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Microrna‑3666 Inhibits Breast Cancer Cell Proliferation by Targeting Sirtuin 7

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Microrna‑3666 Inhibits Breast Cancer Cell Proliferation by Targeting Sirtuin 7 MOLECULAR MEDICINE REPORTS 16: 8493-8500, 2017 MicroRNA‑3666 inhibits breast cancer cell proliferation by targeting sirtuin 7 DI LI1 and LIFEI LI2 1Medical College of Inner Mongolia University for The Nationalities, Tongliao, Inner Mongolia 028000; 2Department of Respiratory Medicine, Affiliated Hospital of Inner Mongolia University for The Nationalities, Tongliao, Inner Mongolia 028007, P.R. China Received October 27, 2016; Accepted June 22, 2017 DOI: 10.3892/mmr.2017.7603 Abstract. The abnormal expression of microRNAs (miRNAs) Introduction is associated with cancer initiation and progression. miRNAs functioning as oncogenes or tumor suppressors represent novel Breast cancer is one of the most prevalent types of malignancy biomarkers for cancer diagnosis, prognosis, and serve as thera- in women worldwide (1). Despite advances in cancer thera- peutic tools. MiR-3666 has been reported as a tumor suppressor peutic strategies, the clinical outcomes and prognosis for breast in various types of cancer; however, its role in breast cancer cancer patients remain particularly poor (2). Numerous genetic remains unknown. In the current study, the aim was to inves- and epigenetic alterations have been proposed to contribute to tigate the potential role of miR-3666 in breast cancer. It was breast cancer pathogenesis and progression (3); however, the identified that miR‑3666 was decreased in breast cancer cell precise molecular mechanism remains poorly understood. lines and that the overexpression of miR-3666 inhibited breast Therefore, investigating the molecular mechanisms, and devel- cancer cell proliferation. Furthermore, miR-3666 promotes oping novel and effective therapeutic targets for breast cancer cell apoptosis of breast cancer cells. Bioinformatics analysis therapy are of great importance. and dual-luciferase reporter assay demonstrated that miR-3666 MicroRNAs (miRNAs) are non-coding, small RNAs targeted the 3'-untranslated region of sirtuin 7 (SIRT7) which (length, ~22 nucleotides) which post-transcriptionally regulate was recognized as an oncogene. Overexpression of miR-3666 gene expression (4,5). miRNAs induce mRNA degradation decreased SIRT7 expression levels, and knockdown of SIRT7 or translational repression by targeting the 3'-untranslated suppressed proliferation and promoted apoptosis of breast region (UTR) of the target mRNAs (4). miRNAs are impor- cancer cells. A rescue assay demonstrated that the restoration tant in carcinogenesis, through modulating various biological of SIRT7 expression markedly reversed the miR-3666-induced processes, including cell proliferation, apoptosis, differen- anti-tumor effects. Thus, the current study indicates that tiation, migration and invasion (6). Numerous miRNAs are miR-3666 suppresses breast cancer cell proliferation by involved in regulating breast cancer pathogenesis and targeting SIRT7, and propose miR-3666 as a potential candi- progression (7-9). Furthermore, miRNAs may serve as novel date for breast cancer therapy. biomarkers for diagnosis, prognosis, and therapeutic tools in breast cancer (10). However, the precise role of miRNAs in breast cancer requires further investigation. The sirtuins (SIRTs) are nicotinamide adenine dinucleo- tide oxidized form-dependent deacetylases that contribute significantly to stress responses, inflammation, metabolism, Correspondence to: Mr. Lifei Li, Department of Respiratory DNA repair and senescence (11-14). To date, seven members, Medicine, Affiliated Hospital of Inner Mongolia University including SIRT1-7 have been characterized in mammals (15). for The Nationalities, 1742 Huolinhe Street, Tongliao, Inner SIRT1 is the most evaluated sirtuin that regulates various Mongolia 028007, P.R. China cellular and metabolic processes (16). SIRT2 has been reported E-mail: [email protected] as an important regulator for neurodegenerative diseases (17). SIRT3 is the major mitochondrial deacetylase, which regu- Abbreviations: miRNAs, microRNAs; SIRT7, sirtuin7; UTR, lates global mitochondrial lysine acetylation (18,19). SIRT4 untranslated region; FBS, fetal bovine serum; MTT, and SIRT5 have been significantly implicated in metabolic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; BrdU, Bromodeoxyuridine; RT-qPCR, reverse transcription-quantitative processes (20,21). SIRT6 predominantly regulates DNA polymerase chain reaction damage and genome integrity (22,23), and SIRT7 is the latest characterized SIRT and evaluation of its function has just Key words: breast cancer, miR-3666, sirtuin 7, cell proliferation, begun (24). SIRT7 is important in regulating rDNA transcrip- cell apoptosis tion and protein synthesis (25,26). Furthermore, SIRT7 has been reported as a response gene in response to hypoxia, low glucose stress, genomic stress and endoplasmic reticulum 8494 LI and LI: ROLE OF miR-3666/SIRT7 IN BREAST CANCER stress (27-30). It is involved in cardiac health, hepatic steatosis, ageing and senescence (31,32) and SIRT7 has been suggested as an oncogene in various cancer types, including hepatocel- lular carcinoma (26) and colorectal cancer (33), representing a potential pharmacologic target for cancer therapy (34). High expression levels have been observed in breast cancer tissues associated with metastasis and adverse outcomes (35,36). However, the regulation of SIRT7 in breast cancer remains poorly understood. Recent studies reported miR-3666 as a tumor suppressor miRNA in various cancer types (37-39). However, the role of miR-3666 in breast cancer remains unknown. According to the reported features of miR-3666, it was hypothesized that miR-3666 exerts a tumor suppressor role in breast cancer. The Figure 1. Expression levels of miR-3666 in breast cancer cell lines was present study aimed to investigate the role and underlying detected by reverse transcription-quantitative polymerase chain reaction. mechanism of miR-3666 in regulating the development and Four breast cancer cell lines, including MCF-7, MDA-MB-468, BT474 and MDA-MB-231 were used. The normal breast epithelial cell line MCF-10A progression of breast cancer. served as a control. *P<0.05 vs. MCF-10A. miR, microRNA. Materials and methods Cell lines and culture. Human breast cancer cell lines (MCF-7, 5'-CAC AGT TCT GAG ACA CCA CA-3' for SIRT7; and BT474, MDA-MB-231, and MDA-MB-468), normal breast forward, 5'-CCA TGT TCG TCA TGG GTG TG-3' and reverse, epithelial cell line MCF-10A and 293T cells were purchased 5'-GGT GCT AAG CAG TTG GTG GTG-3' GAPDH. from the American Type Culture Collection (Manassas, VA, USA). BT474 and MDA-MB-231 cells were cultured in Cell transfection. The miR-3666 mimics and negative Hyclone RPMI-1640 medium (GE Healthcare Life Sciences, control (miR-NC) were obtained from Origene Technologies, Logan, UT, USA) while MCF-7, MDA-MB-468, MCF-10A Inc. (Beijing, China) and transfected into cells using and 293T cells were cultured in Hyclone Dulbecco's modi- Lipofectamine 2000 (Invitrogen; Thermo Fisher Scientific, fied Eagle's medium (GE Healthcare Life Sciences). All cells Inc.) at a final concentration of 50 nM. SIRT7 small inter- were grown in medium containing 10% fetal bovine serum fering RNA (siRNA) and negative control (NC siRNA) were (Hyclone; GE Healthcare Life Sciences) supplemented with purchased from Santa Cruz Biotechnology, Inc. (Dallas, 1% penicillin‑streptomycin (Gibco; Thermo Fisher Scientific TX, USA) and transfected into cells according to the manu- Inc., Waltham, MA, USA) in a humidified atmosphere of facturer's instructions. SIRT7-overexpressing vector was 5% CO2 at 37˚C. generated by cloning SIRT7 cDNA without a 3'-UTR into a pcDNA3.1 vector (Invitrogen; Thermo Fisher Scientific, Inc.). Reverse transcription‑quantitative polymerase chain reac‑ The pcDNA3.1-SIRT7 vector was transfected into cells using tion (RT‑qPCR). Total RNAs were extracted using TRIzol Lipofectamine 2000. (Invitrogen; Thermo Fisher Scientific, Inc.). To detect miR-3666 expression, cDNA was synthesized by Moloney 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium murine leukemia virus reverse transcriptase (Takara bromide (MTT) assay. Cells were seeded into 96-well plates Biotechnology, Co., Ltd., Dalian, China). To detect SIRT7 at a density of 1x104 cells/well and cultured overnight. Cells expression levels, cDNA was synthesized using a miScript were then transfected with miR-3666 mimics and cultivated Reverse Transcription kit (Qiagen GmbH, Hilden, Germany). for 48 h, and 20 µl of MTT (5 mg/ml; Sigma-Aldrich; Merck The RT-qPCR was conducted using a SYBR-Green master KGaA, Darmstadt, Germany) was added to each well and mix kit (Bio-Rad Laboratories, Inc., Hercules, CA, USA) incubated at 37˚C for 4 h. Subsequently, the culture media with an Applied Biosystems AB7500 Real Time PCR system were discarded and 200 µl dimethyl sulfoxide was added to (Applied Biosystems; Thermo Fisher Scientific, Inc.) according each well. Optical density values at a wavelength of 490 nm to the following procedure: 94˚C for 5 min; 30 cycles of were detected using an ELISA reader (Bio-Rad Laboratories, 94˚C for 20 sec, 55˚C for 25 sec, and 72˚C for 35 sec; and Inc.). 72˚C for 10 min. Small nuclear RNA U6 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) served as the internal Bromodeoxyuridine (BrdU) assay. The BrdU assay was controls. The relative gene expression was calculated using performed using a BrdU cell proliferation assay kit (Cell the 2−ΔΔCq method as compared with U6 or GAPDH (40). The Signaling Technology, Inc., Danvers, MA, USA) in accor- fold-change of gene expression was
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