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TRIM24 Aggravates the Progression of Ovarian Cancer Through Negatively Regulating FOXM1 Level

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TRIM24 Aggravates the Progression of Ovarian Cancer Through Negatively Regulating FOXM1 Level European Review for Medical and Pharmacological Sciences 2019; 23: 10647-10656 TRIM24 aggravates the progression of ovarian cancer through negatively regulating FOXM1 level H.-E. ZHOU, S.-S. PAN, H. HAN Department of Gynaecology, First People’s Hospital of Fuyang District, Hangzhou, China Abstract. – OBJECTIVE: This study aims to Introduction uncover the biological functions of the feedback loop tripartite motif-containing 24 (TRIM24)/ The mortality of ovarian cancer (OC) ranks Forkhead Box M1 (FOXM1) in the pathological the first in gynecological malignant tumors due progression of ovarian cancer (OC) and the un- 1-3 derlying mechanism. to its high rate of metastasis . The detective rate PATIENTS AND METHODS: The expression of the early-stage OC is extremely low because levels of TRIM24 and FOXM1 in OC tissues of the physiological structure of ovaries, atypical and cells were determined by quantitative Re- symptoms, and ineffective screening methods4-6. al Time-Polymerase Chain Reaction (qRT-PCR). About 70% of OC patients are accompanied with The potential correlation between TRIM24 level metastases at the initial diagnosis4-6. The two-tier and clinical indexes of OC patients was analyzed. system for grading OC classifies it into high grade The Kaplan-Meier curves were depicted for eval- 7,8 uating the prognostic potentials of TRIM24 and and low grade . High-grade ovarian epithelial FOXM1 in OC patients. The regulatory effects of cancer accounts for 75% of OC cases, and 90% TRIM24 and FOXM1 on proliferative, migratory, of OC-induced deaths. It is manifested as rapid and invasive capacities of SKOV3 and OVCAR3 onset and strong invasiveness, often accompanied cells were assessed through functional experi- by extensive pelvic and abdominal metastasis ments. The rescue experiments were performed and implantation, resulting in an extremely poor to clarify the feedback loop TRIM24/FOXM1 in 9,10 influencing the progression of OC. prognosis . In contrast, the low-grade ovarian RESULTS: TRIM24 was upregulated in OC tis- epithelial cancer has a slow onset and often expe- sues and cells. The high level of TRIM24 was riences the phenotype progression from benign, linked to higher rates of lymphatic and distant borderline, to low-grade malignancy. Patients metastasis and worse survival in OC patients. with low-grade ovarian epithelial cancer often The silence of TRIM24 attenuated proliferative, have a relatively good prognosis11,12. So far, the migratory, and invasive capacities of SKOV3 and potential mechanisms underlying the invasion OVCAR3 cells. FOXM1 level was negatively reg- ulated by TRIM24, which was downregulated in and metastasis of the high-grade ovarian epithe- 12-14 OC. The low level of FOXM1 predicted worse lial cancer remain unclear . survival in OC patients. Besides, the rescue ex- TRIM24 (tripartite motif-containing 24), also periments demonstrated that the feedback loop known as TIF1α (transcription intermediary fac- TRIM24/FOXM1 aggravated the malignant pro- tor 1α), is a founding member of the transcrip- gression of OC. tional mediator family15,16. TRIM24 has a TRIM CONCLUSIONS: TRIM24 is upregulated in OC tissues, and closely linked to the occurrence of motif (RING-B box-coiled-coil, RBCC) at the lymphatic and distant metastasis. Through neg- amino terminus PHD and Bromo domains at the atively regulating FOXM1 level, TRIM24 aggra- carboxy terminus17. RBCC exerts the activity of vates the progression of OC. ubiquitin-protein ligase E3, which could mediate ubiquitination degradation of p53, while PHD Key Words: TRIM24, FOXM1, OC, Malignant progression. and Bromo domains recognize specific modified histone molecules17. In addition, the LxxLL se- Corresponding Author: Honger Zhou, BM; e-mail: [email protected] 10647 H.-E. Zhou, S.-S. Pan, H. Han quence in the TRIM24 promoter region is capable Cell Proliferation Assay of ligand-dependently binding to several nuclear 2.0×10 3 cells per well were inoculated in a 96- receptors, while the PxVxL sequence contrib- well plate. The viability was determined at the ap- utes to chromatin structural change by binding pointed time points using the Cell Counting Kit-8 to HP118,19. Due to the diversity of its structure, (CCK-8) kit (Dojindo Laboratories, Kumamoto, the biological roles of TRIM24 in tumor diseases Japan). Absorbance at 490 nm was recorded for have been revealed20. For liver cancer, TRIM24 plotting the viability curve. acts as a tumor-suppressor gene. Conversely, TRIM24 functions as an oncogene in granulocyte Colony Formation Assay leukemia and breast cancer21-23. The cells were seeded in a 6-well plate with In this paper, we determined TRIM24 levels in 200 cells per well and incubated for 14 days. The tumor tissues and adjacent normal tissues of OC medium was replaced once in the first week and patients. The correlation between TRIM24 level twice in the second week. Subsequently, the cells and clinical indexes of OC patients was analyzed were fixed in 100% methanol and dyed with 0.5% as well. Subsequently, the potential influences of crystal violet for 20 min. The colonies were cap- TRIM24 on cellular behaviors of OC cells were tured and calculated in a good light environment. assessed, as well as the underlying mechanism. Our results may provide references for clinical di- Transwell Cell Migration agnosis and treatment of OC. and Invasion Assay The transfected cells for 48 h were digested and adjusted to 5.0×105/mL. 200 μL/well suspen- Patients and Methods sion was applied in the upper side of the Matri- gel-coated transwell chamber (Millipore, Bill- Patients and OC Samples erica, MA, USA). In the bottom side, 500 μL of OC tissues and paracancerous tissues were medium containing 10% FBS was applied. After surgically resected from 39 OC patients and 48 h of incubation, the invasive cells were fixed in pathologically diagnosed by hematoxylin-eosin methanol for 15 min, dyed with 0.2% crystal vi- staining (HE) staining. The samples were pre- olet for 20 min, and counted using a microscope. served at -80°C. None of OC patients were treated The penetrating cells were counted in 10 random- with preoperative anti-tumor therapy. The clini- ly selected fields per sample. The transwell mi- cal indexes and follow-up data of the enrolled pa- gration assay was conducted in the same proce- tients were collected. The patients and their fam- dures except for Matrigel pre-coating. ilies in this work have been fully informed. This study was approved by the Ethics Committee of Wound Healing Assay the First People’s Hospital of Fuyang District. The cells were seeded in a 6-well plate with 5.0×10 5/well. Until 90% confluence, an artificial Cell Culture wound was created in the confluent cell monolay- Six human-derived OC cell lines (SKOV3, er using a 1 mL pipette tip. Wound closure images OVCAR3, PEO1, A2780, 3AO, CAOV3) and were taken at 0 and 24 h using an inverted mi- the human ovarian surface epithelial cell line croscope, respectively. The percentage of wound (HOSEPiCs) were provided by American type closure was calculated. culture collection (ATCC; Manassas, VA, USA). The cells were cultured in Dulbecco’s Modified Quantitative Real Time-Polymerase Eagle’s Medium (DMEM; Hyclone, South Lo- Chain Reaction (qRT-PCR) gan, UT, USA) containing 10% fetal bovine se- We extracted the total RNA from cells using rum (FBS; Hyclone, South Logan, UT, USA) and TRIzol reagent (Invitrogen, Carlsbad, CA, USA), maintained at 37°C in a 5% CO2 incubator. and purified them by DNase I treatment. The ex- tracted RNA was reversely transcribed into com- Transfection plementary deoxyribonucleic acids (cDNAs) using TRIM24 shRNAs and sh-NC were construct- Primescript RT Reagent (TaKaRa, Otsu, Shiga, ed by GenePharma (Shanghai, China). The cells Japan). The cDNA was amplified by Real Time inoculated in a 6-well plate were transfected at quantitative-PCR using SYBR®Premix Ex Taq™ 40% confluence. At 48 h, the cells were harvested (TaKaRa, Otsu, Shiga, Japan). β-actin was used for subsequent experiments. as an internal reference. The primer sequences 10648 TRIM24 and OC were as follows: TRIM24: forward: 5’-ACTCGG- Statistical Analysis GACATACCTGCTCT-3’, reverse: 5’-GCCCTAG- The Statistical Product and Service Solutions GGGAGTGACTACA-3’; FOXM1: forward: (SPSS) 22.0 (IBM Corp., Armonk, NY, USA) 5’-AAGGACAGCAAGAAGAAGG-3’, reverse: was used for data analyses. Data were expressed 5’-GAGGAACAGGTGGAGAGT-3’; β-actin: for- as mean ± standard deviation. The Student’s t-test ward: 5›-CCTGGCACCCAGCACAAT-3›, reverse: was applied for analyzing differences between 5›-GCTGATCCACATCTGCTGGAA-3›. the two groups. Kaplan-Meier was introduced for survival analysis, followed by Log-rank test for Western Blot comparing two curves. p<0.05 was considered The cells were lysed for extracting the total statistically significant. protein using radioimmunoprecipitation assay (RIPA), quantified by bicinchoninic acid (BCA) method and loaded for electrophoresis (Beyo- Results time, Shanghai, China). After transferring on a polyvinylidene difluoride (PVDF) membrane TRIM24 Was Highly Expressed in OC (Millipore, Billerica, MA, USA), it was blocked Totally, 39 matched OC tissues and adjacent in 5% skim milk for 2 hours, incubated with pri- normal tissues were collected. Compared with mary antibodies at 4°C overnight and secondary normal ones, TRIM24 was upregulated in OC antibodies for 2 h. The bands were exposed by en- tissues (Figures 1A, 1B). Similarly, in vitro abun- hanced chemiluminescence (ECL) and analyzed dance of TRIM24 was higher in OC cells relative by Image Software (Media Cybernetics, Silver to that of the human ovarian surface epithelial cell Springs, MD, USA). HOSEPiCs (Figure 1C). A B C D Figure 1. TRIM24 was highly expressed in OC. A-B, TRIM24 levels in OC tissues and adjacent normal ones. C, TRIM24 levels in the human ovarian surface epithelial cells (HOSEPiCs) and OC cells (3AO, PEO1, A2780, CAOV3, OVCAR3 and SKOV3). D, Survival in OC patients expressing high and low level of TRIM24.
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