Long non‑coding RNA MCM3AP‑AS1 drives ovarian cancer progression via the microRNA‑143‑3p/TAK1 axis
Retraction in: /10.3892/or.2021.8129
- Authors:
- Published online on: July 17, 2020 https://doi.org/10.3892/or.2020.7694
- Pages: 1375-1384
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Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Ovarian cancer (OC) is one of most common cancer types in women, with high morbidity and mortality worldwide (1). Despite the therapeutic advances aimed at more effectively treating OC in recent years, overall prognosis remains poor, and patients are often affected by either tumor recurrence or distant metastasis (2,3). It is thus essential that the molecular mechanisms governing OC are further characterized in order to identify novel diagnostic or therapeutic targets that can be utilized to better understand, prevent and treat this deadly disease.
Long non-coding RNAs (lncRNAs) are RNAs >200 nucleotides in length that largely lack the ability to encode for proteins (4). These lncRNAs play diverse biological roles in regulating essential processes, such as cell proliferation, cell cycle progression, cancer development and cell death (5,6). Numerous lncRNAs are relevant in the context of cancer, and some act as suppressors or promoters of tumor progression in OC, which makes these molecules potential diagnostic and/or therapeutic targets in patients with OC (7,8). MCM3AP anti-sense RNA 1 (MCM3AP-AS1) is an oncogenic lncRNA that was found to promote the progression of non-small cell lung cancer, hepatocellular carcinoma, glioblastoma and papillary thyroid cancer (9–13). Whether this lncRNA is important in the context of OC remains uncertain. The present study assessed the expression, clinical relevance, biological function and molecular mechanisms of MCM3AP-AS1 in OC.
Materials and methods
Clinical samples
The Ethics Committee of the First Hospital of Jilin University (Changchun, China) approved this study, and the participants provided written informed consent. In total, 52 pairs of OC tumors and adjacent non-tumor tissues were collected between March 2013 and March 2014 at the First Hospital of Jilin University. None of the patients had undergone anticancer treatments prior to surgical resection. Two histopathologists independently confirmed all tissue specimen results. All tissue samples were immediately snap-frozen in liquid nitrogen after surgery and subsequently stored at −80°C until use. The patient demographic and clinicopathological features are listed in Table I.
 | Table I.Association of MCM3AP-AS1 expression with the clinicopathologic factors of the 52 patients with OC. |
Cell culture and transfection
Two human OC cell lines (SKOV3 and A2780) and a human ovarian surface epithelial cell line HOSEpiCs were purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA). DMEM (Gibco; Thermo Fisher Scientific, Inc.) containing 10% FBS (Gibco; Thermo Fisher Scientific, Inc.), 100 mg/ml streptomycin and 100 U/ml penicillin was used for all cell cultures at 37°C in a humidified 5% CO2 incubator.
For short hairpin RNA (shRNA) transfection, an shRNA plasmid directly targeting MCM3AP-AS1 (sh-MCM3AP-AS1; 5′-GGGAGUAAGUGAAAGUAAU-3′) as well as an appropriate non-targeting plasmid used as a negative control (NC) (sh-NC; 5′-UUCUCCGAACGUGUCACGU-3′) were produced by Sangon Biotech Co., Ltd.) In addition, Shanghai GenePharma Co., Ltd. provided microRNA (miRNA or miR)-143-3p mimics, NC mimics (miR-NC) and the miR-143-3p inhibitor (miR-143-3p in). SKOV3 cells underwent transient transfection with the abovementioned constructs using Lipofectamine 3000 (Invitrogen; Thermo Fisher Scientific, Inc.) based on the provided protocols, and the efficiency of transfection was assessed at 48 h after transfection by reverse transcription-quantitative PCR (RT-qPCR).
RT-qPCR
TRIzol (Invitrogen; Thermo Fisher Scientific, Inc.) was utilized for total RNA extraction from samples, and RNA was then used for RT with TransScript First-Strand cDNA Synthesis SuperMix (TransGen Biotech Co., Ltd.). Subsequently, SYBR Green qPCR SuperMix (Applied Biosystems; Thermo Fisher Scientific, Inc.) was used for quantification of relative gene expression on an ABI Prism 7900 System (Applied Biosystems; Thermo Fisher Scientific, Inc.). Reaction conditions were: 95°C for 1 min, 40 cycles of 95°C for 30 sec and 58°C for 40 sec. The 2−ΔΔCq method was used to compare relative expression following normalization to U6 for miR-143-3p or to GAPDH for MCM3AP-AS1. The primer sequences are presented in Table II.
Cell Counting Kit-8 (CCK-8) assay
Transfected cells were plated in 96-well plates (5×103 cells/well) for 24, 48 or 72 h. Subsequently, CCK-8 solution (Dojindo Molecular Technologies, Inc.) was added to these wells for an additional 2-h incubation. The absorbance of each well at 450 nm was then assessed with a microplate reader (Bio-Rad Laboratories, Inc.).
Colony formation assay
SKOV3 cells were seeded into 6-well plates 48 h post-transfection (500 cells/well). After 10 days of growth, the colonies underwent 4% paraformaldehyde fixation, followed by 0.1% crystal violet (Sigma-Aldrich; Merck KGaA) staining.
EdU incorporation assay
For this assay, an EdU kit (Roche Diagnostics) was utilized according to the manufacturer's instructions, and a Zeiss fluorescence photomicroscope (magnification, ×200; Carl Zeiss AG) was used for imaging and quantification of 5 random fields per sample.
Wound healing assay
To assess how MCM3AP-AS1-knockdown influenced cell migration, following transfection, cells were added to 12-well plates until becoming fully confluent. Next, a wound was generated in the cell monolayer using a micropipette tip. Cells were then allowed to grow in serum-free medium for 24 h, and were imaged at 0 and 24 h with an inverted microscope (magnification, ×100; Leica Microsystems, Inc.).
Transwell invasion assay
For assessment of cell invasion, 24-well plates containing Matrigel-coated chambers (8-µm pores; Corning Inc.) were used. Transfected cells in serum-free medium were added to the upper chamber, with normal medium containing 10% FBS being added to the lower chamber for chemoattraction. Following a 24-h incubation, the cells that had undergone invasion were then assessed via 20% methanol fixation and subsequent 0.1% crystal violet staining. The invasive cells in 5 random fields of view were quantified with an inverted microscope (magnification, ×200; Leica Microsystems, Inc.).
Luciferase reporter assays
Potential miRNAs interacting with MCM3AP-AS1 were predicted using starBase v2.0 (http://starbase.sysu.edu.cn/starbase2/), with miR-143-3p ultimately being selected for further investigation. Next, MCM3AP-AS1 fragments containing the putative miR-143-3p binding sites were produced by Guangzhou RiboBio Co., Ltd. and inserted into the psiCHECK2 vector (Promega Corp.), yielding the wild-type (WT)-MCM3AP-AS1 vector. In addition, a site-directed mutagenesis kit (Tiangen Biotech Co., Ltd.) was used to generate a mutated form of this vector termed mutant (MT)-MCM3AP-AS1. These vectors were then used in luciferase reporter assays, wherein cells were grown in 24-well plates and co-transfected with the WT or MT-MCM3AP-AS1 plasmids alongside appropriate miR-143-3p mimics or controls using Lipofectamine 3000. After 48 h, a Dual-Luciferase Reporter Assay (Promega Corp.) was employed to assess luciferase activity.
Subcellular fractionation
A PARIS Kit (Thermo Fisher Scientific, Inc.) was used to separate the nuclear and cytoplasmic fractions of SKOV3 cells according to the manufacturer's instructions. RT-qPCR was then used to assess U6, GAPDH and MCM3AP-AS1 expression in these fractions, with U6 serving as a nuclear control and GAPDH as a cytoplasmic control.
RNA immunoprecipitation (RIP) assay
After 48 h of transfection with appropriate miRNA mimics or controls, an anti-Argonaute2 (Ago2) antibody (cat. no. MABE253; EMD Millipore) and the Magna RIP RNA-Binding Protein Immunoprecipitation Kit (EMD Millipore) were used to conduct a RIP assay. A NanoDrop spectrophotometer (NanoDrop Technologies; Thermo Fisher Scientific, Inc.) was used to quantify the purified RNA concentration, and the resultant RNA was then used in RT-qPCR to assess the MCM3AP-AS1 and miR-143-3p expression levels.
Animal experiments
The Institutional Animal Care and Use Committee of Jilin University (Changchun, China) approved all the animal experiments conducted in our study. A total of 2×106 SKOV3 cells that had been stably transfected using either sh-MCM3AP-AS1 or sh-NC were resuspended in 100 µl of a 1:1 mixture of serum-free DMEM and Matrigel. These cells were then implanted subcutaneously into 5-week-old female nude BALB/c mice (n=5 mice/group, the Animal Laboratory Center of Jilin University). All mice were bred in standard mouse irradiated food and tap water ad libitum, and maintained under conditions of 25°C and 50% humidity with a 12-h light/dark cycle. Tumor growth was assessed using calipers on a weekly basis, with tumor volume (V) being determined as follows: V=0.5 × L × W2, with L and W being the tumor length and width, respectively. Tumors were allowed to grow for 5 weeks, and the animals were then anesthetized by intraperitoneal injection with 10% chloral hydrate (300 mg/kg), and were sacrificed using cervical dislocation. The xenografts were excised, and weighed, and the fragments were frozen at −80°C for RNA isolation. In addition, a number of tumor samples were used for Ki-67 immunostaining, as described in a previous report (14).
Statistical analysis
Data are represented as means ± SD from at least three replicates and analyzed with SPSS v19.0 (IBM Corp.). Continuous variables were compared via Student's t tests (two-tailed) and one-way analysis of variance (ANOVA) followed by the Tukey's post hoc test for 2 and ≥2 groups, respectively. The association between MCM3AP-AS1 expression and clinicopathological characteristics was assessed with χ2 test. Correlations were assessed with Pearson's correlation test. Survival curves were plotted using the Kaplan-Meier method and were analyzed using a log-rank test. GraphPad Prism 5 (Graph-Pad Software, Inc.) was used to generate graphs presenting the results. P<0.05 was considered to indicate a statistically significant difference.
Results
Increased MCM3AP-AS1 expression is positively correlated with OC progression
Our study first assessed MCM3AP-AS1 expression in 52 paired OC tissues and adjacent non-tumor control samples, revealing a significant elevation in the expression of this lncRNA in tumor samples (Fig. 1A). Consistent with this, when OC cell lines (SKOV3 and A2780) were examined, a significant increase compared with that in the human ovarian surface epithelial cell line HOSEpiC was observed (P<0.001 for SKOV3; P<0.01 for A2780; Fig. 1B). As SKOV3 cells expressed the highest levels of MCM3AP-AS1, these cells were used for all downstream experiments (Fig. 1B). To assess how MCM3AP-AS1 expression is associated with clinicopathological features in patients with OC, the median MCMAP3-AS1 expression level was used to separate patients into MCMAP3-AS1-high and -low expression groups. As shown in Table I, MCM3AP-AS1 expression was positively correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) staging (P=0.0030) and lymph node metastasis (0.0105) (Table I). In addition, Kaplan-Meier survival analysis revealed that MCM3AP-AS1-high patients had a significantly poorer overall survival than that of MCM3AP-AS1-low patients (P=0.0261; Fig. 1C). These findings suggest a possible key role for MCM3AP-AS1 in OC progression.
Knockdown of MCM3AP-AS1 disrupts OC cell proliferation
To knockdown this lncRNA in OC cells, a shRNA specific for MCM3AP-AS1 was transfected into SKOV3 cells, leading to a significant decrease in MCM3AP-AS1 expression, as expected following targeted shRNA transfection when compared to the sh-NC group (Fig. 2A). After knockdown of this lncRNA, CCK-8 assay was used to measure cell proliferation, revealing that the proliferative activity of SKOV3 cells was significantly decreased after MCM3AP-AS1 knockdown when compared to the sh-NC group (P<0.01 at 72 h) (Fig. 2B). Colony formation assay yielded comparable results (Fig. 2C). EdU assay was able to further confirm a marked decrease in SKOV3 cell proliferation following sh-MCM3AP-AS1 transfection in contrast to sh-NC transfection (Fig. 2D). These results confirmed that a reduction in MCM3AP-AS1 expression was able to impair OC proliferation.
Knockdown of MCM3AP-AS1 disrupts OC cell migration and invasion
Wound healing and Transwell invasion assays were next used to assess how MCM3AP-AS1 knockdown influences the ability of SKOV3 cells to undergo migration and invasion, respectively. The results revealed that reduced MCM3AP-AS1 expression significantly impaired the cell migration (Fig. 3A) and invasion (Fig. 3B) activities when compared to the sh-NC group (P<0.01).
MCM3AP-AS1 directly targets miR-143-3p in OC cells
Our study next used starBase 2.0 in order to predict miRNAs that have the potential to directly bind MCM3AP-AS1 based on their complementarity. This predictive analysis identified miR-143-3p as one such putative MCM3AP-AS1-binding miRNA (Fig. 4A). This was confirmed via luciferase reporter assays, which revealed a significant decrease in WT but not in MT MCM3AP-AS1 luciferase reporter activity upon miR-143-3p overexpression in SKOV3 cells (P<0.01; Fig. 4B). Our study next assessed the expression of MCM3AP-AS1 in the nuclear and cytoplasmic fractions of SKOV3 cells to evaluate its potential to serve as a ceRNA for miR-143-3p, and the results indicated that it was primarily located within the cytoplasm (Fig. 4C). RIP assay additionally confirmed that MCM3AP-AS1 and miR-143-3p were more abundant in Ago2 pellets than in IgG pellets prepared from SKOV3 cells (Fig. 4D). In addition, knockdown of MCM3AP-AS1 expression led to a significant increase in the miR-143-3p level in SKOV3 cells when compared to the sh-NC group (P<0.01; Fig. 4E). We also detect the expression of miR-143-3p in SKOV3 cells transfected with miR-143-3p mimic (miR-143-3p) or miR-143-3p inhibitor (in), and found that transfection with the miR-143-3p mimic significantly increased miR-143-3p expression (P<0.01; Fig. 4F), while transfection with the inhibitor significantly decreased miR-143-3p expression in SKOV3 cells when compared with the relevant NC group (P<0.01; Fig. 4F). When miR-143-3p was overexpressed, this was associated with a significant decrease in MCM3AP-AS1 expression (P<0.01; Fig. 4G). Moreover, reduced miR-143-3p expression levels were further observed in OC tissues (Fig. 4H), and this expression in tissue samples was negatively correlated with that of MCM3AP-AS1 (Fig. 4I), consistent with a role for miR-143-3p as an MCM3AP-AS1 target in OC cells.
Inhibition of miR-143-3p is a mechanism by which MCM3AP-AS1 influences OC progression
Our study next assessed whether inhibition of miR-143-3p activity might be a mechanism by which MCM3AP-AS1 affects OC cells. For that purpose, rescue experiments were conducted in SKOV3 cells co-transfected with sh-MCMAP-AS1 and miR-143-3p inhibitors. MCM3AP-AS1 downregulation led to an increase in miR-143-3p expression that was partially reversed by miR-143-3p inhibition (Fig. 5A). It was also found that, when miR-143-3p expression was inhibited in the rescue experiments, the ability of MCM3AP-AS1 downregulation to impair the proliferation, migration and invasion of SKOV3 cells was markedly attenuated (Fig. 5B-F).
Transforming growth factor-β-activated kinase 1 (TAK1) is known to be a miR-143-3p target gene in the context of OC (15). Therefore, our study sought to assess whether MCM3AP-AS1 might regulate TAK1 expression in OC cells. Indeed, when MCM3AP-NS1 expression was knocked down in SKOV3 cells, TAK1 expression was significantly decreased, whereas this was partially reversed by miR-143-3p inhibition (Fig. 5G). OC tissue samples also exhibited increased TAK1 expression (Fig. 5H), with this expression being positively correlated with MCM3AP-AS1 expression in OC tissues (Fig. 5I). This suggested that MCM3AP-AS1, at least in part, exerts its influence on OC via the miR-143-3p/TAK1 axis.
MCM3AP-AS1 knockdown inhibits tumor growth in vivo
The influence of MCM3AP-AS1 on OC was explored in vivo using a xenograft model in which mice were injected with SKOV3 cells stably expressing either sh-MCM3AP-AS1 or sh-NC. A significant reduction in tumor growth was observed for tumors in which MCM3AP-AS1 had been knocked down relative to control tumors, with a significantly smaller tumor weight at the end of the study (Fig. 6A-C). In addition, Ki-67 staining confirmed a reduction in tumor proliferation in MCM3AP-AS1-knockdown tumors, as evidenced by reduced expression of this proliferative marker (Fig. 6D). RT-qPCR was further used to assess the expression of MCM3AP-AS1, miR-143-3p and TAK1 in these tumor samples. The results revealed decreased expression of MCM3AP-AS1 and TAK1 in the sh-MCM3AP-AS1 group, along with a corresponding increase in miR-143-3p expression relative to that of the sh-NC group (Fig. 6E). These results suggested that depleting MCM3AP-AS1 expression can significantly constrain tumor growth in vivo.
Discussion
A substantial body of evidence supports a role for long non-coding (lnc)RNAs in the regulation of tumor progression and development, with lncRNAs such as MALAT1, HOXA11-AS and UAC1 having previously been shown to promote ovarian cancer (OC) progression (7,8), while others such as TUG1, BANCR and H19 having been reported to play a tumor-suppressive role (16,17). Previous studies have demonstrated that MCM3AP-AS1 can promote the progression of several tumor types (9–13). However, the role of MCM3AP antisense 1 (MCM3AP-AS1) in OC remains to be investigated. In this study, a clear upregulation of this lncRNA was observed in OC tissue samples and cells, with tissue expression being associated with a poorer prognosis. When MCM3AP-AS1 was knocked down, it constrained tumor growth in vitro and in vivo. MCM3AP-AS1 was able to drive OC progression at least in part by regulating miR-143-3p. Our results clearly demonstrate that MCM3AP-AS1 plays an oncogenic role in OC.
Numerous lncRNAs have been shown to regulate diverse biological processes by serving as ceRNAs capable of binding and sequestering specific target miRNAs (18–20). Using predictive bioinformatics techniques, our study identified miR-143-3p as a miRNA likely to bind MCM3AP-AS1, which was confirmed by dual-luciferase reporter assays. Thus, it was hypothesized that MCM3AP-AS1 may serve as a ceRNA for this target miRNA. To confirm this hypothesis, the subcellular localization of MCM3AP-AS1 was additionally assessed, revealing that it was expressed primarily in the cytoplasm of SKOV3 cells. RIP assays additionally confirmed a direct binding interaction between MCM3AP-AS1 and miR-143-3p, consistent with the role of MCM3AP-AS1 as a miR-143-3p ceRNA that binds and sequesters this miRNA. miR-143-3p has previously been shown to act as a tumor suppressor in several tumor types (21–23). Decreased miR-143-3p expression has been detected previously in OC tissues and cell lines, and overexpression of this miRNA suppresses the growth and metastasis of OC tumors in vitro and in vivo (15,24). In line with these previous findings, our study observed decreased miR-143-3p levels in OC tissues and cell lines, and found this expression to be negatively correlated with that of MCM3AP-AS1 in OC tissue samples. Importantly, inhibition of miR-143-3p partially abrogated the inhibition of proliferation and migration observed in SKOV3 cells upon MCM3AP-AS1 knockdown. Together, these findings suggest that MCM3AP-AS1 knockdown inhibits OC growth by regulating miR-143-3p expression.
The role of lncRNAs as ceRNAs allows them to indirectly control the expression of target genes of miRNAs (21–23). Transforming growth factor-β-activated kinase 1 (TAK1) has previously been reported as a miR-143-3p target in OC cells (15). TAK1, a member of the MAP kinase kinase kinase (MAP3K) family, was reported to participate in various cellular processes by regulating several signaling pathways, including the p38MAPK and NF-κB pathways, which play critical roles in cell survival and proliferation (25,26). TAK1 overexpression can promote the progression of several cancer types, and is considered a key therapeutic target in multiple types of cancer (27,28). In OC tissues, TAK1 has been found to be overexpressed, and its knockdown suppresses the growth and metastasis of OC cells (15,29,30). In line with these findings, our study observed increased TAK1 expression in OC samples, which was positively correlated with that of MCM3AP-AS1. Knockdown of MCM3AP-AS1 was associated with a marked decrease in TAK1 expression in these cells, and this could be partially reversed by inhibiting miR-143-3p. This suggests that, by acting as a miR-143-3p ceRNA, MCM3AP-AS1 is able to regulate TAK1 expression.
In summary, the present study revealed that MCM3AP-AS1 expression was upregulated in OC samples and cell lines, and that the levels are positively associated with advanced FIGO stage, lymph node metastasis and poor overall survival. MCM3AP-AS1 knockdown caused a conspicuous inhibition of proliferation and migratory activity in OC cells in vitro, as well as suppression of xenograft tumor growth in vivo. MCM3AP-AS1 exerted its oncogenic role in OC by regulating the miR-143-3p/TAK1 axis. Further research is required using additional OC cell lines in order to confirm the biological relevance of these findings, and to validate MCM3AP-AS1 as a potential therapeutic target.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used during the present study are available from the corresponding author upon reasonable request.
Authors' contributions
YW conceived and designed the study. JW and SH performed the experiments and wrote the manuscript. MC reviewed and edited the study.
Ethics approval and consent to participate
The Ethics Committee of the First Hospital of Jilin University (Changchun, China) approved this study, and the participants provided written informed consent. In addition, The Institutional Animal Care and Use Committee of Jilin University (Changchun, China) approved all the animal experiments conducted in our study.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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