of miR-210 expression in CNE-2R cells and overexpression in CNE-2 cells was identified.

Correlation of miR-210 expression levels with cell cycle and apoptosis in tumor cells

Low expression of miR-210 in CNE-2 cells, there was a significant decrease in the percentage of cells in S phase, and a significant increase in the percentage of cells in G2/M phase, when compared with CNE-2-miR-210 cells (Fig. 4A; P<0.05). In addition to the low expression of miR-210 in CNE-2R-miR-210-inhibitor cells leading to a significant decrease in the percentage of cells in S phase, there was a significant increase in the percentage of CNE-2R-miR-210-inhibitor cells in G2/M phase when compared with the control CNE-2R cells (Fig. 4B, P<0.05). The authors exposed cells to 0 or 4 Gy of X-ray radiation, and apoptosis was measured by flow cytometry. The results of flow cytometry indicated that the apoptosis percentage of CNE-2-miR-210 cells was significantly lower than CNE-2 cells (Fig. 5A; P<0.05), and the apoptosis percentage of CNE-2R-miR-210-inhibitor cells was significantly greater than CNE-2R cells (Fig. 5B; P<0.05), following irradiation by 4 Gy. However, there were no significant differences in the percentages of apoptosis of these cells in the absence of irradiation (Fig. 5A and B).

miR-210 negatively regulates cell viability following irradiation

To determine whether miR-210 negatively regulates cell viability, a cell viability assay was used to determine the effect of miR-210 on cell viability with different doses of X-ray radiation of 0, 4, 8 and 12 Gy. The cell viability of CNE-2 cells was lower than CNE-2-miR-210 cells when they were radiated with 4, 8 and 12 Gy (Fig. 6A; P<0.05). The cell viability of CNE-2R cells was higher than CNE-2R-miR-210-inhibitor cells following being irradiated by 4, 8 and 12 Gy (Fig. 6B; P<0.05), demonstrating that suppression of miR-210 expression increased the viability of tumor cells.

miR-210 promotes the radioresistance of tumor cells

In order to identify and confirm that miR-210 promotes radioresistance of tumor cells, the authors irradiated CNE-2, CNE-2R, CNE-2-miR-210 and CNE-2R-miR-210-inhibitor cells with different doses of X-ray radiation of 0, 4, 8 and 12 Gy, and determined the cell survival using a colony formation assay (Fig. 7). As expected, the CNE-2 cells were more radiosensitive than CNE-2-miR-210 cells following X-ray treatment, and CNE-2R cells were more radioresistant than the CNE-2R-miR-210-inhibitor cells, confirming that miR-210 can promote radioresistance of tumor cells.

Target gene analysis

It was predicted that miRNAs exerted their functions via regulating the expression of the target genes miRbase (http://mirbase.org/index.shtml), miRecords (http://mirecords.biolead.org), Tarbase (http://microrna.gr/tarbase) and TargetScan (http://www.targetscan.org). There were many potential target genes, such as HIF-1α, CTR1A, ADAMTS5 and CAMTA1. In future studies, the authors will use the luciferase reporter to identify target genes, and western blot analyses to detect differences in the translation products of these target genes. Furthermore, it is planned to characterize the mechanism of target gene radiosensitivity.

Discussion

Radiotherapy has emerged as the most important treatment for tumor, because it inhibits tumor growth and prolongs patient survival (16,17). Radiotherapy, which primarily involves the induction of DNA damage, is the most common therapeutic method for many types of cancers (18). Numerous studies have reported that miRNAs are involved in the control of DNA damage or its repair mechanisms (19,20). In addition, miRNAs are involved in various malignant cell behaviors, including radioresistance (2124). miR-205, miR-7, miR-100 and miR-101 have been reported to be associated with tumor radioresistance (2528). For example, miR-218 is often absent in cervical cancer, which sensitizes human cervical cancer cells to radiotherapy by promoting apoptosis (29). miR-148b increases the radiosensitivity of non-Hodgkin lymphoma (NHL) cells via enhancing radiation-induced apoptosis, which reported that miR-148b serves a significant role in the response of NHL to radiation (30). miR-504 is downregulated following radiotherapy of NPC, which can be regarded as a new radioresistant biomarker to monitor the tumor response to radiation treatment (31). Taken together, these studies have indicated that miRNAs are crucial in mediating the radioresistance to cancer. However, there have been few reports of the possible role of miR-210 in radiation resistant tumor cells. Therefore, the objective of the present study was to investigate the possible correlation between miR-210 and the radiosensitivity of tumor cells.

The results demonstrated that miR-210 induced cell cycle arrest, and cells that had high expressions of miR-210 in the S phase were significantly decreased while the percentage of cells in G2/M phase increased. There are significant differences in the radiosensitivity of cells in the cell cycle. The radiosensitivity of the G2/M phase is high, and the S phase is the most radioresistant (32). In addition, increased expression of miR-210 suppressed cell apoptosis. Similar to the trends observed for cell viability, the higher the expression level of miR-210, the higher the cell viability after irradiation. The colony formation assay confirmed that tumor cells with high levels of miR-210 were less sensitive to radiation. Based on these results, the expression of miR-210 is inversely correlated with the radiosensitivity of tumor cells.

However, the radiation resistance mechanism of miR-210 remains unclear (33). It has been reported that vascular endothelial growth factor (VEGF) is one of the targets of miRNA-210 (34). VEGF can contribute to tumorigenesis, by promoting angiogenesis and enhancing the blood supply (35). Moreover, miR-210 has been reported to be the most highly induced miRNA in hypoxic cells (36), and hypoxia reduces the radiosensitivity of tumor cells both in vitro and in vivo (37). Previous studies have reported that some miRNAs can regulate the DNA damage response to radiation and participate in DNA repair pathways (38,39), but the mechanisms involved in radioresistance, angiogenesis, apoptosis, cell cycle control and DNA damage/repair are still unknown. Further studies are needed to identify the binding sites of miR-210 and characterize signaling pathways of miR-210.

Taken together, the presented findings provide insight into improving tumor radiosensitivity, and strongly suggest that miR-210 expression is negatively associated with the radiosensitivity of tumor cells. In addition, the results demonstrated that miR-210 may be used to predict the therapeutic effects of radiotherapy in cancer patients, suggesting that miR-210 could be a prognostic biomarker for cancer patients with radiotherapy, and may provide novel insights into the identification of therapeutic targets.

Acknowledgments

The current work was supported by Natural Science Foundation Project of Chongqing (grant no. cstc2012jjA10138), and the Oncology of National Clinical Specialist Project (grant no. [2013] 544).

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August-2017
Volume 16 Issue 2

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Online ISSN:1791-3004

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Copy and paste a formatted citation
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Spandidos Publications style
Li BY, Luo Y, Zhao WS, Zhang L, Zhou HJ, Zou YC and Zhang T: MicroRNA‑210 negatively regulates the radiosensitivity of nasopharyngeal carcinoma cells. Mol Med Rep 16: 1401-1408, 2017.
APA
Li, B., Luo, Y., Zhao, W., Zhang, L., Zhou, H., Zou, Y., & Zhang, T. (2017). MicroRNA‑210 negatively regulates the radiosensitivity of nasopharyngeal carcinoma cells. Molecular Medicine Reports, 16, 1401-1408. https://doi.org/10.3892/mmr.2017.6694
MLA
Li, B., Luo, Y., Zhao, W., Zhang, L., Zhou, H., Zou, Y., Zhang, T."MicroRNA‑210 negatively regulates the radiosensitivity of nasopharyngeal carcinoma cells". Molecular Medicine Reports 16.2 (2017): 1401-1408.
Chicago
Li, B., Luo, Y., Zhao, W., Zhang, L., Zhou, H., Zou, Y., Zhang, T."MicroRNA‑210 negatively regulates the radiosensitivity of nasopharyngeal carcinoma cells". Molecular Medicine Reports 16, no. 2 (2017): 1401-1408. https://doi.org/10.3892/mmr.2017.6694