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The Expression and Biological Function of the PHF2 Gene in Breast

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The Expression and Biological Function of the PHF2 Gene in Breast RSC Advances View Article Online PAPER View Journal | View Issue The expression and biological function of the PHF2 gene in breast cancer Cite this: RSC Adv.,2018,8,39520 Lu Zhang, †a Tian-Li Hui,†a Yu-Xian Wei,b Zhu-Min Cao,c Fan Feng,d Guo-Sheng Renab and Fan Li*b PHD Finger Protein 2 (PHF2), as a protein code and a transcription regulatory gene, is a member of the Jumonji-C domain (JmjC). PHF2 is located at human chromosome 9q22.31 and is frequently decreased in various malignancies. However, the definite role of PHF2 in breast cancer remains unclear. To detect the expression and function of PHF2 in breast cancer, a q-PCR assay was used to detect the mRNA expression of PHF2 in breast cancer cell lines and paired breast cancer tissues, and immunohistochemistry was used to test the protein expression in breast cancer tissues and adjacent tissues. In addition, an adenovirus vector system was utilized to upregulate the expression of PHF2 in breast cancer cells. In our study, we found that PHF2 was down-expressed in breast cancer on both the mRNA and protein levels and the low expression of PHF2 was significantly associated with lymph node Creative Commons Attribution-NonCommercial 3.0 Unported Licence. metastasis, Ki67 positive rate, ER negative expression and poor prognosis in breast cancer patients. The Received 18th July 2018 ectopic expression of PHF2 obviously inhibited the proliferation of breast cancer cell lines and the Accepted 12th November 2018 growth of xenograft tumors. Due to the tumor suppressor signature of PHF2 in breast cancer, we have DOI: 10.1039/c8ra06017g reasons to believe that it could be a promoting marker and target for the prognosis and therapy of rsc.li/rsc-advances breast cancer. Introduction of dimethylated Lys-9 of histone H3 (H3K9me2), subsequently activating the expression of target genes.9,10 PHF2 is located at This article is licensed under a Breast cancer is one of the most common malignancies in the human chromosome 9q22.31, but numerous studies have women, and it is the leading cause of female deaths worldwide.1 revealed that the human chromosome 9q22.32-22.33 was Recently, the incidence and mortality of breast cancer has frequently deleted in various malignancies, such as basal cell Open Access Article. Published on 27 November 2018. Downloaded 9/28/2021 4:51:22 PM. increased year by year in China. Although the diagnosis and carcinoma (BCC) and squamous cell carcinoma (SCC), as well treatment of breast cancer has been greatly improved, the as bladder, prostate, esophageal, and blood cancer, and head prognosis for patients is still very poor, especially for those who and neck cancer.11,12 Consequently, PHF2 may be a tumor have been diagnosed at an advanced stage.2,3 Therefore, it is an suppressor gene. Until now, the role of PHF2 in breast cancer urgent mission for us to thoroughly understand the underlying remains unclear. So, the aim of the present study was to biological features of breast cancer. Meanwhile, it is crucial for explore the expression and functions of PHF2 in breast us to explore new targets for the early diagnosis and treatment cancer. of breast cancer. Generally, emerging evidence has shown that the inactivation of tumor suppressor genes plays a vital role in the development of malignance.4–6 PHD Finger Protein 2 Materials and methods (PHF2), as a protein code and transcription regulatory gene, is Cell culture a member of the Jumonji-C domain (JmjC) and contains a zinc Breast cancer cell lines (MDA-MB-231, MDA-MB-468, BT549, nger-like PHD (plant homeodomain).7,8 A large number of MCF-7, and SK-BR-3) and normal human mammary epithelial studies have shown that PHF2 can mediate the demethylation cells (MCF-10A) were obtained from the American Type Culture Collection (Rockville, MD, USA). MCF10A cells were grown in aDepartment of Oncology, Chongqing Key Laboratory of Molecular Oncology and DMEM/F12 containing 5% horse serum (Sigma USA; H0146), ffi À À Epigenetics, The First A liated Hospital of Chongqing Medical University, China EGF 20 ng ml 1, hydrocortisone 0.5 mg ml 1, cholera toxin 100 bDepartment of Endocrine Surgery and Breast Cancer Center, The First Affiliated À À ng ml 1 and insulin 10 mgml 1. Other cell lines were cultured Hospital of Chongqing Medical University, #1 YouYi Road, YuZhong District, Chongqing 400016, China. E-mail: [email protected] in RPMI 1640 (Gibco BRL, Karlsruhe, Germany) containing 10% cDepartment of Oncology, The Seventh People’s Hospital of Chongqing, 400016, China fetal bovine serum (FBS; Invitrogen, Carlsbad, CA) with 100 U À1 À1 dDepartment of Breast Surgery, Hangzhou Women’s Hospital, Zhejiang 310000, China ml penicillin and 100 mg ml streptomycin and maintained † These authors contributed equally to this paper. in a humidied incubator at 37 C with 5% CO2. 39520 | RSC Adv.,2018,8,39520–39528 This journal is © The Royal Society of Chemistry 2018 View Article Online Paper RSC Advances Patients and samples subsequently immerged with goat anti-rabbit secondary antibody (SSA004, 1 : 1000), which was purchased from Beijing Yiqiao The paired breast cancer tissues (n ¼ 28) were obtained from the (China), at 37 C for 20 min and stained by DAB for 3–5min First Affiliated Hospital of Chongqing Medical University (2014/ under a microscope. Finally, the slides were counterstained with 08-2014/12). Paraffin embedded specimens including breast hematoxylin, dehydrated, made transparent and sealed. The cancer tissue (n ¼ 80), and normal breast tissue (n ¼ 40) which results were scored by two pathologists without knowing the have the total clinical parameters (Table 2) were obtained from information. Firstly, they were scored according to the staining the Clinic Pathology Test Center of the First Affiliated Hospital ¼ # ¼ of Chongqing Medical University. All patients who were percentage of the tumor cell: 0 positive staining 5%, 1 – ¼ – ¼ involved in this study signed an informed consent. The study positive staining 6 25%, 2 positive staining 26 50%, 3 positive staining 51–75%, and 4 ¼ positive staining >75%; and was performed in strict accordance with the NIH guidelines for secondly, the intensity of the staining: 0 ¼ negative, 1 ¼ buff,2¼ the care and use of laboratory animals (NIH Publication no. 85- yellow, and 3 ¼ brown. The total score was determined by the 23 Rev. 1985) and was approved by the Institutional Ethics multiplication of the intensity of the staining and the percentage Committee of The First Affiliated Hospital of Chongqing of the positive cells: scores of #4 were negative, and scores of 5– Medical University (Chongqing, China). 12 were positive. Negative staining means a low expression of PHF2, and positive means a high expression of PHF2. Reverse transcription-polymerase chain reaction (RT-PCR) Total RNA was extracted from the tissues and cells using TRIzol Survival analysis reagent (Invitrogen; Thermo Fisher Scienti c, Inc.) and An online data base (http://kmplot.com/analysis/) was used to m complementary DNA was synthesized by 1 g of total RNA to analyze the prognosis of breast cancer patients with different m a nal volume of 20 l, according to M-MLVE reverse tran- expression levels of PHF2. scription (Applied Biosystems, Foster City, CA, USA), according Creative Commons Attribution-NonCommercial 3.0 Unported Licence. ’ to the manufacturer s instructions. The semi-quantitative PCR The transfection of adenovirus Ad-PHF2 and Ad-RFP conditions were as follows: initial denaturation at 95 C for We purchased the adenovirus of the over-expressed PHF2 gene 2 min, denaturation at 94 C for 30 s with 32 cycles, annealing at (Ad-PHF2/PHF2) and the negative control which lacked the PHF2 55 C for 30 s, and extension at 72 C for 30 s, with extension at geneandexpressedenhancedreduorescence (Ad-RFP/vector) 72 C for 3 min in the nal step. The RNA and c-DNA solution from the Hanbio Shanghai company. Breast cancer cell lines were was stored at 80 C. The quantitative polymerase chain reaction 5 seeded in six well plates at a density of 1 Â 10 per well and (qPCR) conditions were as follows: initial denaturation at 95 C cultured overnight. Then the cells were transfected with the Ad- for 30 s, followed by 40 cycles with denaturation at 95 C for 5 s, PHF2 and Ad-RFP (the multiplicity of infection is 60) in serum-free annealing and extension at 60 C for 34 s. The reaction was This article is licensed under a medium for 2 h, then replaced by the complete medium. performed on ABI 7500 Primes (Applied Biosystems, Foster City, CA, USA) using a SYBR Green PCR Master Mix/Rox II (Takara Biotechnology Co., Ltd.). Each sample with 10 ml of the mixture The colon formation assay of cells m m m Open Access Article. Published on 27 November 2018. Downloaded 9/28/2021 4:51:22 PM. (containing 2 l cDNA, 1.8 l of ddH2O (RNase Free), 5 l of One A er 72 h post-transfection, cells were collected and seeded in Step SYBR Premix Buffer (2Â), 0.2 ml of ROX Reference Dye II six well plates at a density of 600 per well following ectopic (50Â), 0.4 ml of PCR forward primer (10 mM) and 0.4 ml of PCR expression of PHF2 by Ad-PHF2 and the control (Ad-RFP/vector), reverse primer (10 mM)) was run in triplicate, and the average selected for 2 weeks. Surviving colonies ($50 cells per colony) value was analysed. The relative expression of target gene DDCt were counted aer staining with gentian violet. Finally, photos was normalized with the GAPDH. The primers for the reaction were taken.
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