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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 4  |  Page : 676-682

MicroRNA-30c inhibits metastasis of ovarian cancer by targeting metastasis-associated gene 1


1 Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
2 Clinical Medicine Research Centre, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China

Date of Web Publication13-Sep-2017

Correspondence Address:
Di Wang
Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_132_17

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 > Abstract 

Background: It is important to find reliable molecular markers or biological targets that associate with ovarian cancer (OC) metastasis for diagnosis and treatment. In this study, researchers investigated the regulated chain of microRNA-30c (miR-30c) and metastasis-associated gene 1 (MTA1) in OC tissues and cells.
Materials and Methods: Expression of miR-30c and MTA1 was detected with quantitative real-time polymerase chain reaction and immunohistochemistry in 33 OC and matched adjacent tissues. MiR-30c mimics were synthetized and transfected into SKOV3 cells to target MTA1. The wound healing and transwell assays were detected to observe migration and invasion of transfected OC cells.
Results: Compared with matching normal ovarian tissues, the MTA1 expression was upregulated and localized in the cytoplasm, and the expression of miR-30c was significantly reduced. The expression intensity of MTA1 was correlated with the Federation of Gynecology and Obstetrics stage, tumor grade, and metastasis of OC. Transfecting miR-30c mimics could significantly reduce the expression of MTA1 in SKOV3 cells and obviously inhibit the migration and invasion of SKOV3 cells.
Conclusion: MiR-30c and MTA1 abnormally expressed in OC, which may be related to metastasis of OC. In MiR-30c as a tumor suppressor gene, its expression in OC could lead to reduced expression of MTA1, which may be one of the mechanisms of metastasis of OC cells.

Keywords: Metastasis, metastasis-associated gene 1, microRNA-30c, ovarian cancer


How to cite this article:
Wang X, Qiu LW, Peng C, Zhong SP, Ye L, Wang D. MicroRNA-30c inhibits metastasis of ovarian cancer by targeting metastasis-associated gene 1. J Can Res Ther 2017;13:676-82

How to cite this URL:
Wang X, Qiu LW, Peng C, Zhong SP, Ye L, Wang D. MicroRNA-30c inhibits metastasis of ovarian cancer by targeting metastasis-associated gene 1. J Can Res Ther [serial online] 2017 [cited 2018 May 22];13:676-82. Available from: http://www.cancerjournal.net/text.asp?2017/13/4/676/214461

Xia Wang and Li-Wei Qiu co-first authors and contributed equally to this work.



 > Introduction Top


Ovarian cancer (OC) is the eighth most common cancer in women, leading the fifth cause of cancer death with over 140,000 numbers reported annually worldwide.[1],[2],[3] This high lethality is attributed to the fact that the early stage of OC is mostly asymptomatic; therefore, the disease often remains undiagnosed until cancer has already disseminated throughout the peritoneal cavity.[4],[5],[6] Approximately 70% of OC patients are diagnosed at the stage of Federation of Gynecology and Obstetrics (FIGO) III/IV with widespread cancer cells beyond ovaries or distant metastasis.[7],[8] Despite surgical and chemotherapeutic improvements, most patients may eventually relapse and have a poor prognosis after primary treatment.[9] Hence, finding reliable molecular markers or biological targets that associate with OC metastasis is essential for diagnosis and treatment.

MicroRNAs (miRNAs) have been recognized as a class of molecular regulators and potential therapeutic agents in a number of cancers.[10],[11],[12] miRNAs are short single-stranded noncoding RNAs (~21 nucleotides in length) which are able to negatively regulate gene expression by binding to complementary sites in the target messenger RNA (mRNA) at the 3' untranslated regions (UTR).[13] Several miRNAs have been shown to be implicated in metastasis and invasion of cancer including OC.[14],[15],[16]

MiR-30c is a member of the miR-30 family. Five distinct mature miRNA sequences are included in this family: miR-30a, miR-30b, miR-30d, miR-30e, and miR-30c.[17] Accumulating pieces of evidence indicate that the deregulation of miR-30c contributes to various malignant tumors, including breast cancer, endometrial cancer, lung cancer, and liver cancer.[18],[19],[20],[21] MiR-30c suppresses the tumor metastasis in these above-mentioned types of cancers by directly interacting with their corresponding targets. Nevertheless, relatively few studies have been available to report the implication of miR-30c in the metastasis and invasion of OC.

Metastasis-associated gene 1 (MTA1) was originally identified in a complementary DNA (cDNA) library screen of metastatic and nonmetastatic adenocarcinoma cell lines from rat mammary glands.[22] MTA1 is interesting in cancer biology because of its dual nature either as a corepressor or a coactivator, as well as its widespread overexpression in human cancers.[23] MTA1 is thought to play an essential role in the progression of OC because of its significant upregulation in OC tissues in advanced cancer stages and higher grading.[24] These findings indicate that MTA1 may be related to metastasis of OC; however, its exact underlying mechanism is not fully clear so far.

In our study, the researchers determined the abnormal expression of miR-30c on OC tissues and OC cell line. Furthermore, it has been investigated that the MTA1 was the target gene of miR-30c and the miR-30c-MTA1 regulatory chain played a crucial role in metastasis and invasion of OC. Consequently, miR-30c and MTA1 might both be potential biomarkers and therapeutic targets for OC prognosis and treatment.


 > Materials and Methods Top


Clinical materials

All clinicopathological data of 33 specimens of OC tissue and matched adjacent normal tissue from patients who underwent a curative resection at the Affiliated Hospital of Nantong University were collected. The specimens were immediately frozen in liquid nitrogen after surgical removal and stored at −80°C until further use. None of the patients received preoperative chemotherapy or radiotherapy. All tissue samples after operation were diagnosed as OC and analyzed the pathological characteristics by two experienced pathologists. The study protocol was approved by the Research Ethics Committee of Affiliated Hospital of Nantong University.

Metastasis-associated gene 1 immunohistochemical staining

The tissue sections were incubated with the antibody against MTA1 (Abcam Corporation, UK) at 1/10 dilution and 4°C overnight. The next day, the tissue sections were incubated with horseradish peroxidase-conjugated goat anti-mouse IgG, and the color was developed with the DAB Horseradish Peroxidase Color Development Kit (Maixin Biological Technology Ltd., China). Brown cytoplasmic and nuclear staining for MTA1 were considered as positive. For MTA1 protein assessment, immunoreactivity was evaluated using a semiquantitative scoring system for both staining intensity (0, negative staining; 1, weak staining; 2, moderate staining; and 3, intense staining) and percentage of positively stained cancer cells (0; 0%–5%; 1; 6%–25%; 2; 26%–50%; 3; 51%–75%; 4; ≥76%). The final staining score was the sum of the scores of staining intensity and percentage of positive cells and was further graded as follows: (0), 0–1; (1), 2–3; (2), 4–5; (3), 6–7.[25]

Cell lines and culture

Human OC SKOV3 cells (ATCC, USA) were cultured in RPMI-1640 medium (Thermo Fisher Scientific Inc., USA) supplemented with 10% fetal bovine serum (FBS) (Thermo Fisher Scientific Inc., USA) and 1% antibiotics (Beyotime, China) at 37°C and 5% CO2. The (normal) human ovarian surface epithelial cells HOSE (Bioleaf, China) were maintained in MCDB 105: Medium 199 (1:1, v/v) contained 10% FBS (Thermo Fisher Scientific Inc., USA) and 1% antibiotics (Beyotime, China) at 37°C and 5% CO2.

Cell transfection

The mimics and the negative control oligonucleotides of miR-30c were designed and synthesized (RiboBio, China) [Table 1]. All of the oligonucleotides were transfected into cells using Lipo2000 (Invitrogen, USA) in antibiotic-free Opti-MEM medium (Invitrogen, USA) according to the manufacturer's protocol at a final concentration of 50 nM. For the co-transfections, 25 nM of each oligonucleotide was used. Total RNA and proteins were extracted at 48 h posttransfection for further analysis. Three independent experiments were performed.
Table 1: The sequences of mimics and negative control oligonucleotides of micro RNA-30c

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Quantitative real-time polymerase chain reaction

Total RNA of tissue and cells was extracted using TRIzol reagent (Invitrogen, USA). The primers of miR-30c, MTA1, U6, and GAPDH for quantitative real-time polymerase chain reaction (qRT-PCR) were designed and synthesized (RiboBio, China) [Table 2]. cDNA was synthesized from total RNA by reverse transcription using the PrimeScript RT reagent Kit (TakaRa, China). qRT-PCR was performed using the SYBR PrimeScript RT-PCR Kit (TakaRa, China) according to the manufacturer's protocol. The relative expression levels of miR-30c and MTA-1 were determined using the 2−ΔΔCT analysis method; the levels of GAPDH and U6 were used as internal controls for MTA-1 and miR-30c.
Table 2: Primer sequences of target genes and reference genes

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Luciferase reporter assay

The 3'UTR of the MTA1 harboring either the miR-30c binding site (MTA1-3'UTR-wild type) or a mutant (MTA1-3'UTR-Mutant) was cloned into the psiCHECK-2 vectors (Promega, USA). Plasmid DNA and miR-30c mimics/NC were co-transfected into 293T cells by Lipo2000. Luciferase activities were detected using the Luciferase Assay System (Promeg, USA).

Western blotting

Total cell protein concentration was determined using the BCA Assay Kit (Beyotime, China). Samples (20 μg) were resolved by 15% SDS-polyacrylamide gel electrophoresis and transferred onto polyvinylidene fluoride membranes. After blocking with 5% bovine serum albumin (BSA; Sigma, USA) in Tris-buffered saline, the membranes were immunoblotted overnight at 4°C with monoclonal primary antibody rabbit anti-human MTA1 (1:500 dilution) and monoclonal primary antibody mouse anti-human β-actin (1:500) antibodies (Santa Cruz, USA), washed three times, followed by incubation with the corresponding horseradish peroxidase-conjugated secondary antibodies (1:1000). Immunoreactive bands were visualized by chemiluminescence detection (Milipore, USA) and analyzed by densitometric analysis using the Gel Doc XR system (Bio-Rad, USA).

Wound healing assay

Cell migration was measured using the wound healing assay. Primary or transfected cells were seeded into 12-well plates. The cell monolayer was scratched (wound) with a plastic pipette tip, washed with phosphate-buffered saline to clear debris and detached cells. The cells were then incubated in serum-free medium for 24 h. The individual gaps were observed and photographed using an inverted microscope at 0 h and 24 h at the same position of the wound.

Transwell invasion assay

Cell invasion assays were performed in 24-well, Matrigel-coated invasion chambers. Primary or transfected cells (2.0 × 104) were resuspended in 0.2 ml serum-free-DMEM and added to the upper chambers with an 8 μm Pore Polycarbonate Filter (Corning, USA), which were coated with Matrigel Basement Membrane Matrix (BD, USA) for 2 h at 37°C. The insert was placed in a well with complete medium. Cells were incubated for 48 h, and cells that did not migrate through the pores were removed with a cotton swab. The invading cells were stained with 0.5% crystal violet (Beyotime, China) and counted under a microscope (×200). The experiment was performed in triplicate.

Statistical analysis

The measurement data are presented as the means ± standard deviation. Student's t-test was used to compare the values of the test and control samples. Statistical analyses of ranked data were examined using rank sum test. All above statistical analyses were performed using SPSS version 20.0 software (SPSS, Chicago, Illinois, USA), and P < 0.05 was considered statistically significant.


 > Results Top


Abnormal expression of microRNA-30c and metastasis-associated gene 1 in ovarian cancer tissues and cells

The relative expression levels of miR-30c in 33°C tissues and matched adjacent normal ovarian tissues were quantitated by real-time PCR. The results showed that compared to normal ovarian tissues, OC tissues expressed lower miR-30c [P < 0.01; [Figure 1]a. The similar data also were found in SKOV-3°C cell line and normal ovarian epithelial cell (HOSE) [P < 0.05; [Figure 1]b. These data suggest that miR-30c has decreased expression in OC and may be associated with OC as a suppressor gene. Then, the putative targets of miR-30c by three web-based algorithms, miRWalk, TargetScan, and PicTar (http://www.umm.uniheidelberg.de/apps/zmf/mirwalk2/index.html, http://www.targetscan.org, and http://pictar.mdc-berlin.de/) were scanned. MTA1, a tumor metastasis-associated protein, was chosen for the further study. Real-time PCR was performed to analyze the expression of MTA1 mRNA in OC tissues and cells. Results showed that relative expression levels of MTA1 mRNA were significantly upregulated in OC tissues and OC cells [P < 0.01; [Figure 1]c and [Figure 1]d. Therefore, the potential regulated chain of miR-30c and MTA1 in OC was noticed.
Figure 1: The related expression levels of microRNA-30c and metastasis-associated gene 1 in ovarian cancer tissues and cells. (a) Expression of microRNA-30c in tissues; (b) Expression of microRNA-30c in cells; (c) Expression of metastasis-associated gene 1 mRNA in tissues; (d) Expression of Metastasis-associated gene 1 mRNA in cells (* P < 0.05; ** P < 0.01)

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The expression profiles of metastasis-associated gene 1 in ovarian cancer tissues

The expression of MTA1 in OC tissues and adjacent noncancerous ovarian tissues was analyzed by immunohistochemistry. As shown in [Figure 2]a, MTA1 was mainly expressed in the cytoplasm of the OC cells. Further analysis revealed that 97.0% (32/33) of OC tissues showed high expression of MTA1, in contrast to low expression (6.0%, 2/33) or negative expression [Figure 2]b in adjacent normal ovarian tissues. The clinical characteristics of MTA1 in OC patients are shown in [Table 3]. All above-mentioned data suggested that MTA1 expression increase in OC and correlate with the FIGO stage, tumor grade, and metastasis of OC.
Figure 2: Immunohistochemistry staining of Metastasis-associated gene 1 (×400). (a) Positive expression of metastasis-associated gene 1 in ovarian cancer tissues; (b) Negative expression of metastasis-associated gene 1 in adjacent normal ovarian tissues

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Table 3: Correlation between metastasis-associated gene 1 expression and clinicopathological parameters in ovarian cancer patients

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Publicly available algorithms (PicTar, TargetScan, and miRWalk) were used to predict the target of miR-30c. The 3'UTR of MTA1 was found that containing a target sequence for miR-30c at nt 213–219 [Figure 3]a. Hence, the target sequence of MTA1 3'UTR (WT) or the mutant sequence (MT) into a luciferase reporter vector and co-transfected these reporter vectors into 293T cells with miR-30c or controls. Result showed that the expression of miR-30c reduced the luciferase activity in cells transfected with Fluc-MTA1-WT but no significant change in cells with Fluc – MTA1-MT [Figure 3]a. After transfected miR-30c mimics, the relative expression levels of miR-30c obvious increased in OC SKOV3 cells [Figure 3]b. Contrarily, transfecting miR-30c mimics into SKOV3 cells caused a significant decrease of MTA1 protein levels [Figure 3]c and [Figure 3]d. Taken together, MTA1 was a direct target gene by miR-30c, upregulated miR-30c expression in OC cells could significantly inhibit the protein levels of MTA1.
Figure 3: Metastasis-associated gene 1 is a direct target of microRNA-30c in SKOV3 cells. (a) Luciferase report system was analyzed after metastasis-associated gene 1-WT and Metastasis-associated gene 1-MT plasmids were co-transfected with microRNA-30c or control in SKOV3 cells; (b) Relative expression of microRNA-30c were detected after miR-30c mimics transfected into SKOV3 cells by real-time quantitative real-time polymerase chain reaction; (c) Western blot assay of metastasis-associated gene 1 protein expression in SKOV3 cells transfected with mimics and (d) quantitative presentation (** P < 0.01)

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MicroRNA-30c suppressed the migratory and invasive of ovarian cancer cells in vitro

For demonstrating the effect of the up-regulated expression of miR-30c on the migration and invasion of SKOV3, wound healing assay and transwell invasion assay were performed. The results showed that the up-regulation of miR-30c obviously inhibits the migration and invasion of SKOV3 cells [Figure 4]a and [Figure 4]b. These data suggested that miR-30c is a suppressor of OC metastasis; high expression of miR-30c could direct target MTA1, a metastasis promoter, to inhibit migration and invasion of OC cells, and then prevent the metastasis of OC.
Figure 4: MicroRNA-30c suppressed the migratory and invasive of ovarian cancer cells in vitro. (a) Representative photographs of the wound-healing assay showing the migratory ability of the transfected cells at 0 and 24 h after wounding. (b) Representative photographs and quantitative presentation of cell invasion in a transwell assay (* P < 0.05)

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 > Discussion Top


OC is one of the three most common malignant tumors in gynecology and its morbidity has increased in recent years.[1] Extensive and distant metastasis is a major factor causing death in OC patients.[2] As a result, the research on the mechanism of OC invasion and metastasis, and then controlling the metastasis and invasion at the molecular level to delay OC progression has important significance in the OC treatment.

The occurrence and development of a malignant tumor is a complex process with multiple genes, pathways, and stages. miRNA has been considered a key regulator to downregulate target gene to participate in many pathophysiological processes of malignant tumors such as tumorigenesis, development, invasion, and metastasis.[11] MiR-30c locates on the long arm of chromosome 6 and the short arm of chromosome 1.[17] It is abnormally expressed in lung cancer, breast cancer, prostate cancer, endometrial cancer, and other malignant tumors.[18],[19],[20],[26] Some research has reported that miR-30c is closely related to multiple pathological processes in various tumors. For example, it has been found that miR-30c can inhibit the proliferation, invasion, and metastasis of prostate cancer cells.[26] Zhong et al.'s study showed that the knockdown of miR-30c could lead to the stronger invasion in lung cancer A549 cell line.[27] Moreover, overexpression of miR-30c has been observed a dramatical inhibition of the invasion and metastasis of lung cancer cells in vitro. In the estrogen receptor positive and progesterone receptor negative breast cancer cells, the expression of miR-30c can also inhibit the proliferation, invasion, and metastasis of tumor cells.[28] Notably, a recent study has shown that miR-30c dramatically decreased with hypermethylation in OC cells. The deficiency of miR-30c has also been closely related to drug resistance and EMT of OC cells, but the exact regulatory mechanism remains unclear.[29]

Remarkably, in a series of tumor research, MTA1 as the main target gene of miR-30c has been paid more and more attention in metastasis and invasion.[30] MTA is a newly discovered family of cancer progression-related genes and their encoded products. MTAs are integral parts of nucleosome remodeling and histone deacetylation (NuRD) complexes, function as transcriptional co-repressors which regulate varieties pathways, including hormonal action, EMT, differentiations, protein stability, and development.[31] MTA1, the first gene found in this family, has been repeatedly reported to be overexpressed in a wide range of human cancers such as endometrial adenocarcinomas, gastrointestinal carcinoids, colorectal carcinomas, hepatocellular carcinomas, and nonsmall cell lung cancers.[23],[32],[33] However, the expression of MTA1 in OC and whether it is also regulated by miR-30c have not yet been investigated.

In this study, the researchers detected the expression of miR-30c and MTA1 in OC tissues and SKOV3°C cells by quantitative PCR. The localization and expression levels of MTA1 in OC tissues by immunohistochemistry staining were also analyzed. Compared with matching normal ovarian tissues, the results showed that MTA1 expression was upregulated and localized in the cytoplasm, and the expression of miR-30c was significantly reduced. The expression intensity of MTA1 was correlated with the stage and metastasis of OC. These results suggest that MTA1 and miR-30c are abnormally expressed in OC and may be involved in the invasion and metastasis of OC. The regulation of MTA1 by miR-30c on the invasion and metastasis has been confirmed in lung cancer and endometrial cancer, but it has not been reported whether such a regulatory relationship in OC. The researchers confirmed that MTA1 is the target gene of miR-30c by the luciferase reporter system, and synthesized miR-30c mimics to be transfected into OC SKOV3 cells. The wound healing and transwell assays found that the increased expression of miR-30c can significantly inhibit not only MTA1 but also the invasion and metastasis of SKOV3 cells.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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