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Mechanism of Lncrna FEZF1-AS1 in Promoting the Occurrence and Development of Oral Squamous Cell Carcinoma Through Targeting Mir-196A

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Mechanism of Lncrna FEZF1-AS1 in Promoting the Occurrence and Development of Oral Squamous Cell Carcinoma Through Targeting Mir-196A European Review for Medical and Pharmacological Sciences 2019; 23: 6505-6515 Mechanism of lncRNA FEZF1-AS1 in promoting the occurrence and development of oral squamous cell carcinoma through targeting miR-196a L. XU, T.-J. HOU, P. YANG Department of Stomatology, Liaocheng People’s Hospital, Liaocheng, China Lin Xu and Tiejun Hou contributed equally to this work Abstract. – OBJECTIVE: Previous studies have Meanwhile, the miR-196a expression was nega- demonstrated that long non-coding ribonucleic tively correlated with FEZF1-AS1. Subsequent acid (lncRNA) FEZF1-AS1 acts as a cancer-pro- Luciferase reporter gene assay confirmed that moting gene. However, no reports have investi- overexpression of miR-196a could markedly re- gated the role of FEZF1-AS1 in oral squamous cell duce the activity of Luciferase containing wild- carcinoma (OSCC) yet. Therefore, the aim of this type FEZF1-AS1 vector rather than decrease the study was to explore whether FEZF1-AS1 promot- activity of Luciferase containing mutant-type ed the expression characteristics of OSCC by tar- vector or empty vector. These findings further geting miR-196a and to further elucidate the un- indicated that FEZF1-AS1 could be targeted by derlying mechanism of FEZF1-AS1 in promoting miR-196a through this binding site. In addition, the metastasis of OSCC. recovery assay demonstrates that there was a PATIENTS AND METHODS: The expression mutual regulatory effect between FEZF1-AS1 levels of FEZF1-AS1 and miR-196a in 42 pairs of and miR-196a, jointly affecting the malignant OSCC tissues and para-carcinoma tissues were progression of OSCC. detected via quantitative Real Time-Polymerase CONCLUSIONS: The expression of lncRNA Chain Reaction (qRT-PCR). The correlation FEZF1-AS1 was markedly up-regulated in OSCC, of FEZF1-AS1 expression with clinical indexes which was significantly correlated with patho- and prognosis of OSCC patients was analyzed. logical stage and poor prognosis of OSCC pa- Moreover, the expression levels of FEZF1-AS1 tients. Therefore, it was believed that FEZF1- and miR-196a in OSCC cells were detected via AS1 might promote the malignant progression qRT-PCR. FEZF1-AS1 knockdown and miR-196a of OSCC by regulating miR-196a. over-expression models were established using Key Words: lentivirus transfection in OSCC cell lines (CAL- LncRNA FEZF1-AS1, MiR-196a, Oral squamous cell 27 and Tca8113). Subsequently, the influences carcinoma (OSCC), Proliferation. of FEZF1-AS1 and miR-196a on the biological functions of OSCC cells were analyzed via Cell Counting Kit-8 (CCK-8) assay, colony formation assay and 5-Ethynyl-2’-deoxyuridine (EdU) assay, respectively. Furthermore, the potential mecha- Introduction nism was explored using the Luciferase reporter gene and recovery assays. The oral cavity is located at the initial position RESULTS: The results of qRT-PCR proved of the digestive and respiratory tract, which pos- that the expression level of FEZF1-AS1 in OSCC sesses important physiological functions1,2. Oral tissues was significantly higher than that of cancer is considered one of the top ten frequently- para-carcinoma tissues, and the difference was statistically significant. The pathological stage occurring cancers in the body. It can cause dys- was significantly higher in patients with high- functions of eating, speech and respiratory in se- expression FEZF1-AS1 than those with low-ex- vere cases, seriously affecting the quality of life of pression FEZF1-AS1, while the overall survival patients1,2. Squamous cell carcinoma is the most rate was remarkably lower. The proliferation common type of oral cancer, accounting for more ability of cells in FEZF1-AS1 silencing group de- than 90% of oral cancer patients. The prognosis of clined significantly when compared with the NC squamous cell carcinoma is relatively poor, with a group. Similarly, qRT-PCR results verified that 3-5 the expression of miR-196a in OSCC cell lines 5-year survival rate of 50-60% only . Oral squa- and tissues was significantly reduced as well. mous cell carcinoma (OSCC) is generally derived Corresponding Author: Tiejun Hou, MM; e-mail: htjdentist@163.com 6505 L. Xu, T.-J. Hou, P. Yang from oral mucosal epithelium. Due to the reasons ment of tumors. Therefore, the aim of this study that the oral cavity is located at the key position was to investigate the mechanism of lncRNA of the digestive and respiratory tract and there are FEZF1-AS1 in affecting clinical parameters, many important organs, postoperative recurrence prognosis and malignant progression of OSCC and cervical lymph node metastasis of OSCC oc- by absorbing miR-196a. cur easily6,7. In recent years, synthetic serial ther- apy based on surgery has been widely applied in the diagnosis and treatment of OSCC. Meanwhile, the importance of radical and complete treatment Patients and Methods in the prognosis of patients has been emphasized. However, the 5-year survival rate of patients with Patients and OSCC Specimens advanced tumor and recurrence remains far from A total of 42 paired OSCC tissues and para- satisfactory despite various treatment methods8-10. carcinoma tissues were collected. All specimens Therefore, the study of the pathogenesis of OSCC, were obtained from tissues subjected to operation especially the detection and diagnosis of specific and needle biopsy or bronchoscopic biopsy in the early tumor markers, has been increasingly more Oncology Department and Stomatology Depart- important8,10. ment. In addition, no patient underwent anti- Previous molecular biological studies11,12 on tumor therapies such as radiotherapy and che- tumors have mainly focused on genes that can motherapy before the operation. This study was encode proteins. However, non-coding genes are approved by the Ethics Committee of Liaocheng ignored. Non-coding genes are a general term People’s Hospital. Informed consent was obtained for genes with no protein-encoding functions, from each subject before the study. All patients and their transcription products are non-coding were followed up via telephone and clinic after ribonucleic acid (ncRNA)13,14. There are many discharge. Follow-up information was collected, members of the ncRNA family, of which micro including general conditions, clinical symptoms RNA (miRNA) and long ncRNA (lncRNA) are and imaging examinations. the most notable15,16. Currently, molecular biologi- cal mechanism of miRNA has been studied. It has Cell Lines and Reagents been found that miRNA can silence mRNA at the Four human OSCC cell lines (Fadu, SCC-25, post-transcriptional level through complementary CAL-27, and Tca8113) and one normal human base pairing. The correlations of miRNA with oral cell line (Hs 680.Tg) were purchased from the pathogenesis of malignancies and diagnostic the American Type Culture Collection (ATCC; values have been confirmed as well17,18. LncRNAs Manassas, VA, USA). Dulbecco’s Modified Ea- are a kind of RNA molecules with more than 200 gle’s Medium (DMEM) and fetal bovine serum nt in length, with no protein-encoding ability. (FBS) were purchased from Life Technologies Previous studies19-21 have indicated that they ex- (Gaithersburg, MD, USA). All cells were cultured ert biological functions in the form of RNA. Ln- in DMEM containing 10% FBS in an incubator cRNA was regarded as “noise” produced in the with 5% CO2 at 37°C. gene transcription process in the past. However, increasingly more evidence has suggested that ln- Cell Transfection cRNAs are involved in regulating gene expression Control group (NC) and FEZF1-AS1 silencing at epigenetic, transcriptional and post-transcrip- group containing FEZF1-AS1 lentiviral sequence tional levels. Moreover, lncRNAs play extensive (sh-FEZF1-AS1), and control group (miR-NC) and important roles in life processes, such as cell and overexpression group containing miRNA- differentiation, cell fate determination, prolifera- 196a lentiviral sequence (miRNA-196a mimics) tion and migration12,21. were purchased from Shanghai GenePharma Co., In the present work, the expressions of Ltd. (Shanghai, China). The cells were first seed- FEZF1-AS1 and miR-196a in 42 pairs of OSCC ed into 6-well plates, followed by culture until tissues and para-carcinoma tissues were ana- cell density reached 70%. Subsequently, the cells lyzed. The influences of FEZF1-AS1 and miR- were transfected with lentivirus according to the 196a on the biological functions of OSCC cells manufacturer’s instructions. 48 h after transfec- were explored as well. Previous studies have tion, the cells were collected for quantitative Real pointed out that FEZF1-AS1 and miR-196a play Time-Polymerase Chain Reaction (qRT-PCR) important roles in the occurrence and develop- analysis and functional cell assays. 6506 LncRNA FEZF1-AS1 and oral squamous cell carcinoma Cell Proliferation Assay was used for amplification, including 2×SYBR 48 h after transfection, the cells were collected Green PCR Master Mix (Thermo Fisher Scientific, and seeded into 96-well plates (2000 cells/well). Waltham, MA, USA), an appropriate amount of After culturing for 6 h, 24 h, 48 h, and 72 h, the cDNA as a template and primers (0.4 mol/L). Three cells were added with Cell Counting Kit-8 (CCK- replicates were set for each sample. The correspond- 8) reagent (Dojindo Laboratories, Kumamoto, Ja- ing forward and reverse primers were designed and pan), respectively. After incubation for another 2 synthesized according to target genes. PCR ampli- h in the dark, the optical density (OD) value of fication was conducted on a qPCR instrument, with each well at the wavelength of 490 nm was mea- β-actin as an internal reference. The expression level sured using a microplate reader. Finally, experi- of the genes was calculated by the RQ=2-ΔΔCt meth- mental data were analyzed. od. This experiment was repeated three times Primers used in this study were as follows: Colony Formation Assay FEZF1-AS1: forward: 5’-TCGCTCAATG- 48 h after transfection the cells were collected, GAGTGACGGCA-3’, reverse: 5’-CGGCT- and 200 cells were inoculated into each well of GAGACCGCTGAGAACTT-3’.
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