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Microrna‑451A Prevents Cutaneous Squamous Cell Carcinoma Progression Via the 3‑Phosphoinositide‑Dependent Protein Kinase‑1‑Mediated PI3K/AKT Signaling Pathway

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Microrna‑451A Prevents Cutaneous Squamous Cell Carcinoma Progression Via the 3‑Phosphoinositide‑Dependent Protein Kinase‑1‑Mediated PI3K/AKT Signaling Pathway EXPERIMENTAL AND THERAPEUTIC MEDICINE 21: 116, 2021 MicroRNA‑451a prevents cutaneous squamous cell carcinoma progression via the 3‑phosphoinositide‑dependent protein kinase‑1‑mediated PI3K/AKT signaling pathway JIXING FU*, JIANHUA ZHAO*, HUAMIN ZHANG, XIAOLI FAN, WENJUN GENG and SHAOHUA QIAO Department of Dermatology, Liaocheng Second People's Hospital, Shandong First Medical University Affiliated Liaocheng Second Hospital, Linqing, Shandong 252601, .R.P China Received February 12, 2020; Accepted August 11, 2020 DOI: 10.3892/etm.2020.9548 Abstract. The role of microRNAs (miRNAs/miRs) in pathway, which may offer potential therapeutic targets for the governing the progression of cutaneous squamous cell carci‑ treatment of cSCC. noma (cSCC) has been the focus of recent studies. However, the functional role of miR‑451a in cSCC growth remains Introduction poorly understood. Therefore, the present study aimed to determine the expression levels of miR‑451a in cSCC cell Skin cancer or cutaneous carcinoma is a major worldwide lines and the involvement of miR‑451a in cSCC progression. public health burden which is highly prevalent and demon‑ The results revealed that the expression levels of miR‑451a strates an ever‑increasing incidence with ~108,420 new cases were downregulated in cSCC tissues and cell lines, and that and 11,480 death in the United States in 2020 (1,2). The this subsequently upregulated 3‑phosphoinositide‑dependent majority of diagnosed skin cancer cases are non‑melanoma‑ protein kinase‑1 (PDPK1) expression levels. PDPK1 was tous, consisting of basal cell carcinoma and cutaneous cell validated as a direct target of miR‑451a in cSCC using carcinoma (cSCC), which originate from keratinized epithelial bioinformatics software Starbase, dual‑luciferase reporter cells (3). Common risk factors for most non‑melanomatous gene assays and western blotting. Additionally, CCK‑8, EdU cancers include ultraviolet light exposure, radiation exposure, and Transwell assays, as well as flow cytometry and Hoechst immunosuppression and genetic factors (4). The most effective 3325 staining, were performed to assess the malignant aggres‑ treatment for the majority of lesions is surgery; however, other siveness of cSCC cells. Overexpression of miR‑451a was interventions, including radiation, topical immunomodulators demonstrated to impair the proliferation, migration, invasion and novel systemic drugs are also applied (5). The incidence and epithelial‑mesenchymal transition (EMT), and promoted rates of cSCC are much higher in populations with fairer apoptosis in cSCC cells by interacting with PDPK1, possibly by skin compared with individuals with darker skin and notably direct targeting. Furthermore, the western blotting results indi‑ higher, still, in regions with high ambient ultraviolet radiation cated that miR‑451a overexpression may block the PI3K/AKT levels (6). For instance, incidence rates have ranged from 60 per signaling pathway by interacting with PDPK1. In conclusion, 100,000 people annually in Canada (latitude, 54˚N; 2006) to the findings of the present study suggested that miR‑451a may 290 per 100,000 people annually in the United States (latitude, prevent the proliferation, migration, invasion and EMT of 31‑37˚N; 1991); these rates were higher compared with those cSCC cells through the PDPK1‑mediated PI3K/AKT signaling in Norway (annually, 20 per 100.000 men and 15 per 100,000 women; 2008‑11) (7‑9). cSCC is characterized by neoplastic squamous epithelial cells invading into the dermis, which may present as nodules, squamous islands or cystic structures (10). The past decade has seen significant advancements in the Correspondence to: Dr Jixing Fu, Department of Dermatology, development of diagnostic and prognostic biomarkers, which Liaocheng Second People's Hospital, Shandong First Medical may help elucidate the mechanisms that promote tumor initia‑ University Affiliated Liaocheng Second Hospital, 306 Health Street, tion, progression and metastasis (11). Linqing, Shandong 252601, P.R. China MicroRNAs (miRNAs/miRs) are a group of non‑coding E‑mail: [email protected] RNAs of ≤25 nucleotides in length (12). miRNAs modu‑ *Contributed equally late gene expression post‑transcriptionally and numerous miRNAs, including miR‑34a, miR‑181a and miR‑148a, have Key words: cutaneous squamous cell carcinoma, microRNA‑451a, been revealed to function as tumor suppressors in patients 3‑phosphoinositide‑dependent protein kinase‑1, PI3K/AKT with cSCC (13). A previous study revealed that miR‑451a signaling pathway, migration, invasion expression levels were markedly downregulated in human basal cell carcinoma tissues and mouse models (14), indicating its potential role in skin cancer. The present 2 FU et al: TUMOR SUPPRESSIVE ROLE OF miR‑451a IN CSCC study predicted that 3‑phosphoinositide‑dependent protein RT‑qPCR. Total RNA was extracted from HaCaT, A431, kinase‑1 (PDPK1) may be a target gene of miR‑451a, which HSC‑5, SCC‑12 and SCL‑1 cells using TRIzol® reagent was discovered by performing a dual‑luciferase reporter gene (Invitrogen; Thermo Fisher Scientific, Inc.), according to the assay. PDPK1 was previously illustrated to serve a pivotal manufacturer's protocol. Total RNA was reverse transcribed role in the proliferation of angiosarcoma cells, indicating its into cDNA using a PrimeScript™ RT reagent kit according to potential use as a target against angiosarcoma, an aggressive the manufacturer's protocol with a gDNA Eraser (Takara Bio, malignancy of endothelial cells (15). In non‑small cell lung Inc.) at 70˚C for 5 min, ice‑bathed for 3 min, at 37˚C for 60 min cancer, miR‑503 upregulation was revealed to downregulate and at 95˚C for 10 min. qPCR was subsequently performed PDPK1 expression levels, thus blocking the PI3K/AKT using a SYBR Green PCR Master mix (Invitrogen; Thermo signaling pathway (16). The present study determined the Fisher Scientific, Inc.). The thermocycling conditions were expression profiles of miR‑451a and PDPK1 in cSCC tissues as follows: Pre‑denaturation at 95˚C for 5 min; denaturation using bioinformatics analysis and cSCC cell behavioral at 94˚C for 45 sec; annealing at 56˚C for 45 sec and extension examination. The association between miR‑451a and PDPK1 at 72˚C for 45 sec for a total of 35 cycles. The primer sequences was also investigated using bioinformatics analysis and a used for qPCR are provided in Table II. GAPDH and U6 were dual‑luciferase reporter gene assay. A431 and SCC‑12 cell used as the internal loading controls. Fold changes in the rela‑ lines overexpressing miR‑451a were generated to determine tive expression of the targets were calculated using the 2‑ΔΔCq the regulatory role of miR‑451a in the cSCC malignant method (20). phenotype and the PI3K/AKT signaling pathway. Cell Counting Kit‑8 (CCK‑8) assay. The proliferative ability Materials and methods of cSCC cells was evaluated using a CCK‑8 assay (Roche Diagnostics). At 48 h post‑transfection, A431 and SCC‑12 were Bioinformatics analysis. The cSCC‑associated dataset seeded into 96‑well plates (5x103 cells/well) at 37˚C. At the GSE57768, which was comprised of 30 cSCC tissues and baseline, 24, 48 and 72 h post‑incubation, 50 µl CCK‑8 reagent 18 normal skin tissues (17), was downloaded from the Gene was added to determine the optical density values at 490 nm Expression Omnibus (GEO) database (ncbi.nlm.nih.gov/geo). with a Multiskan Sky microplate reader. The differentially expressed genes (DEG) between control and cancerous samples were identified using the limma package of 5‑ethynyl‑2'‑deoxyuridine (EdU) staining. Additionally, the R software (version no. 3.6.2; master.bioconductor.org/pack‑ proliferative ability of cSCC cells was analyzed using EdU ages/release/bioc/html/limma.html). The cut‑off values for staining, as previously described (21). Briefly, stably transfected DEG selection were P<0.05 and |Log FoldChange|>1, which A451 and SCC‑12 cells (5x103 cells/well) were seeded into were used to plot a heatmap of DEGs using the heatmap 96‑well petri dishes for a 24‑h culture and fixed with 100 µl package (version no. 1.0.12) of R software (cran.r‑project. 4% paraformaldehyde for 30 min at room temperature. Then, org/web/packages/pheatmap/index.html). RPMI‑1640 medium (100 µl) containing 20 µM EdU (Beijing The target mRNAs of miR‑451a were subsequently Solarbio Science & Technology Co., Ltd.) was added into predicted using the StarBase version 2.0 website (http://star‑ each well, after which cells were cultured at 37˚C for 2 h. The base.sysu.edu.cn). Signaling pathway enrichment analysis was EdU positive cells were stained red. Nuclei were subsequently conducted with the target mRNAs identified by Starbase using counterstained with 4',6‑diamidino‑2‑phenylindole at 37˚C the Kyoto Encyclopedia of Genes and Genomes (KEGG) for 30 min. The number of EdU positive cells was observed database (kegg.jp) through The Database for Annotation, in five different visual fields using a fluorescence microscope Visualization and Integrated Discovery (version no. 6.8; david. (magnification, x200; Olympus Corporation). The EdU positive ncifcrf.gov) (18,19). cell index (EdU positive cells/total cells) was measured using ImageJ (version no. 1.52; National Institutes of Health). Cell lines and culture. The human keratinocyte cell line HaCaT (cat. no. GDC106) and cSCC cells, A431, HSC‑5, Flow cytometric analysis of apoptosis. Apoptotic cSCC SCC‑12 and SCL‑1, were all purchased from The Cell Bank of cells were analyzed following miR‑451a transfection using Type Culture Collection of the Chinese Academy of Sciences. an Annexin V‑fluorescein isothiocyanate (FITC)/propidium Cells were cultured in RPMI‑1640 medium (Gibco; Thermo iodide (PI) apoptosis detection kit (Best‑Bio, Ltd.) and flow Fisher Scientific, Inc.) supplemented with 10% FBS (Gibco; cytometry as previously reported (22). Briefly, cells were resus‑ Thermo Fisher Scientific, Inc.) at 37˚C with 5% CO2. pended in 200 µl binding buffer and dual‑stained in the dark Subsequently, A431 and SCC‑12 cells in the logarithmic for 15 min at room temperature using PI and Annexin V‑FITC growth phase were seeded into 6‑well plates (2x105 cells/well) (both, 100 µl).
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