miR‑217‑5p suppresses epithelial‑mesenchymal transition and the NF‑κB signaling pathway in breast cancer via targeting of metadherin
- Authors:
- Published online on: March 23, 2022 https://doi.org/10.3892/ol.2022.13282
- Article Number: 162
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Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Breast cancer (BC) is the most common malignancy in women, accounting for ~22% of all new cancer cases worldwide and >1.05 million new cases annually (1). Globally, 450,000 patients succumb to BC each year, which accounts for 3.7% of all cancer mortalities in women (1,2). BC is a heterogeneous disease that has a wide spectrum of clinical, pathological and prognostic subtypes. BC occurs when normal epithelial cells become hyperplastic and develop into carcinoma in situ, eventually transitioning to an invasive carcinoma to facilitate metastasis (3,4). Therefore, the molecular mechanism of BC tumorigenesis and development requires further study to identify novel therapeutic strategies for the treatment of this disease.
MicroRNAs (miRNAs/miRs) serve an important role in cancer metastasis (5). Abnormal expression profiles of miRNAs have been reported in numerous types of BC (6). Moreover, the dysregulation of miRNAs has been demonstrated to be involved in the tumorigenesis and progression of BC, including miR-142 (7), miR-205 (8) and miR-92 (9). Previous studies have identified various miRNAs that are aberrantly expressed in human malignancies (10–12). miR-217-5p is downregulated in gastric cancer (10), pancreatic ductal adenocarcinoma (11) and osteosarcoma (12). However, the biological function of miR-217-5p in BC remains to be elucidated.
The epithelial-mesenchymal transition (EMT) refers to the biological process whereby cells of the epithelial phenotype transform into those with a mesenchymal phenotype. This process serves an important role in embryonic development, chronic inflammation, tissue remodeling, cancer metastasis and various fibrotic disease states (13). The main characteristics of EMT are a reduction in the expression of cell adhesion molecules, including E-cadherin, and the transformation of the cytokeratin cytoskeleton (14). Vimentin-based cytoskeletons and morphological features are typical characteristics of cells with mesenchymal phenotypes (14). Through the EMT, epithelial cells lose polarity and their connection with the basement membrane, whereas other cells acquire mesenchymal phenotypes, such as increased migration and invasion, reduced apoptosis and the increased ability to degrade the extracellular matrix (15). The EMT is an important biological process that allows malignant tumor cells derived from epithelial cells to acquire metastatic capabilities (15).
Metadherin (MTDH) was first identified by Su et al (16) in 2002. MTDH has a functional role in several crucial aspects of tumor progression, including transformation, proliferation, cell survival, evasion of apoptosis, migration and invasion, metastasis, angiogenesis and chemoresistance. MTDH is located on the 8q22 locus and has been previously associated with the initiation and progression of numerous types of cancer. MTDH is also known as astrocyte-elevated gene-1 and is a type of oncogene (17). The upregulated expression of MTDH has been observed in BC, ovarian, prostate, lung, esophageal and colorectal cancer (17–19). Moreover, it promotes the invasiveness of human BC cells by inducing the EMT (18). The NF-κB signaling pathway has been reported to participate in the MTDH-induced EMT of BC cells in vitro (18). Previous reports suggest that MTDH activates NF-κB via the degradation of IκBα and by directly binding to the p65 NF-κB subunit (19,20).
miR-217 possibly functions as a tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS (11,21). Furthermore, miR-217 has been reported to induce endothelial cell senescence via targeting of sirtuin 1 (22). Previously identified miR-217 targets include E2F transcription factor 3, enhancer of zeste homolog 2 and runt-related transcription factor 2, the suppression of which inhibits clear cell renal cell carcinoma, gastric cancer and glioma, respectively (21,23,24). However, miR-217 is also an oncogene that targets PTEN and peroxisome proliferator-activated receptor γ co-activator 1-α to enhance germinal center responses in mature B-cell lymphomagenesis (25,26). Based on these previous reports, it can be hypothesized that miR-217 can mediate context-dependent functions during carcinogenesis. miR-217-5p is the main member of the miR-217 family, and it is also the main research object of the aforementioned studies.
The clinical significance of miR-217-5p expression in BC remains controversial with previous studies reporting conflicting results (27,28). The mechanism by which miR-217 targets MTDH to regulate BC cell function remains unclear. Therefore, in the present study, miR-217-5p and MTDH expression levels were examined in human BC tissue and cell lines. The possible function of miR-217-5p and MTDH in BC was also investigated.
Materials and methods
Clinical tissues
In total 35 pairs of BC tissues and matched adjacent non-tumor tissues were obtained from patients (age, 28–65 years; 35 females) who were surgically treated at the Breast Center, The Fourth Hospital of Hebei Medical University (Shijiazhuang, China) between August 2020 and November 2021. These patients were all pathologically diagnosed with breast cancer. None of the patients received any treatment prior to surgery and written informed consent was obtained from all patients. The clinicopathological information of the patients is presented in Table I. Tissue samples were frozen in liquid nitrogen and stored in a refrigerator at −80°C. The present study was approved by the Ethics Committee of The Fourth Hospital of Hebei Medical University (approval no. 2021KY056). The present study was conducted in accordance with the principles described in The Declaration of Helsinki.
 | Table I.Clinicopathological characteristics of patients with breast cancer (n=35) in the present study. |
Cell culture and transfection
The human breast epithelial MCF10A cell line and BC SK-BR3, MCF7 and BT549 cell lines were purchased from Procell Life Science & Technology, Co., Ltd. Cells were cultured in RPMI-1640 media (Invitrogen; Thermo Fisher Scientific, Inc.) containing 10% FBS (Invitrogen; Thermo Fisher Scientific, Inc.) and incubated with 5% CO2 at 37°C. miR-217-5p mimic, miR-negative control (NC) mimic, miR-217-5p inhibitor and miR-NC-inhibitor were synthesized by Shanghai GenePharma Co., Ltd., and transfected into SK-BR3 or BT549 cells at a final concentration of 100 nM using Lipofectamine® 3000 (Invitrogen; Thermo Fisher Scientific, Inc.) at 37°C for 6 h. Subsequent experimentation was performed 48 h after transfection. The following sequences were used: miR-217-5p mimic, 5′-UACUGCAUCAGGAACUGAUUGGA-3′; miR-NC mimic, 5′-UUGUCCGAACGUGUCACGU-3′; miR-217-5p inhibitor, 5′-UCCAAUCAGUUCCUGAUGCAGUA-3′; and miR-NC inhibitor, 5′-CAGCUGGUUGAAGGGGACCAAA-3′.
RNA extraction and reverse transcription-quantitative PCR (RT-qPCR)
TRIzol® reagent (Invitrogen; Thermo Fisher Scientific, Inc.) was used to extract total RNA from BC tissues and BC cell lines, including miRNA. RNA quality was assessed using the A260/A280 ratio. This value was determined using a microplate reader (Multiskan Sky; Thermo Fisher Scientific, Inc.). RNA quantity was also assessed using a microplate reader. Total RNA was reverse transcribed into complementary (c)DNA using a Transcriptor First Strand cDNA Synthesis Kit [Roche Diagnostics (Shanghai) Co., Ltd.] using the following temperature protocol according to the manufacturer's instructions: 37°C for 15 min and 85°C for 5 sec. The volume of each RT reaction system was 20 µl, including 1 µg of total RNA. DNase was used to remove genomic DNA interference. Subsequently, qPCR was performed to examine gene expression using a SYBR Green PCR Master Mix (Applied Biosystems; Thermo Fisher Scientific, Inc.). The following thermocycling conditions were used for qPCR: Initial denaturation at 95°C for 5 min; followed by 40 cycles of denaturation at 95°C for 5 sec, 60°C for 30 sec and 72°C for 30 sec, with a final extension step at 72°C for 2 min. The 2−ΔΔCq method was used to calculate the relative expression levels using GAPDH or U6 as the internal reference gene (29). The primer sequences used for RT-qPCR are presented in Table II.
Cell proliferation assay
Cell proliferation was analyzed using the Cell Counting Kit-8 (CCK-8; Dojindo Molecular Technologies, Inc.) assay. Briefly, transfected SK-BR3 or BT549 cells were seeded into 96-well plates at a density of 2×103 cells/well. Following incubation at 37°C for 24, 48 and 72 h, 10 µl CCK-8 solution was added into each well and incubated at 37°C for 4 h. The absorbance of each well at a wavelength of 450 nm was assessed using a microplate reader (Multiskan Sky; Thermo Fisher Scientific, Inc.).
Colony formation assay
Colony formation assays were performed to detect cell proliferation. Transfected SK-BR3 and BT549 cells were seeded at 1×103 cells/well in six-well plates and incubated with 5% CO2 at 37°C. After 15 days, colonies were visible to the naked eye. These colonies were fixed with 4% paraformaldehyde for 15 min at ambient temperature and stained with 1% crystal violet (Beyotime Institute of Biotechnology) for 15 min at ambient temperature. The number of colonies (containing >50 cells) was counted microscopically.
Wound healing assay
After 48 h of transfection, 2×105 SK-BR3 or BT549 cells were transferred into a 35-mm2 petri dish, cultured at 37°C and grown to 90% confluence. A wound was then created using a 200-µl pipette tip to scratch the monolayer before any detached cells were washed away with PBS. The remaining cells were cultured in serum-free culture media, and wound closure was then observed. Images of the wounds were taken at 0 and 24 h after the scratch was made using a light microscope (magnification, ×100; Olympus Corporation). Migratory ability was calculated as the mobility ratio using the following formula: Mobility ratio=(scratch width at 24 h-scratch width at 0 h)/scratch width at 0 h.
Western blotting
Total protein was extracted using RIPA lysis buffer (Beyotime Institute of Biotechnology) from transfected SK-BR3 and BT549 cell lines. Protein concentration was determined by BCA assay (Thermo Fisher Scientific, Inc.). Next, the protein lysates (30 µg) were separated using SDS-PAGE on a 10% gel and separated proteins were then transferred onto PVDF membranes (MilliporeSigma). Subsequently, the membranes were incubated with 5% skimmed milk at room temperature for 2 h, before they were incubated with the following primary antibodies against: MTDH (1:2,000; cat. no. ab227981; Abcam), GAPDH (1:10,000; cat. no. 10494-1-Ig; ProteinTech Group, Inc.), p65 (1:2,000; cat. no. 10745-1-Ig; ProteinTech Group, Inc.), p-p65 (1:2,000; cat. no. 3033; Cell Signaling Technology), IκBα (1:2,000; cat. no. 10268-1-Ig; ProteinTech Group, Inc.), E-cadherin (1:2,000; cat. no. 20874-1-Ig; ProteinTech Group, Inc.), Vimentin (1:20,000; cat. no. 10366-1-Ig; ProteinTech Group, Inc.) and snail family transcriptional repressor 2 (slug; 1:2,000; cat. no. 12129-1-AP; ProteinTech Group, Inc.), overnight at 4°C. After washing with TBST (0.05% Tween 20), the membranes were incubated with the HRP-conjugated goat polyclonal anti-rabbit IgG secondary antibody (1:10,000; cat. no. SA00001-2; ProteinTech Group, Inc.) for 1 h. Protein expression was determined by enhanced chemiluminescence (MilliporeSigma).
Invasion assay
After transfection with miR-217-5p mimic, miR-NC mimic, miR-217-5p inhibitor and miR-NC inhibitor for 48 h at 37°C, a total of 5×105 SK-BR3 and BT549 cells were resuspended in 200 µl serum-free medium and subsequently seeded into the upper chamber of a Transwell insert (Corning, Inc.) precoated with 1 µg/µl Matrigel (BD Biosciences) overnight at 37°C. The lower chamber was filled with 500 µl basal medium with 10% FBS to stimulate cell invasion. Following 48 h of cell culture at 37°C, the cells that did not cross the membrane were wiped with a cotton swab, whereas the cells adhering to the lower surface of the membrane were stained with 0.1% crystal violet solution at room temperature for 10 min. The number of invading cells was counted in five randomly selected fields using a light microscope (magnification, ×200; Olympus Corporation).
Migration assay
A total of 5×105 transfected SK-BR3 and BT549 cells were resuspended in 200 µl serum-free medium and were subsequently seeded into the upper chamber of a Transwell insert without Matrigel. All other procedures were performed as described for the invasion assay.
Bioinformatics analysis
The TargetScan (http://www.targetscan.org/vert_70/) database was used to predict the target genes of miR-217-5p.
Dual-luciferase reporter assay
The 3′-untranslated regions (UTR) of wild type or mutant MTDH were inserted into the pmirGLO luciferase vector (Shanghai GeneChem Co., Ltd.). These vectors and miR-217-5p mimic or miR-NC mimic were co-transfected into BT549 cells using Lipofectamine® 3000 (Invitrogen; Thermo Fisher Scientific, Inc.) for 48 h at 37°C. The lysate was cleared and the luciferase reporter activity was assayed at 48 h post-transfection using the Dual-Luciferase Reporter Assay System (Promega Corporation). The firefly luciferase activity was normalized using Renilla luciferase activity.
Statistical analysis
Data were analyzed using SPSS 23.0 (IBM Corp.) and GraphPad Prism 8 (GraphPad Software, Inc.). Data are presented as the mean ± SD. All comparisons between two groups of cells were performed using unpaired Student's t-tests. Paired Student's t-tests were performed for comparisons between paired tumor and adjacent non-tumor tissues. Two-way ANOVA followed by Bonferroni's post hoc test were used to compare data from the dual-luciferase reporter assay. The gene expression correlation between miR-217-5p and MTDH was assessed using the Pearson's correlation coefficient test. All experiments were performed at least three times. P<0.05 was considered to indicate a statistically significant difference.
Results
miR-217-5p expression levels are reduced in BC tissues and cell lines
miR-217-5p expression levels were demonstrated to be markedly reduced in MCF7, BT549 and SK-BR3 cell lines compared with MCF10A cells (Fig. 1A). Furthermore, the expression levels of miR-217-5p were significantly lower in BC tissues compared with those in the adjacent non-tumor tissues (Fig. 1B). This indicated that miR-217-5p expression levels were lower in both BC cell lines and tissues.
Overexpression of miR-217-5p inhibits cell proliferation, colony formation, migration and invasion of BC cells
To investigate the specific function of miR-217-5p in BC, miR-217-5p mimic was transfected into SK-BR3 cells, whereas miR-217-5p inhibitor was transfected into BT549 cells (two cell lines with highest transfection efficiency). Compared with the negative control (NC), the results demonstrated that transfection with the miR-217-5p mimic significantly increased miR-217-5p expression levels, whereas miR-217-5p inhibitor transfection significantly decreased miR-217-5p expression levels (Fig. 2A and C). The CCK-8 assay demonstrated that compared with the NC, transfection with the miR-217-5p mimic in SK-BR3 cells significantly inhibited cell proliferation at 48 and 72 h, whereas transfection with the miR-217-5p inhibitor into BT549 cells significantly promoted cell proliferation at 48 and 72 h (Fig. 2B and D). Furthermore, colony formation assays demonstrated that miR-217-5p overexpression resulted in the significant inhibition of BC cell proliferation, whereas miR-217-5p expression knockdown significantly promoted colony formation compared with the NC group (Fig. 2E and F). Wound healing assays determined that transfection with the miR-217-5p inhibitor into BT549 cells significantly promoted cell migration, whereas miR-217-5p overexpression in SK-BR3 cells significantly suppressed cell migration, compared with the NC group (Fig. 2G and H). Transwell assays demonstrated that miR-217-5p knockdown significantly promoted cell migration and invasion in BT549 cells, but miR-217-5p overexpression significantly inhibited SK-BR3 cell migration and invasion compared with the NC group (Fig. 2I and J). The aforementioned results indicated that miR-217-5p exerted a tumor suppressive role in BC cells.
Overexpression of miR-217-5p prevents the EMT in BC cells
E-cadherin, Vimentin and slug mRNA and protein expression levels were analyzed using RT-qPCR and western blotting to explore the effects of miR-217-5p on SK-BR3 and BT549 cells further. Overexpression of miR-217-5p markedly enhanced E-cadherin mRNA and protein expression levels, whereas Vimentin and slug expression levels were markedly inhibited compared with the NC group (Fig. 3A and C). However, compared with the NC, miR-217-5p knockdown markedly decreased E-cadherin mRNA and protein expression levels but markedly promoted Vimentin and slug mRNA and protein expression levels (Fig. 3B and D). These results suggested that miR-217-5p overexpression may suppress the EMT in BC.
Overexpression of miR-217-5p inhibits the NF-κB signaling pathway
The mRNA and protein expression levels of NF-κB markers were subsequently assessed to determine the effects of miR-217-5p on SK-BR3 and BT549 cells. RT-qPCR and western blotting demonstrated that miR-217-5p overexpression markedly inhibited p65 phosphorylation but markedly promoted IκBα expression levels compared with the NC (Fig. 4A and C). However, miR-217-5p knockdown markedly suppressed IκBα mRNA and protein expression levels but markedly promoted p65 phosphorylation compared with the NC (Fig. 4B and D). These results indicated that the downregulation of miR-217-5p may activate the NF-κB signaling pathway.
miR-217-5p directly targets MTDH in BC cells
TargetScan (http://www.targetscan.org/vert_71/) was used to predict miR-217-5p target genes. MTDH was determined to be a candidate target for miR-217-5p. Therefore, dual-luciferase reporter assays were performed to assess the potential binding between MTDH mRNA and miR-217-5p (Fig. 5A). MTDH mRNA expression levels were demonstrated to be markedly increased in MCF7, BT549 and SK-BR3 cell lines compared with MCF10A cells (Fig. 5B). Moreover, significantly higher MTDH mRNA expression levels were demonstrated in BC tissues compared with adjacent non-tumor tissues (Fig. 5C). Transfection with miR-217-5p mimic significantly reduced the luciferase activity of the wild-type MTDH 3′UTR compared with the miR-NC mimic. However, there was no change in luciferase activity in the mutant-MTDH 3′UTR group (Fig. 5D). Furthermore, MTDH mRNA expression levels were demonstrated to be significantly inversely correlated with those of miR-217-5p in BC tissues (Fig. 5E). The results also demonstrated that compared with the NC, miR-217-5p overexpression markedly inhibited MTDH mRNA and protein expression levels (Fig. 5F), whereas miR-217-5p knockdown markedly promoted MTDH mRNA and protein expression levels (Fig. 5G). These data therefore suggested that miR-217-5p may directly target MTDH and that the expression of miR-217-5p is inversely correlated with MTDH in BC cells.
Discussion
Previous studies have demonstrated that miRNAs serve important roles in the growth and metastasis of malignant types of cancer, including BC (7,30). miR-217 has been reported to suppress tumors associated with gastric cancer (24), pancreatic ductal adenocarcinoma (23), hepatocellular carcinoma (31), osteosarcoma (12) and chronic myelogenous leukemia (32). However, results from previous studies on BC are controversial. Zhang et al (27) reported that miR-217 is frequently overexpressed in BC, which enhances tumor growth by targeting Dachshund homolog 1 expression and promoting cell cycle progression. However, Zhou et al (28) demonstrated that miR-217 suppresses triple-negative BC cell proliferation, migration and invasion, at least in part by downregulating Kruppel-like factor 5 expression. miR-217-5p is an important member of the miR-217 family. In the present study, miR-217-5p downregulation was detected in BC tissues and BT549 and SK-BR3 cells. Therefore, miR-217-5p may serve distinct roles in different BC cell lines.
The EMT is a process that describes the molecular reprogramming and phenotypic changes during the transition of polarized, immotile epithelial cells into motile mesenchymal cells, which exhibit increased migratory and invasive capacities (13). The activation of the EMT is characterized by the reduced expression of epithelial markers, such as E-cadherin, coupled with the increased expression of mesenchymal markers, such as Vimentin and slug. It has also been reported that miRNAs can serve as regulators of malignant transformation and metastasis (14). In the present study, miR-217-5p was found to regulate the mRNA and protein expression levels of E-cadherin, Vimentin and slug. Therefore, these results indicated that miR-217-5p expression potentially inhibits the EMT of BC cells.
Previous studies have demonstrated that the activation of the NF-κB signaling pathway is associated with BC development (33,34). IκB is a specific intracellular inhibitor of NF-κB. In the majority of cell types, NF-κB exists in an inactive form by forming a complex with IκB in the cytoplasm (34). A previous study reported that NF-κB is constitutively activated in hepatocellular carcinoma cell lines (31). Results from the present study demonstrated that the overexpression of miR-217-5p significantly inhibited NF-κB signaling. These results therefore indicated that miR-217-5p may prevent BC progression by potentially regulating the NF-κB signaling pathway.
Given the potential importance of miR-217-5p in BC, further experiments were performed to assess the consequences of miR-217-5p activation. Using bioinformatics analysis combined with the dual-luciferase reporter assay, MTDH was demonstrated to be a direct target of miR-217-5p. A previous study reported that miR-217 can target MTDH to promote the progression of meningioma (35). MTDH has also been reported to be an important oncogene in the carcinogenesis, progression and metastasis of numerous malignancies, via regulating and PI3K/AKT, ERK/MAPK, Wnt/β-catenin and aurora-A kinase signaling pathways (36,37). Furthermore, the positive effects of MTDH on cell migration, invasion and EMT have also been previously determined in BC (36). Furthermore, MTDH has been reported to regulate tumorigenesis by interacting with several miRNAs, including miR-145 (38) and miR-630 (39). In the present study, miR-217-5p was demonstrated to significantly negatively regulate MTDH expression in BC. These results suggested that miR-217-5p may be involved in BC progression via the inhibition of MTDH.
A previous study by Wang et al (40) reported that decreased miR-217 expression is associated with poor prognosis in patients with colorectal cancer. In the present study, based on the available data, none of the enrolled patients with BC experienced disease progression or death. As the prognosis of breast cancer is relatively good, it is usually difficult to observe differences in survival after a short period of follow-up, such as several months. The small sample size may also cause some bias. Therefore, in future research, the sample size will be expanded and the follow-up time extended, and related research on the impact of miR-217-5p on the prognosis of breast cancer will continue to be conducted.
In conclusion, the data from the present study suggested that miR-217-5p overexpression may inhibit cell migration, invasion and the EMT via targeting MTDH expression in BC. It can therefore be hypothesized that the miR-217-5p/MTDH axis is likely to be involved in BC via the regulation of the NF-κB signaling pathway. These findings indicated that miR-217-5p may serve as an important potential target in BC therapy.
Acknowledgements
Not applicable.
Funding
Funding was provided by the Natural Science Foundation of Hebei Province (grant nos. H2020206365 and H2021206071), the Special Fund for Clinical Research of Wu Jieping Medical Foundation (grant no. 320.6750.2020-07-17) and the Beijing Xisike Clinical Oncology Research Foundation (grant no. Y-SY201901-0021).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
ZS designed and conceptualized the present study. LXY, BX and SL were responsible for data acquisition. LY, XK and MW analyzed and interpretated the data. LXY drafted the manuscript. ZS and XK revised the manuscript for critically important intellectual content. LXY and ZS confirm the authenticity of all the raw data. All authors contributed to the article and read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the Ethics Committee of The Fourth Hospital of Hebei Medical University (approval no. 2021KY056). The present study was conducted in accordance with the principles described in The Declaration of Helsinki.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 6:69–90. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Parkin DM: Global cancer statistics in the year 2000. Lancet Oncol. 2:533–543. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Poortmans P, Marsiglia H, Heras MDL and Algara M: Clinical and technological transition in breast cancer. Rep Pract Oncol Radiother. 18:345–352. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Rivenbark AG, O'Connor SM and Coleman WB: Molecular and cellular heterogeneity in breast cancer: Challenges for personalized medicine. Am J Pathol. 183:1113–1124. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Bartel D: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Iorio MV and Croce CM: MicroRNAs in cancer: Small molecules with a huge impact. J Clin Oncol. 27:5848–5856. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Liang L, Fu J, Wang S, Cen H, Zhang L, Mandukhail SR, Du L, Wu Q, Zhang P and Yu X: MiR-142-3p enhances chemosensitivity of breast cancer cells and inhibits autophagy by targeting HMGB1. Acta Pharm Sin B. 10:1036–1046. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Greene SB, Herschkowitz JI and Rosen JM: The ups and downs of miR-205: Identifying the roles of miR-205 in mammary gland development and breast cancer. RNA Biol. 7:300–304. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Al-Nakhle H, Burns PA, Cummings M, Hanby AM, Hughes TA, Satheesha S, Shaaban AM, Smith L and Speirs V: Estrogen receptor {beta}1 expression is regulated by miR-92 in breast cancer. Cancer Res. 70:4778–4784. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Lu Y and Tang S: miR-217 targeted to MAPK1 for the inhibition of metastasis and invasion of gastric cancer cell. Mod Med J Chin. 11:21–23. 2014.(In Chinese). | |
|
Zhao WG, Yu SN, Lu ZH, Ma YH and Chen J: The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. Carcinogenesis. 31:1726–1733. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Wei R, Deng Z and Su J: miR-217 targeting Wnt5a in osteosarcoma functions as a potential tumor suppressor. Biomed Pharmacother. 72:158–164. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Pastushenko I and Blanpain C: EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29:212–226. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Savary K, Termén S, Thuault S, Keshamouni V and Moustakas A: Epithelial-mesenchymal transition as a mechanism of metastasis. Lung Cancer Metastasis. Keshamouni V, Arenberg D and Kalemkerian G: 1st edition. Springer; New York, NY: pp. 65–92. 2010 | |
|
Abe-Yutori M, Chikazawa T, Shibasaki K and Murakami S: Decreased expression of E-cadherin by porphyromonas gingivalis-lipopolysaccharide attenuates epithelial barrier function. J Periodontal Res. 52:42–50. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Su ZZ, Kang DC, Chen Y, Pekarskaya O, Chao W, Volsky DJ and Fisher PB: Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene. 21:3592–3602. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Jin H, Shi X, Zhao Y, Peng M, Kong Y, Qin D and Lv X: MicroRNA-30a mediates cell migration and invasion by targeting metadherin in colorectal cancer. Technol Cancer Res Treat. 17:1533033818758102018. View Article : Google Scholar : PubMed/NCBI | |
|
Guo J, Xia B, Meng F and Lou G: MiR-137 suppresses cell growth in ovarian cancer by targeting AEG-1. Biochem Biophys Res Commun. 441:357–363. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Gnosa S, Ticha I, Haapaniemi S and Sun XF: MTDH genetic variants in colorectal cancer patients. Sci Rep. 6:231632016. View Article : Google Scholar : PubMed/NCBI | |
|
Gnosa S, Shen YM, Wang CJ, Zhang H, Stratmann J, Arbman G and Sun XF: Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines. J Transl Med. 10:1092012. View Article : Google Scholar : PubMed/NCBI | |
|
Zhu Y, Zhao H, Li F and Xu S: MicroRNA-217 inhibits cell proliferation and invasion by targeting Runx2 in human glioma. Am J Transl Res. 8:1482–1491. 2016.PubMed/NCBI | |
|
Menghini R, Casagrande V, Cardellini M, Martelli E, Terrinoni A, Amati F, Vasa-Nicotera M, Ippoliti A, Novelli G, Melino G, et al: MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation. 120:1524–1532. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Li H, Zhao J, Zhang JW, Huang QY, Huang JZ, Chi LS, Tang HJ, Liu GQ, Zhu DJ and Ma WM: MicroRNA-217, down-regulated in clear cell renal cell carcinoma and associated with lower survival, suppresses cell proliferation and migration. Neoplasma. 60:511–515. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Chen DL, Zhang DS, Lu YX, Chen LZ, Zeng ZL, He MM, Wang FH, Li YH, ZhangH Z, Pelicano H, et al: MicroRNA-217 inhibits tumor progression and metastasis by downregulating EZH2 and predicts favorable prognosis in gastric cancer. Oncotarget. 6:10868–10879. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang S, Liu X, Liu J, Guo H, Xu H and Zhang G: PGC-1 alpha interacts with microRNA-217 to functionally regulate breast cancer cell proliferation. Biomed Pharmacother. 85:541–548. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Yébenes VG, Bartolomé-Izquierdo N, Nogales-Cadenas R, Pérez-Durán P, Mur SM, Martínez N, Lisio LD, Robbiani DF, Pascual-Montano A, Cañamero M, et al: miR-217 is an oncogene that enhances the germinal center reaction. Blood. 124:229–239. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Q, Yuan Y, Cui J, Xiao T and Jiang D: MiR-217 promotes tumor proliferation in breast cancer via targeting DACH1. J Cancer. 6:184–191. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou W, Song F, Wu Q, Rong L, Liu R, Wang L, Liu C, Peng Y, Mao S, Feng J and Chen C: miR-217 inhibits triple-negative breast cancer cell growth, migration, and invasion through targeting KLF5. PLoS One. 12:e01763952017. View Article : Google Scholar : PubMed/NCBI | |
|
Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Martello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, Enzo E, Guzzardo V, Rondina M, Spruce T, et al: A microRNA targeting dicer for metastasis control. Cell. 141:1195–1207. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Su J, Wang Q, Liu Y and Zhong M: miR-217 inhibits invasion of hepatocellular carcinoma cells through direct suppression of E2F3. Mol Cell Biochem. 392:289–296. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Nishioka C, Ikezoe T, Yang J, Nobumoto A, Tsuda M and Yokoyama A: Downregulation of miR-217 correlates with resistance of Ph (+) leukemia cells to ABL tyrosine kinase inhibitors. Cancer Sci. 105:297–307. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
El-Ashmawy NE, El-Zamarany EA, Khedr EG and Abo-Saif MA: Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway. Mol Cell Biochem. 457:83–91. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou J, Hao Z, Gu P, Bai J, Margolick JB and Zhang Y: NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells. Breast Cancer Res Treat. 111:419–427. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Ghafouri-Fard S, Abak A, Hussen BM, Taheri M and Sharifi G: The emerging role of non-coding RNAs in pituitary gland tumors and meningioma. Cancers (Basel). 13:59872021. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou CX, Wang CL, Yu AL, Wang QY, Zhan MN, Tang J, Gong XF, Yin QQ, He M, He JR, et al: MiR-630 suppresses breast cancer progression by targeting metadherin. Oncotarget. 7:1288–1299. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Wan L and Kang K: Pleiotropic roles of AEG-1/MTDH/LYRIC in breast cancer. Adv Cancer Res. 120:113–134. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Meng X, Thiel KW and Leslie KK: Drug resistance mediated by AEG-1/MTDH/LYRIC. Adv Cancer Res. 120:135–157. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Lu Q, Shan S, Li Y, Zhu D, Jin W and Ren T: Long noncoding RNA SNHG1 promotes non-small cell lung cancer progression by up-regulating MTDH via sponging miR-145-5p. FASEB J. 32:3957–3967. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Wang B, Shen ZL, Jiang KW, Zhao G, Wang CY, Yan YC, Yang Y, Zhang JZ, Shen C, Gao ZD, et al: MicroRNA-217 functions as a prognosis predictor and inhibits colorectal cancer cell proliferation and invasion via an AEG-1 dependent mechanism. BMC Cancer. 15:4372015. View Article : Google Scholar : PubMed/NCBI |
