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Lncrna CDKN2BAS Aggravates the Progression of Ovarian Cancer by Positively Interacting with GAS6

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Lncrna CDKN2BAS Aggravates the Progression of Ovarian Cancer by Positively Interacting with GAS6 European Review for Medical and Pharmacological Sciences 2020; 24: 5946-5952 LncRNA CDKN2BAS aggravates the progression of ovarian cancer by positively interacting with GAS6 H.-M. WANG, S.-L. SHEN, N.-M. LI, H.-F. SU, W.-Y. LI Department of Obstetrics and Gynecology, Jinan City People’s Hospital, Jinan, China Abstract. – OBJECTIVE: The aim of this symptoms in the early phase. In addition, rapid study was to elucidate the role of long non-cod- progression, low therapeutic efficacy and high re- ing RNA (lncRNA) CDKN2BAS in aggravating current rate result in the high mortality of ovarian the progression of ovarian cancer via binding cancer1,2. It is of significance to clarify the molec- growth arrest-specific 6 (GAS6). PATIENTS AND METHODS: The relative levels ular mechanism of ovarian cancer and to develop of CDKN2BAS and GAS6 in ovarian cancer and effective biomarkers for diagnosis and treatment. normal ovarian tissues were detected. In addi- Long non-coding RNAs (LncRNAs) are non-cod- tion, their levels in ovarian cancer cases with dif- ing RNAs containing more than 200 nucleotides3. ferent FIGO stages and pathological grades were They were used to be considered as transcript nois- detected. Pearson correlation test was applied es4. With the progressed research, it is found that ln- for assessing the correlation between CDKN- 2BAS and GAS6 levels in ovarian cancer tissues. cRNAs are able to epigenetically, transcriptionally, 5 The roles of CDKN2BAS and GAS6 in mediat- and post-transcriptionally target genes . LncRNAs ing proliferative and migratory potentials in HEY are widely involved in tumor progression by influ- and SKOV-3 cells were examined by Cell Count- encing tumor cell phenotypes and angiogenesis6. ing Kit-8 (CCK-8) and transwell assay, respective- LncRNA CDKN2BAS exerts a vital role in cell ly. Subcellular distribution of CDKN2BAS was ex- plored. CDKN2BAS-GAS6 interaction was eval- proliferation and apoptosis, and extracellular matrix 7,8 uated by RIP (RNA immunoprecipitation) assay. remodeling . Its expression is closely associated with RESULTS: CDKN2BAS was upregulated in susceptibilities to human diseases (i.e. coronary ar- ovarian cancer tissues, especially those with ad- tery diseases and diabetes)7. Besides, CDKN2BAS vanced FIGO stage and high pathological grade. has been identified to be a critical regulator in brain It displayed diagnostic potential in ovarian can- 8-10 cer. CDKN2BAS level was positively correlated tumors, breast cancer, and myeloblastoma . to that of GAS6 in ovarian cancer tissues. It was GAS6 (growth arrest-specific 6; 75 kDa) is a mainly expressed in the cytoplasm and could secreted protein that was initially discovered in be interacted with GAS6. The overexpression of the NIH 3T3 mouse embryo fibroblast cell line in CDKN2BAS enhanced proliferative and migratory 198811. GAS6 exerts a negative role in cell growth. potentials in HEY and SKOV-3 cells. The knock- Later, GAS6 has been found to be widely ex- down of GAS6 partially abolished the regulatory 12 effects of CDKN2BAS on promoting proliferative pressed in organs and somatic cells . It is reported and migratory potentials in ovarian cancer. that GAS6 is a vital regulator in the early phase of CONCLUSIONS: LncRNA CDKN2BAS is up- ovarian cancer progression13. LINC00565/GAS6 regulated in ovarian cancer. By positively inter- axis drives the progression of ovarian cancer14. acting with GAS6, CDKN2BAS triggers the pro- This study aims to explore the role of CDKN- gression of ovarian cancer. 2BAS/GAS6 axis in the progression of ovarian Key Words: cancer. Our findings may provide novel ideas in LncRNA CDKN2BAS, GAS6, Ovarian cancer. the clinical treatment of ovarian cancer. Introduction Patients and Methods Ovarian cancer is a prevalent female malignant tumor. The detective rate of advanced ovarian Sample Collection cancer is high because of the anatomic loca- Ovarian cancer tissues (n=44) and normal ovar- tion of the ovaries, insidious onset and atypical ian tissues (n=16) were collected from Jinan City 5946 Corresponding Author: Wenying Li, BM; e-mail: [email protected] LncRNA CDKN2BAS aggravates the progression of ovarian cancer by positively interacting with GAS6 People’s Hospital from May 2017 to July 2019. Technolgies, Kumamoto, Japan) was added in They were pathologically confirmed and stored each well. The absorbance at 450 nm of each at -80°C. All the patients involved in the study sample was measured by a microplate reader were initially treated with surgery and none of (Bio-Rad, Hercules, CA, USA). recruited subjects were treated with preoperative radiotherapy nor chemotherapy. The tissues of the Transwell Assay epithelial ovarian cancer group and the normal 100 μL of suspension (1×105 cells/ml) was inoc- ovarian group were confirmed by postoperative ulated in the upper insert of a transwell chamber pathological diagnosis. This study was approved (Millipore, Billerica, MA, USA), which was in- by the Ethics Committee of Jinan City People’s serted in a 24-well plate with 500 μL of medium Hospital. Signed written informed consents were containing 10% FBS in the bottom. 48 hours obtained from all participants before the study. later, bottom cells were reacted with 15-min methanol, 20-min crystal violet, and captured Cell Culture and Transfection using a microscope. The number of migratory Ovarian cancer cell lines (A2780, HO8910, cells was counted in 10 random fields per sample HEY, and SKOV-3) and the ovarian epithelial cell (magnification 200×). line (IOSE-80) were provided by American Type Culture Collection (ATCC; Manassas, VA, USA). Subcellular Distribution Analysis The cells were cultured in Dulbecco’s Mod- PARIS kit (Invitrogen, Carlsbad, CA, USA) ified Eagle’s Medium (DMEM; Gibco, Rock- was used for isolating cytoplasmic and nuclear ville, MD, USA) in a 5% CO2 incubator at 37°C. fractions. RNAs in cellular components were 10% fetal bovine serum (FBS; Gibco, Rockville, detected by qRT-PCR. U6 and GAPDH were the MD, USA), 100 U/mL penicillin, and 100 μg/mL internal references of nucleus and cytoplasm, streptomycin were applied in the culture medium. respectively. Transfection plasmids were provided by Genechem, Co., Ltd. (Shanghai, China). The cells RIP (RNA Immunoprecipitation) were cultured to 60-70% density, and transfected The cells were collected for incubating with using Lipofectamine 2000 (Invitrogen, Carlsbad, input, anti-IgG or anti-CDKN2BAS at 4°C over- CA, USA) in serum-free medium. 6 hours later, night. Intracellular proteins were captured, fol- the complete medium was replaced. lowed by obtaining the protein-RNA complex. After digestion in proteinase K, protein fraction Quantitative Real Time-Polymerase was cleared. The remaining immunoprecipitant Chain Reaction (qRT-PCR) RNAs were subjected to qRT-PCR. TRIzol (Invitrogen, Carlsbad, CA, USA) was applied for lysing cells or tissues and extracting Statistical Analysis total RNAs. Reverse transcription of RNAs was Statistical Product and Service Solutions performed by the PrimeScript RT reagent Kit (SPSS) 20.0 (IBM Corp., Armonk, NY, USA) was (TaKaRa, Otsu, Shiga, Japan) and complementa- used for data analyses. Data were expressed as ry deoxyribose nucleic acid (cDNA) was sent for mean ± standard deviation (SD). Receiver operat- qRT-PCR. The relative level of the target was cal- ing characteristic (ROC) curves were depicted for culated using 2-ΔΔCt method. The primer sequenc- assessing the diagnostic potential of CDKN2BAS es were as follows. CDKN2BAS: F: 5′-TGCCG- in ovarian cancer. The differences between the GAGCTGTCGACCC-3′, R: 5′-TTTGATCTCT- two groups were analyzed by the t-test. The rela- GCTGTTGAATCAGAATG-3′; GAS6: F: tionship between the expression levels of the two 5′-CCGGAGCGAGGACTGTATCATCT-3′, R: genes was analyzed by Pearson correlation test. 5′-ACTTCCCAGGTTGATTCAGTCCC-3′; glyc- p<0.05 was considered as statistically significant. eraldehyde 3-phosphate dehydrogenase (GAP- DH): F: 5′-CTCCTGCATGCCACGGA-3′, R: 5′-AGACCCTTACAGTTAGTCGT-3′. Results Cell Counting Kit-8 (CCK-8) Assay CDKN2BAS was Upregulated in Cells were inoculated into 96-well plates with Ovarian Cancer Tissues 1×10 3 cells per well. At the appointed time points, Compared with controls, CDKN2BAS was up- 10 μL of CCK-8 solution (Dojindo Molecular regulated in ovarian cancer tissues (Figure 1A). 5947 H.-M. Wang, S.-L. Shen, N.-M. Li, H.-F. Su, W.-Y. Li Figure 1. CDKN2BAS was upregulated in ovarian cancer tissues. A, Relative levels of CDKN2BAS in ovarian can- cer tissues and normal ovar- ian tissues. B, Relative levels of CDKN2BAS in ovarian cancer tissues with FIGO I+II and FIGO III+IV. C, Relative levels of CDKN2BAS in ovar- ian cancer tissues with high and low pathological grade. D, ROC curves depicted for assessing the diagnostic po- tential of CDKN2BAS in ovarian cancer (AUC=0.9474, p<0.001, cut-off value=0.3714, sensitivity=90.7%, specifici- ty=89.92%). *p<0.05. According to the FIGO staging, ovarian cancer Interaction Between CDKN2BAS and patients were assigned into FIGO I+II group GAS6 and FIGO III+IV group. Higher abundance of It is uncovered that CDKN2BAS was main- CDKN2BAS was detected in FIGO III+IV group ly distributed in the cytoplasm of HEY and compared with that in FIGO I+II group (Fig- SKOV-3 cells (Figure 3A, 3B). Moreover, GAS6 ure 1B). Similarly, ovarian cancer patients with was abundantly enriched in anti-CDKN2BAS, high pathological grade expressed higher level of verifying the interaction between CDKN2BAS CDKN2BAS than those with low grade (Figure and GAS6 (Figure 3C).
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