Promotional effect of microRNA-194 on breast cancer cells via targeting F-box/WD repeat-containing protein 7

  • Authors:
    • Yaomin Chen
    • Haiyan Wei
    • Yu Liu
    • Shusen Zheng
  • View Affiliations

  • Published online on: January 23, 2018     https://doi.org/10.3892/ol.2018.7842
  • Pages: 4439-4444
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations

Abstract

Breast cancer is the most common type of malignant cancer in females. An increasing number of studies have revealed that microRNAs (miR), which belong to a class of small non‑coding RNAs, serve an important role in a number of human cancer subtypes. In the present study, the role of miR‑194 in breast cancer cells and its underlying mechanisms were investigated. The results demonstrated that the serum levels of miR‑194 were significantly higher in patients of the poorly differentiated and well‑differentiated groups, compared with in healthy adults. Additionally, the serum level of miR‑194 was significantly higher in the poorly differentiated group compared with in the well‑differentiated group. In order to further investigate the role of miR‑194 in breast cancer cells, the present study transfected two breast cancer cell lines, MCF‑7 and MDA‑MB‑231, with an empty vector (control), miR‑194 (overexpression), antagomiR‑194 (inhibitor, functional knock down) or antagomiR‑194 and miR‑194. An MTT assay was performed in order to detect the proliferation of breast cancer cells in the various groups. The results revealed that the overexpression of miR‑194 significantly accelerated cell proliferation, whereas the inhibition of miR‑194 significantly decelerated the proliferation of MCF‑7 and MDA‑MB‑231 cells. Furthermore, the expression levels of cyclin D and cyclin E were significantly upregulated in miR‑194 overexpressing cells, and the expression levels of cyclin D and cyclin E were significantly downregulated in miR‑194 inhibited cells, as compared with in control cells. No significant change was observed in the level of proliferation of cells co‑transfected with miR‑194 and antagomiR‑194, compared with in the control cells. According to the hypothesis suggesting possible target genes of miR‑194, the present study proposed that F‑box/WD repeat‑containing protein 7 (Fbxw‑7) may be a direct target of miR‑194, which was confirmed by a luciferase reporter assay. The present study suggested that miR‑194 expression promoted the proliferation of breast cancer cells by targeting Fbxw‑7, and may serve as a biomarker and a novel target for breast cancer therapy.

Introduction

Breast cancer is the most commonly occurring type of cancer in females, and excessive proliferation of tumor cells is an important factor affecting the prognosis of breast cancer (1,2). In recent years, an increasing number of studies have demonstrated that microRNAs (miRNA/miR) are involved in the diagnosis, treatment and prognosis of breast cancer (35), including a large-scale scientific investigation into molecular biological markers for monitoring the tumor progression, diagnosis or therapy (6,7). Previous studies have revealed that miR-194 is highly expressed in numerous types of human breast cancer and radiation-induced breast cancer (8,9); however, the underlying mechanisms require further investigation.

F-box/WD repeat-containing protein 7 (Fbxw-7), is a tumor suppressor that has been demonstrated to regulate several oncoproteins (10) including, cyclin D, cyclin E (1113), c-Myc (14,15), aurora kinase A (16), Notch (1720) and the proto-oncogene c-Jun (21,22) c-Jun, an extensively-studied member of the JUN family, has been associated with cell proliferation, tumor cell survival and apoptosis (23). Therefore, it is important to investigate the Fbxw-7-associated signaling pathways involved in the proliferation of breast cancer. Previous studies have focused on the signal factors for the expression of Fbxw-7 prior to and following its transcription (24,25). It has previously been revealed that the Fbxw-7 gene may be suppressed due to methylation of its promoter region (26). In addition, it has been demonstrated that miR-223 serves a critical role in human gastric cancer by targeting Fbxw-7 (27). These studies suggest that Fbxw-7 is important in human types of cancer for its interactions with alternative genes.

The present study demonstrated that the serum expression levels of miR-194 were significantly higher in patients with breast cancer compared with in healthy adults. Additionally, the overexpression of miR-194 significantly inhibited the proliferation of breast cancer cells by directly targeting the 3′-untranslated region (3′-UTR) of Fbxw-7 and by regulating the cell cycle. Overall, the results of the present study demonstrated that miR-194 expression has a significant impact on the progression of breast cancer and may be a potential therapeutic target for breast cancer.

Materials and methods

Patients and samples

Blood samples were obtained by EDTA vacutainer blood collection tubes (BD Biosciences, Franklin Lakes, NJ, USA) and immediately stored at −80°C from 43 patients with breast cancer (aged 18–80 years) at the First Affiliated Hospital of Zhejiang University (Hangzhou, China) between April 2013 and April 2015. The samples were immediately stored at −80°C until use. All of the patients were female and >18 years old. A total of 26 of the patients were identified to have well differentiated breast cancer (grade I–II) and 17 had poorly differentiated breast cancer (grade III). A total of 20 healthy adults were recruited from the First Affiliated Hospital of Zhejiang University to participate in the study as the control group. The Ethics Committee of The First Affiliated Hospital of Zhejiang University approved the present study. Written informed consent was obtained from all participants included in the study.

Cell lines

Two breast cancer cell lines, MCF-7 and MDA-MB-231, were obtained from the American Type Culture Collection (Manassas, VA, USA). They were cultured in Dulbecco's modified Eagle's medium (DMEM) with high glucose (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA), supplemented with 10% fetal bovine serum (FBS) and 100 U/ml penicillin and 100 µg/ml streptomycin, at 37°C in 5% CO2.

Transfection of miRNA or the inhibitor

Breast cancer cells were seeded in a 24-well plate with a density of 4×104 cells/well and cultured for 24 h at 37°C prior to transfection. Subsequently, the cells were starved for 1 h at 37°C using FBS-free medium without antibiotics. Transfection with the negative control oligonucleotides (NC mimic), miR-194, antagomiR-194 or miR-194/antagomiR-194 was performed using Lipofectamine® 2000 reagent (Invitrogen; Thermo Fisher Scientific, Inc.), according to the manufacturer's instructions. Briefly, 0.5 µg miRNA was diluted with 100 µl Opti-MEM (Thermo Fisher Scientific, Inc.) without FBS, which was mixed with 1.25 µl Lipofectamine® LTX reagent (Invitrogen; Thermo Fisher Scientific, Inc.). The mixture (containing the transfection reagents) was incubated for 25 min at room temperature, and then added to wells containing cells and incubated at room temperature for 4 h. Following 48 h transfection at 37°C, the cells from the various groups were seeded (1×104 cells/ml) onto 96-well plates in triplicate, and then cultured at 37°C for 24 h.

RNA isolation and reverse transcription-polymerase chain reaction (RT-PCR)

Total RNA was isolated from breast cancer cell lines using TRIzol® (Invitrogen; Thermo Fisher Scientific, Inc.), chloroform, isopropanol and ethanol, following the manufacturer's instructions. The isolated RNA, including miRNA, was dissolved in 30 µl diethyl pyrocarbonate-treated (high temperature sterilization at 121°C for 20 min) water. In order to detect the serum levels of miR-194, the total RNA was transcribed into cDNA using the miScript II RT kit (Qiagen GmbH, Hilden, Germany). cDNA was synthesized with the Prime-Script RT reagent kit (Takara Bio Inc., Otsu, Japan) from 500 ng of total RNA. RT-PCR was performed in triplicate using Fast SYBR® Green Master Mix (Thermo Fisher Scientific, Inc.), according to the manufacturer instructions of the ABI Prism® 7900HT Sequence Detection System (Applied Biosystems; Thermo Fisher Scientific, Inc.). The primer pairs for miR-194 were as follows: Forward, 5′-CTAAGCTTAGTGGGCATGGGACACTCT-3′ and reverse, 5′-CTGAATTCACCTGCCTCTCCTTCTTCGT-3′. U6 was used as an internal control. The primers for U6 were as follows: Forward, 5′-CTCGCTTCGGCAGCACA-3′ and reverse, 5′-AACGCTTCACGAATTTGCGT-3′. The PCR reaction conditions were as follows: 95°C for 5 min heating; 40 cycles of 95°C for 10 sec; 59°C for 40 sec; and 72°C for 1 min for application. The 2−∆∆Cq method was used for quantification of the relative expression levels of miR-194 in the samples of various groups (28).

Western blot analysis

Total protein was extracted from breast cancer cell lines following a 48-h transfection using the ProteoPrep® Total Extraction Sample kit (Sigma-Aldrich; Merck Millipore, Darmstadt, Germany). The protein concentrations were evaluated using an enhanced Bicinchoninic Acid assay kit (Beyotime Institute of Biotechnology, Haimen, China), according to the manufacturer's instructions. Equal concentrations of the extracted proteins and the 5X SDS-PAGE sample loading buffer were then heated at 95°C for 10 min. Equal quantities of the protein samples (25 µg/lane) were loaded onto the gel for 10% SDS-PAGE. Subsequently, the proteins were transferred to a polyvinylidene fluoride membrane. Following washing with TBS and Tween-20, the membranes were blocked with 5% nonfat milk and 1% Tween-20 in TBS at room temperature for 2 h, and subsequently incubated with the following primary antibodies: Anti-Fbxw-7 (cat. no. ab74054; 1:1,000), anti-cyclin D (cat. no. ab7958; 1:500), anti-cyclin E (cat. no. ab7958; 1:500) and β-actin (cat. no. ab8227; 1:5,000). All primary antibodies were purchased from Abcam (Cambridge, UK). Following washing with TBST three times, the membranes were incubated with the corresponding anti-rabbit IgG (cat. no. A0545; 1:20; Sigma-Aldrich; Merck KGaA) conjugated with horseradish peroxidase (OriGene Technologies, Inc., Rockville, MD, USA) for 1.5 h at room temperature. The membranes were visualized using an enhanced chemiluminescence kit (Pierce; Thermo Fisher Scientific, Inc.).

MTT assay

Breast cancer cells (1×104 cells/well) in the various groups were seeded into a 96-well plate with 100 µl of medium/well. The cells were plated in quintuplicate each day. Following culture at 37°C for 24 h, 20 µl MTT solution (5 mg/ml; Invitrogen; Thermo Fisher Scientific, Inc.) was added to each well and incubated at 37°C for 4 h. Subsequently, the supernatant in each well was removed and 150 µl dimethyl sulfoxide was added in order to dissolve the formazan crystals. The absorbance wavelengths were read at 570 nm with a microplate spectrophotometer. The cell growth curve in each group was drawn according to the optical density values.

Bioinformatic predictions and luciferase assay

The prediction of the miR-194 target genes was performed using TargetScan version 3.1 (29). The results revealed that the 3′-UTR of Fbxw-7 is complementarily base paired with miR-194. In order to confirm the prediction, a luciferase assay was performed. Briefly, 293T cells were seeded (1×104 cells/ml) in a 6-well plate and incubated at room temperature for 24 h. Subsequently, the cells divided into 3 groups and co-transfected with PGL3-Fbxw-7 3′UTR, miR-194 or an NC mimic using Lipofectamine® 2000. Following 40 h, the medium in each well was discarded and 500 µl cell lysis solution was added. Following lysis, the supernatant was centrifuged at 15,000 × g for 5 min at room temperature. A total of 100 µl luciferase assay reagent (Promega Corporation, Madison, WI, USA) was added into 100 µl supernatant from each well. The relative intensity of fluorescence was determined using a multifunctional microplate reader (Tecan Group, Ltd., Mannedorf, Switzerland) with 2 sec measurement intervals at an absorbance wavelength of 366 nm and 10 sec measurement duration.

Statistical analysis

All data were analyzed using SPSS 16.0 (SPSS, Inc., Chicago, IL, USA). Data are presented as the mean ± standard deviation. The miR-194 expression levels and MTT data were statistically analyzed using a two-tailed Student's t-test. P<0.05 was considered to indicate a statistically significant difference.

Results

miR-194 expression associated with the differentiation degree of breast cancer

In order to explore the association between miR-194 expression levels and breast cancer, total RNA was extracted from the sera of 20 healthy adults, 26 patients with well differentiated breast cancer and 17 patients with poorly differentiated breast cancer. The results indicated that the serum expression levels of miR-194 were significantly higher in the well differentiated group (P<0.05; Fig. 1) and the poorly differentiated group (P<0.05; Fig. 1), as compared with in the control group. Additionally, the serum expression level of miR-194 was significantly higher in the poorly differentiated group, as compared with in the well differentiated group (P<0.01; Fig. 1). Therefore, the serum expression level of miR-194 was closely associated with the differentiation degree of breast cancer, suggesting that miR-194 may be involved in the progression of breast cancer.

miR-194 expression enhances the proliferation of breast cancer cells

In order to determine the effect of miR-194 expression on breast cancer cell proliferation, MCF-7 and MDA-MB-231 breast cancer cell lines were transfected with the control, miR-194, antagomiR-194 or miR-194/antagomir-194. Following a 48-h transfection, the cells from the various groups were seeded into a 96-well plate in triplicate, and then cultured for 24 h. Subsequently, an MTT assay was performed in order to determine the proliferation rate of breast cancer cells in the various groups. The results demonstrated that the overexpression of miR-194 significantly enhanced the proliferation of MCF-7 (P<0.01; Fig. 2) and MDA-MB-231 cells (P<0.01; Fig. 2). Additionally, the inhibition of miR-194 expression significantly decreased the proliferation of MCF-7 (P<0.005; Fig. 2) and MDA-MB-231 cells (P<0.005; Fig. 2). No significant change was observed in the proliferation of cells co-transfected with miR-194 and antagomiR-194 (Fig. 2).

miR-194 may directly target its downstream gene, Fbxw-7, in breast cancer cells

According to the bioinformatic database (Targetscan) analysis and a previous study (30), Fbxw-7 may be a potential target of miR194. The binding sites for miR-194 were detected in the 3′-UTR of Fbxw-7, and were highly conserved and consistent between rats, mice and humans (Fig. 3A). Subsequently, the present study performed a luciferase assay to confirm the prediction made using the results of the Targetscan analysis. The assay results revealed that luciferase activity was significantly reduced in breast cancer cells with overexpressed miR-194, compared with in the control cells, following transfection of PGL3-Fbxw-7 3′UTRs (P<0.005; Fig. 3B).

miR-194 promotes the expression levels of cyclin D and cyclin E and inhibits the expression level of Fbxw-7

It has previously been reported that the inhibition of Fbxw-7 may increase cell proliferation by increasing the number of ESCC cells in the S phase and decreasing the number of ESCC cells in the G1/G0 phase (31). The present study performed western blot analysis in order to determine the expression levels of the cyclin proteins, cyclin D and cyclin E. The results revealed that miR-194 expression inhibited the expression of Fbxw-7, which additionally significantly increased the expression levels of cyclin D and cyclin E in MCF-7 (P<0.05, Fig. 4A) and MDA-MB-231 cells (P<0.05, Fig. 4B).

Discussion

Previous studies demonstrated that various expression levels of miRNA have been identified in cancer tissues (6,32). miRNA may have clinical applications for use as a targeted therapy or for molecular diagnosis and prognosis (5,7). The regulatory mechanisms underlying miRNA function in breast cancer have previously been studied (4,3335).

miR-194 was first identified as a suppressor gene in the hepatic epithelial cells of mice by inhibiting the metastasis of liver cancer cells (36). In addition, in cancer of the gut (37,38) and kidney (39), miR-194 served a similar inhibitory role. By contrast, it was suggested that miR-194 served a role in the promotion and progression of breast cancer (9) and pancreatic ductal adenocarcinoma (40). These studies indicated that miR-194 had various target genes (3140). Previous studies have demonstrated that miR-194 inhibited cell migration and invasion, which may have contributed to the anti-tumor activity of trastuzumab on HER2-overexpressing breast cancer cells (41,42). Iizuka et al (9) demonstrated that the expression level of miR-194 was increased in human breast cancer cell lines and a rat mammary cancer model induced by radiation. However, the downstream pathways of miR-194 in breast cancer are not currently known. Therefore, it is important to investigate its specific target genes in breast cancer in order to understand the regulatory mechanisms underlying miR-194.

In the present study, it was demonstrated that the E3 ubiquitin ligase Fbxw-7 was the target gene for miR-194 in breast cancer. The results of the bioinformatic prediction analysis revealed that miR-194 had 367 potential target genes, which may be associated with the numerous functions of miR-194 in a variety of cancer subtypes. According to the ranking results of the bioinformatic analysis and previous studies investigating breast cancer cell proliferation (41,42), the present study focused on the target gene of miR-194, Fbxw-7, which was identified by performing a luciferase assay. Furthermore, the present study demonstrated that miR-194 promoted the proliferation of breast cancer cells by targeting Fbxw-7 and upregulating the expression levels of cyclins D and E. Previous studies revealed that Fbxw-7 acted as a tumor suppressor gene in a number of cancer subtypes (16,43). The mutation or deletion of Fbxw-7 may induce the accumulation of cancer proliferation genes, including cyclin E, c-Myc and aurora kinase A (10). A previous study revealed that the expression level of Fbxw-7 was significantly reduced in colorectal cancer tissues compared with in normal tissues, and the inhibition of Fbxw-7 increased the proliferation of colorectal cancer cells (37). These results are similar to those of the present study. However, the expression level of miR-194 in the sera of patients with breast cancer of various differentiation grades was determined in the present study, and it was revealed that miR-194 expression is closely associated with the grade of breast cancer. The serum expression level of miR-194 was highest in patients with poorly differentiated breast cancer, which suggested that miR-194 may be a promising prognostic factor for breast cancer. In the present study, the inhibition of miR-194 expression by antagomiR-194 decreased the proliferation of breast cancer cells, which suggested that antagomiR-194 may be a potential therapeutic drug.

In conclusion, the present study indicated that miR-194 served an important role in the proliferation of breast cancer cells by directly inhibiting the expression of Fbxw-7 and regulating the cell cycle. As a result, miR-194 may be a potential therapeutic target for inhibiting the progression of breast cancer. Therefore, it is necessary for future studies to verify the clinical values of miR-194 and determine the effects of antagomiR-194 as a treatment for breast cancer.

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APA
Chen, Y., Wei, H., Liu, Y., & Zheng, S. (2018). Promotional effect of microRNA-194 on breast cancer cells via targeting F-box/WD repeat-containing protein 7. Oncology Letters, 15, 4439-4444. https://doi.org/10.3892/ol.2018.7842
MLA
Chen, Y., Wei, H., Liu, Y., Zheng, S."Promotional effect of microRNA-194 on breast cancer cells via targeting F-box/WD repeat-containing protein 7". Oncology Letters 15.4 (2018): 4439-4444.
Chicago
Chen, Y., Wei, H., Liu, Y., Zheng, S."Promotional effect of microRNA-194 on breast cancer cells via targeting F-box/WD repeat-containing protein 7". Oncology Letters 15, no. 4 (2018): 4439-4444. https://doi.org/10.3892/ol.2018.7842