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LHX1 as a potential biomarker regulates EMT induction and cellular behaviors in uterine corpus endometrial carcinoma
Ye Tiana,
Corresponding author
Field617@163.com

Corresponding author.
, Fang Wenb, Shuo Wanga, Na Lvc
a Department of Gynecology, Liaoning Cancer Hospital, Shenyang, China
b Department of Gynecology, The First Hospital, China Medical University, Shenyang, China
c Blood Collection Center, The First Hospital of China Medical University, Shenyang, China
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          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">LHX1 overexpression enhances UCEC cell migration&#44; invasion&#44; proliferation&#44; and EMT induction&#46; &#40;A&#41; LHX1 expression was confirmed to be increased via RT-qPCR and Western blotting compared with that in cells treated with the empty pcDNA3&#46;1 vector&#46; &#40;B&#41; CCK-8 assay was used to analyze cellular proliferation&#46; &#40;C&#41; Overexpressed LHX1 enhanced the colony formation capability of HEC-1B cells compared with empty vector transfection&#46; &#40;D&#41; The influence of LHX1 overexpression on HEC-1B cell migration was examined via wound healing assay&#46; &#40;&#215;100&#59; scale bar&#44; 100&#160;&#956;m&#41; &#40;E&#41; Cellular migration and &#40;F&#41; invasion were analyzed and quantified&#46; &#40;&#215;100&#59; scale bar&#44; 100&#160;&#956;m&#41; &#40;G&#41; LHX1 overexpression enhanced the expression of Slug&#44; Snail&#44; Vimentin&#44; and N-cadherin&#44; while inhibited the expression of E-cadherin&#46; Results are expressed as mean&#160;&#177;&#160;SD&#59; &#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;01&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;001&#46; Data are representative of three independent experiments&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Introduction</span><p id="para0008" class="elsevierStylePara elsevierViewall">Uterine corpus cancer is the second most prevalent type of gynecological malignancy and the sixth most common type of cancer affecting women&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> In&#160;2021&#44; 66&#44;570&#160;new cases of uterine corpus cancer and 12&#44;940&#160;uterine corpus cancer-related deaths were reported worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> The incidence of endometrial cancer is significantly higher in developed countries &#40;5&#46;9&#37;&#41; compared with that in developing countries &#40;4&#46;0&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> and the number of patients with endometrial cancer in the USA has been predicted to rise to&#160;42&#46;13&#160;per&#160;10&#44;000&#160;persons by&#160;2030&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> Despite the advances in the targeted treatment for patients with Uterine Corpus Endometrial Carcinoma &#40;UCEC&#41;&#44; morbidity and mortality continue to rise&#46;<a class="elsevierStyleCrossRefs" href="#bib0001"><span class="elsevierStyleSup">1-3</span></a> Although UCEC is frequently detected in earlier stages and is thus generally associated with a favorable prognosis&#44; 10&#8210;15&#37; of patients ultimately develop metastasis that spreads beyond the regional lymph nodes and pelvis&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> Female patients exhibit a relatively poor prognosis&#44; accounting for a disproportionate fraction of endometrial cancer-related morality&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> For patients with stage IV UCEC&#44; the&#160;5-year survival rate is estimated to range from&#160;12&#37;&#160;to&#160;48&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> Therefore&#44; novel diagnostic&#47;prognostic biomarkers and therapeutic targets for UCEC are essential to guide patient management&#46;</p><p id="para0009" class="elsevierStylePara elsevierViewall">LIM Homeobox&#160;1 &#40;LHX1&#41; is a nuclear transcription factor in the LIM Homeodomain &#40;LIM-HD&#41; family&#44; which consists of key transcriptional regulators that control organogenesis during embryonic development&#46;<a class="elsevierStyleCrossRefs" href="#bib0008"><span class="elsevierStyleSup">8-11</span></a> LHX1 expression is initially detected during gastrulation where it regulates cellular motility&#44; and it is subsequently identified in the intermediate and lateral mesoderm&#46; It has been reported to play an important role as a regulator of cell processes and cytoskeletal organization&#44; as well as oncogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0012"><span class="elsevierStyleSup">12-14</span></a> Reports of LHX1 expression in endometrial tissues from both neonatal&#47;adult mice and humans suggested that this transcription factor may also be an important regulator of endometrial development or remodeling&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> Some studies have demonstrated that LHX1 is expressed in diverse types of cancer cells&#44; including leukemia&#44; renal carcinoma&#44; and breast cancer cells&#44; in addition to epithelial cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0014"><span class="elsevierStyleSup">14-17</span></a> For example&#44; LHX1 overexpression has been reported in clear cell renal cell carcinoma&#44; chronic leukemia and pancreatic cancer tissues&#44;<a class="elsevierStyleCrossRefs" href="#bib0018"><span class="elsevierStyleSup">18-20</span></a> and its activation has also been detected in nephroblastoma and medulloblastoma tissues&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> There is evidence that LHX1 is a susceptibility gene in hepatitis&#160;B infection-associated hepatocellular carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> The functional role of LHX1 in UCEC&#44; however&#44; has not yet been clarified&#46;</p><p id="para0010" class="elsevierStylePara elsevierViewall">In this study&#44; the authors explored the role of LHX1 in UCEC and found that it was overexpressed in UCEC tissues and was significantly associated with poorer Overall Survival &#40;OS&#41; and Disease-Specific Survival &#40;DSS&#41;&#46; Using functional network analyses&#44; it was revealed that the expression level of LHX1 was associated with cellular adhesion and positively correlated with the expression levels of key genes related to induction and invasion of Epithelial-Mesenchymal Transition &#40;EMT&#41;&#46; <span class="elsevierStyleItalic">In vitro</span> analyses further indicated that LHX1 could regulate migratory&#44; invasive&#44; and proliferative capabilities of UCEC cells&#44; and alter expression patterns of EMT-related proteins&#46; Consequently&#44; these data might provide preliminary insight into the role of LHX1 in UCEC cells and tissues and facilitate further research on the targeted treatment of patients with UCEC&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Data collection</span><p id="para0011" class="elsevierStylePara elsevierViewall">The UCSC Xena database &#40;<a href="https://xenabrowser.net/datapages/">https&#58;&#47;&#47;xenabrowser&#46;net&#47;datapages&#47;</a>&#41; was used to download clinical and RNA-seq data in Transcripts Per Million reads &#40;TPM&#41; format from Genotype-Tissue Expression &#40;GTEx&#41; and the Cancer Genome Atlas &#40;TCGA&#41; databases&#46; The RNAseq data were log2-transformed&#44; and LHX1 expression in UCEC tissues and normal tissues was detected&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Data preprocessing</span><p id="para0012" class="elsevierStylePara elsevierViewall">R &#8220;affy&#8221; package was used to analyze the original probe-level data in CEL files by Robust Multi-array average Algorithm &#40;RMA&#41;&#44; and then quantile normalization and correction for the background were performed to obtain gene expression data&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> The average expression value for genes with multiple probes was calculated&#46;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Prognostic analysis</span><p id="para0013" class="elsevierStylePara elsevierViewall">The association of LHX1 expression with OS and DFS of UCEC patients was predicted through Kaplan-Meier and log-rank tests using the survival package in R software&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> with <span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;05 as the significance threshold&#46; Patients were divided into two groups &#40;LHX1 high expression group and LHX1 low expression group&#41; according to the median LHX1 expression level&#44; and survival outcomes between the two groups were compared&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Functional enrichment analysis</span><p id="para0014" class="elsevierStylePara elsevierViewall">The R &#8220;clusterProfiler&#8221; package was used for the classification and enrichment analysis of gene clusters&#44;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> and Gene Ontology &#40;GO&#41; terms and Kyoto Encyclopedia of Genes and Genomes &#40;KEGG&#41; pathways enrichment analyses were conducted to assess the genes co-expressed with LHX1&#46; The p-value threshold was adjusted to&#160;0&#46;05 for the terms with significant enrichment&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Cell culture and transfection</span><p id="para0015" class="elsevierStylePara elsevierViewall">Human Endometrial Stromal Cells &#40;hESCs&#41; and Ishikawa and HEC-1B UCEC cell lines were obtained from the American Type Culture Collection &#40;ATCC&#59; Manassas&#44; VA&#44; USA&#41;&#46; Cells were cultured in a Dulbecco&#39;s modified Eagle&#39;s medium &#40;DMDM&#59; Gibco&#44; New York&#44; NY&#44; USA&#41; containing&#160;10&#37; fetal bovine serum &#40;FBS&#59; Thermo Fisher Scientific&#44; Inc&#46;&#44; Waltham&#44; MA&#44; USA&#41; and penicillin&#47;streptomycin at&#160;37&#176;C in a humidified&#160;5&#37; CO<span class="elsevierStyleInf">2</span> incubator&#46;</p><p id="para0016" class="elsevierStylePara elsevierViewall">Cellular transfection was performed using Lipofectamine&#160;2000 &#40;Invitrogen&#44; Carlsbad&#44; CA&#44; USA&#41; when cells reached a confluence of&#160;80&#37;&#44; in which Ishikawa cells were transfected with short hairpin RNAs &#40;shRNAs&#59; sh1-LHX1 and sh1-LHX2&#41;&#44; while HEC-1B cells were transfected with pcDNA3&#46;1-LHX1 or empty vector control&#46; The target sequences of shRNAs were as follows&#58; sh1-LHX1&#58; 5&#697;- GAACGACTTCTTCCGGTGTTT-3&#697;&#44; sh2-LHX1&#58; 5&#697;- CGTCCAGTGCTGTGAATGTAA -3&#697;&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">RNA extraction and quantitative reverse transcription-polymerase chain reaction &#40;RT-qPCR&#41; analysis</span><p id="para0017" class="elsevierStylePara elsevierViewall">After transfection&#44; RNA was extracted from cells using TRIzol reagent &#40;Invitrogen&#41;&#44; and cDNA was then prepared using the SuperScript&#8482; III with PlatinumTM Taq High Fidelity DNA polymerase &#40;Invitrogen&#41;&#46; The LHX1 expression level was detected using the FastStart Universal SYBR Green Master &#40;Roche&#44; Basel&#44; Switzerland&#41; with an ABI 7500 system&#46; The primers used for RT-qPCR were as follows&#58; LHX1&#58; F&#58;5&#697;-CCTGGACCGCTTTCTCTTGAA-3&#697;&#44; R&#58;5&#697;-ACCGAAACACCGGAAGAAGTC-3&#697;&#59; GAPDH&#58; F&#58;5&#697;-CTCACCGGATGCACCAATGTT-3&#697;&#44; R&#58;5&#697;- CGCGTTGCTCACAATGTTCAT-3&#697;&#46;</p><p id="para0018" class="elsevierStylePara elsevierViewall">Thermocycling conditions were as follows&#58; at&#160;95&#176;C for&#160;5&#160;min&#59; 30&#160;cycles at&#160;95&#176;C for&#160;30&#160;s&#44; at&#160;60&#176;C for&#160;45&#160;s&#44; at&#160;72&#176;C for&#160;30&#160;s&#59; and at&#160;72&#176;C for&#160;5&#160;min&#46; All experiments were performed in triplicate&#44; and the relative gene expression levels were calculated using the&#160;2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> method&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Western blot analysis</span><p id="para0019" class="elsevierStylePara elsevierViewall">RIPA buffer &#40;Cell Signaling Technology &#91;CST&#93;&#44; Danvers&#44; MA&#44; US&#41; was used to lyse cells&#44; and the extracted proteins were quantified via a BCA Protein Assay kit &#40;CST&#41;&#46; A total of&#160;30&#160;&#181;g of each sample was then separated using sodium dodecyl-sulfate polyacrylamide gel electrophoresis &#40;SDS-PAGE&#59; 90&#160;min&#44; 120&#160;V&#44; 60&#160;mA&#41;&#44; followed by transferring onto Polyvinylidene Difluoride &#40;PVDF&#41; membranes &#40;Sangon Biotech Co&#46;&#44; Ltd&#46;&#44; Shanghai&#44; China&#41;&#46; Blots were blocked with&#160;5&#37; non-fat milk &#40;Sangon Biotech Co&#46;&#44; Ltd&#46;&#41; and incubated overnight with appropriate primary antibodies at&#160;4&#176;C&#46; Glyceraldehyde 3-Phosphate Dehydrogenase &#40;GAPDH&#41; served as a loading control&#46; Afterwards&#44; the membranes were incubated with primary antibodies &#40;anti-E-cadherin &#40;CST&#44; &#35;3195&#44; 1&#58;1000&#44; Rabbit mAb&#41;&#44; anti-N-cadherin &#40;CST&#44; &#35;13116&#44; 1&#58;1000&#44; Rabbit mAb&#41;&#44; anti-vimentin &#40;CST&#44; &#35;5741&#44; 1&#58;1000&#44; Rabbit mAb&#41;&#44; anti-Snail &#40;CST&#44; &#35;3879&#44; 1&#58;1000&#44; Rabbit mAb&#41;&#44; and anti-Slug &#40;CST&#44; &#35;9585S&#44; 1&#58;1&#44;000&#44; Rabbit mAb&#41; antibodies&#41; at&#160;4&#176;C overnight using GAPDH &#40;CST&#44; &#35;5174&#44; 1&#58;1000&#44; Rabbit mAb&#41; as an internal reference gene&#46; Blots were then probed with the secondary Horseradish Peroxidase &#40;HRP&#41;-conjugated anti-rabbit IgG antibody &#40;CST&#44; &#35;7074&#44; 1&#58;3000&#41; for&#160;1h at room temperature&#46; Protein bands were subsequently detected using the SignalFire&#8482; ECL Reagent &#40;CST&#41;&#44; and the ImageLab software &#40;ver&#46;&#160;4&#46;1&#59; Bio-Rad Laboratories Inc&#46;&#44; Hercules&#44; CA&#44; USA&#41; was used for the subsequent data analysis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Cell counting kit-8 &#40;CCK-8&#41; assay</span><p id="para0020" class="elsevierStylePara elsevierViewall">24&#160;h after transfection&#44; cells were seeded onto 96-well plates &#40;1000&#160;cells&#47;well&#41;&#46; After&#160;0&#160;h&#44; 24&#160;h&#44; 48&#160;h&#44; and 72&#160;h&#44; 10&#160;&#181;L ccK-8 reagent was added to each well and cultured at&#160;37&#176;C for another&#160;2&#160;h to assess cell proliferation&#46; The absorbance was recorded at&#160;450&#160;nm using a microplate reader and the proliferation curve was plotted&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Colony formation assay</span><p id="para0021" class="elsevierStylePara elsevierViewall">UCEC cells were suspended in a DMEM containing&#160;10&#37; FBS at&#160;1000&#160;cells&#47;mL and added to&#160;6&#160;cm culture plates&#46; After&#160;2&#160;weeks of incubation&#44; cells were rinsed three times with phosphate-buffered saline&#44; fixed using&#160;4&#37;&#160;paraformaldehyde&#44; and stained with Giemsa for&#160;20&#160;min&#46; Visible colonies composed of&#160;&#62; 50&#160;cells were counted under a microscope &#40;Leica&#44; Wetzlar&#44; Germany&#41;&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Wound healing assay</span><p id="para0022" class="elsevierStylePara elsevierViewall">Cell migration was assessed via wound healing assay as reported previously&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> Briefly&#44; cells were grown to reach a confluence of&#160;30&#8210;50&#37; in a&#160;6-well plate&#44; with a straight scratch wound that was generated in the monolayer surface using a&#160;20&#160;&#956;L pipette tip&#46; An Olympus&#160;1&#215;71 camera system &#40;Olympus&#44; Tokyo&#44; Japan&#41; was then used to image the closure of the generated wound at&#160;0 and&#160;24&#160;h&#44; respectively&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Transwell analyses</span><p id="para0023" class="elsevierStylePara elsevierViewall">Transwell inserts &#40;Corning Inc&#46;&#44; Corning&#44; NY&#44; USA&#41; were used to assess the invasion and migration of UCEC cells&#46; For invasion assays&#44; Transwell chambers were pre-coated with Matrigel &#40;BD Biosciences&#44; Franklin Lakes&#44; NJ&#44; USA&#41; and incubated for&#160;4h at&#160;37&#176;C&#46; 24&#160;h after transfection&#44; a total of&#160;5000&#160;or&#160;10&#44;000&#160;cells in serum-free media were added to the upper chamber of each Transwell to analyze migration and invasion&#44; respectively&#46; The lower chamber was filled with&#160;500&#160;&#956;L of media containing&#160;10&#37; FBS&#46; Following 24-h incubation&#44; cotton swabs were used to remove non-migratory&#47;invasive cells&#44; while the remaining cells were fixed&#44; stained for&#160;30&#160;min&#44; and imaged by microscopy &#40;Olympus&#41;&#46;</p></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Statistical analysis</span><p id="para0024" class="elsevierStylePara elsevierViewall">The frequency and mRNA expression levels of LHX1 were calculated&#46; Descriptive analyses of normality and homogeneity of variance were conducted for continuous variables&#46; Relationships between specific variables and LHX1 expression levels were analyzed via the <span class="elsevierStyleItalic">t</span>-test&#44; Mann-Whitney <span class="elsevierStyleItalic">U</span> test&#44; Kruskal-Wallis test&#44; or Analysis of Variance &#40;ANOVA&#41;&#44; as appropriate&#46; These analyses and the Receiver Operating Characteristic &#40;ROC&#41; curve were generated using GraphPad Prism&#160;5&#46;0 software &#40;GraphPad Software Inc&#46;&#44; San Diego&#44; CA&#44; USA&#41;&#46; Survival analysis was conducted by Kaplan-Meier curves and the log-rank test with a 95&#37; Confidence Interval &#40;95&#37;&#160;CI&#41; using R software&#59;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a><span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;05 was considered statistically significant&#46; Variables with <span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;2 in univariate analysis were retained for multivariate logistic regression analysis&#44; and a stepwise forward Cox regression approach was used for further analysis&#46;</p></span></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">Results</span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">LHX1 expression was a diagnostic biomarker for UCEC</span><p id="para0025" class="elsevierStylePara elsevierViewall">To explore the effect of LHX1 expression on UCEC&#44; the authors downloaded gene expression data from TCGA database and compared LHX1 expression levels in UCEC tissues and adjacent healthy endometrial tissues&#46; LHX1 expression levels were higher in UCEC tissues than in adjacent healthy endometrial tissues &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>A&#41;&#46; Besides&#44; LHX1 was found to be expressed at higher levels in tumors from patients with stage III&#47;IV disease compared with stage&#160;I&#47;II disease &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>B&#41;&#46; The LHX1 expression level was also found to be higher upon loss of histological differentiation&#44; indicating that the LHX1 expression level was significantly higher in G3 tumors compared with G1&#47;G2 tumors &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>C&#41;&#46; In UCEC patients&#44; the LHX1 expression level was also positively correlated with the depth of tumor invasion &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>D&#41;&#46; When LHX1 mRNA levels were compared between UCEC cells and control hESCs via RT-qPCR and Western blotting&#44; they were found to be significantly upregulated in UCEC cells &#40;p &#60; 0&#46;00001&#59; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>E&#41;&#46; Therefore&#44; LHX1 can be regarded a diagnostic biomarker for UCEC&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">Upregulation of LHX1 expression levels was correlated with a poorer prognosis of UCEC patients</span><p id="para0026" class="elsevierStylePara elsevierViewall">Survival analysis was conducted to assess the association of LHX1 expression levels with a prognosis of UCEC patients&#46; ROC curves indicated that LHX1 expression levels could be utilized to diagnose UCEC patients with high sensitivity &#40;Area Under the Curve &#8210; AUC&#160;&#61;&#160;0&#46;742&#44; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A&#41;&#44; while Kaplan-Meier curves showed that the reduced LHX1 expression level was correlated with worse OS of UCEC patients &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>B&#41;&#46; The AUC values for&#160;1-&#44; 3-&#44; and 5-year survival rates in time-dependent ROC curve analyses were&#160;0&#46;723&#44; 0&#46;646&#44; and&#160;0&#46;622&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>C&#41;&#44; supporting the potential of this gene as an independent predictor of patient prognosis&#46; LHX1 expression levels were also significantly associated with DSS of UCEC patients &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>D&#41;&#44; with AUC values of&#160;0&#46;720&#44; 0&#46;655&#44; and&#160;0&#46;607 for&#160;1-&#44; 3-&#44; and 5-year DSS&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>E&#41;&#46; These results suggested that LHX1 expression levels could be used a prognostic biomarker for UCEC&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">Analysis of the functional roles of genes co-expressed with LHX1 in UCEC</span><p id="para0027" class="elsevierStylePara elsevierViewall">To more fully understand how LHX1 expression levels can influence UCEC cell development or malignancy&#44; Spearman correlation analysis was used to identify genes co-expressed with LHX1&#46; In total&#44; 102&#160;and&#160;3&#160;genes were respectively found to be positively and negatively correlated with LHX1 expression levels significantly &#40;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>A&#41;&#46; The GO functional analysis of these co-expressed genes revealed that they were enriched in biological processes&#44; including regulation of neurotransmitter receptor activity and multicellular organismal signaling &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>B&#41;&#44; cellular component terms&#44; such as neuron-to-neuron synapse and postsynaptic membrane &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>C&#41;&#44; and molecular function terms&#44; including various channel activities and metal ion transmembrane transporter activity &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>D&#41;&#46; The KEGG pathway analysis additionally indicated the enrichment of these genes in pathways associated with cellular adhesion &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>E&#41;&#46; The expression association between LHX1 and invasion- and EMT-associated genes was further assessed through Spearman correlation analysis&#44; revealing a strongly positive correlation between LHX1 and SNAI1&#44; MMP8&#44; and CXCR4 &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>F&#41;&#46; Collectively&#44; these data supported the role of LHX1 expression levels as a regulator of cellular adhesion and EMT induction&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">Overexpression of LHX1 enhanced UCEC cell proliferation&#44; invasion&#44; migration&#44; and EMT induction</span><p id="para0028" class="elsevierStylePara elsevierViewall">According to the results of RT-qPCR and Western blotting&#44; pcDNA3&#46;1-LHX1 transfection was confirmed to enhance LHX1 expression in HEC-1B cells &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>A&#41;&#46; Such overexpression markedly increased the proliferation of these cells in CCK-8 and colony formation assays compared with pcDNA3&#46;1 empty vector transfection &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Figs&#46; 4</a>B&#44; C&#41;&#46; The exogenous upregulation of LHX1 expression levels additionally enhanced migration of HEC-1B cells in wound healing assay &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>D&#41;&#44; and augmented invasion and migration in Transwell assays compared with pcDNA3&#46;1 empty vector transfection &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Figs&#46; 4</a>E&#44; F&#41;&#46; Given the critical role of EMT induction in tumor progression&#44; the authors also assessed the expression levels of EMT-associated genes in these cells and observed significantly reduced expression of E-cadherin following LHX1 overexpression and a concomitant rise in expression levels of Slug&#44; Snail&#44; Vimentin&#44; and N-cadherin &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>G&#41;&#46; Taken together&#44; the above-mentioned results demonstrated that LHX1 expression enhanced UCEC cell malignancy and EMT induction&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">Knockdown of LHX1 suppressed UCEC cell invasion&#44; migration&#44; proliferation&#44; and EMT induction</span><p id="para0029" class="elsevierStylePara elsevierViewall">When Ishikawa cells were transfected with the sh1-LHX1 and sh2-LHX1 constructs&#44; a successful downregulation of LHX1 was confirmed via RT-qPCR and Western blotting &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>A&#41;&#46; CCK-8 and colony formation assays subsequently revealed that LHX1 knockdown significantly impaired the proliferation of Ishikawa cells compared with sh-NC transfection &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>&#160;B&#44; C&#41;&#46; Consistently&#44; LHX1 knockdown impaired the ability of Ishikawa cells to migrate in the wound healing assay &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>D&#41;&#44; in addition&#44; to suppress migration and invasion in the Transwell assay compared with sh-NC treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>&#160;E&#44; F&#41;&#46; Consistently&#44; these results suggested that the knockdown of LHX1 suppressed proliferation&#44; migration&#44; and invasion of Ishikawa cells&#46; Western blotting additionally indicated that E-cadherin expression was elevated following LHX1 knockdown&#44; whereas the expression levels of Slug&#44; Snail&#44; Vimentin&#44; and N-cadherin were reduced &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>G&#41;&#46; Collectively&#44; these data confirmed the ability of LHX1 to modulate the expression levels of EMT-associated proteins in UCEC cells&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">Discussion</span><p id="para0030" class="elsevierStylePara elsevierViewall">Currently&#44; UCEC is one of the most common gynecological malignancies and the sixth most prevalent type of cancer affecting women globally&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> The incidence rate of UCEC continues to rise with changes in lifestyle and life expectancy&#44; and the incidence rate has noticeably increased in younger women over the last&#160;20&#160;years&#46;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> While the mechanisms governing UCEC incidence have still remained elusive&#44; genetic factors&#44; obesity and drug use are all thought to be involved&#46;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> Therapeutic efficacy can be achieved in less than&#160;95&#37; of patients with early-stage UCEC&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> Although serum biomarkers including carbohydrate antigen-19-9&#44; carbohydrate antigen-125&#44; and carcinoembryonic antigen have been shown to play a role in the diagnosis of UCEC&#44; they were upregulated in only&#160;20&#8210;30&#37; of patients with UCEC&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a> When UCEC diagnosis is delayed&#44; therapeutic options are limited and patients are at a higher risk of postoperative recurrence or metastasis&#44; both of which are associated with poorer prognostic outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a> The expression of certain genes that are frequently dysregulated in patients with UCEC can serve as diagnostic biomarkers&#46;<a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a> Consequently&#44; further research is essential to explore more potential biomarkers to guide clinicians in the faster diagnosis&#44; prognostic evaluation&#44; and treatment of UCEC patients&#46;</p><p id="para0031" class="elsevierStylePara elsevierViewall">LHX1 was initially found to play a role in the functions of renal and brain tissues&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a> More recent evidence&#44; however&#44; has also shown that it was overexpressed or reactivated in certain types of cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a> In the present study&#44; the authors found that LHX1 was upregulated in UCEC tissues compared with healthy tissues&#44; which was significantly associated with poorer OS and DFS outcomes&#46; This is consistent with prior evidence&#44; indicating that LHX1 can be regarded as a tumor cell marker&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a></p><p id="para0032" class="elsevierStylePara elsevierViewall">In light of the above-mentioned evidence&#44; the authors conducted functional assays using HEC-1B and Ishikawa cells&#44; confirming the oncogenic role of LHX1 in UCEC&#46; EMT induction is a key stage in the process of metastatic progression that alters the adhesion&#44; migration&#44; and invasion of malignant cells&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> Reduced E-cadherin expression is a fundamental stage in this process&#44;<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a> and the authors found that LHX1 knockdown was associated with increased E-cadherin expression&#44; whereas the opposite outcome was observed in HEC-1B cells when LHX1 was overexpressed&#46; Bioinformatics-based enrichment analyses suggested that changes in LHX1 expression levels could regulate cellular adhesion and EMT induction&#44; demonstrating that LHX1 could control the EMT process at least in part via regulating E-cadherin expression levels&#44; which is consistent with the ability of mesenchymal transcription factors to inhibit E-cadherin expression and promote progression of the EMT&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a> In the present study&#44; it was found that expression levels of Slug&#44; Snail&#44; Vimentin&#44; and N-cadherin were higher in cells overexpressing LHX1&#44; which is in line with the ability of LHX1 to regulate UCEC progression at least in part via modulation of the EMT process&#46;</p><p id="para0033" class="elsevierStylePara elsevierViewall">These results suggested new insights into the mechanistic relationship between LHX1 expression levels and UCEC malignancy&#44; but there are also certain limitations&#46; First&#44; the authors only conducted <span class="elsevierStyleItalic">in vitro</span> mechanistic studies&#44; and further <span class="elsevierStyleItalic">in vivo</span> validation is therefore required&#46; In addition&#44; several other signaling pathways play an interrelated role in the coordination of EMT induction&#44; including the Wnt&#47;beta-catenin and Akt&#47;PI3K signaling pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0041"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0042"><span class="elsevierStyleSup">42</span></a> More detailed insights regarding the role of LHX1 in UCEC need to be further investigated by more studies&#46;</p><p id="para0034" class="elsevierStylePara elsevierViewall">In summary&#44; it was found that LHX1 expression levels were highly upregulated in UCEC cells and tissues&#44; which was associated with a decrease in OS&#46; The oncogenic role of LHX1 expression levels was further confirmed through knockout and overexpression studies&#44; which revealed that it enhanced the proliferative&#44; invasive&#44; and migratory capabilities of UCEC cells while regulating the expression levels of key EMT-associated proteins&#44; including Slug&#44; Snail&#44; Vimentin&#44; E-cadherin&#44; and N-cadherin&#46; LHX1 expression levels may thus be a prognostic biomarker and a promising therapeutic target for UCEC patients&#46;</p></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Authors&#39; contributions</span><p id="para0035" class="elsevierStylePara elsevierViewall">Ye Tian and Fang Wen designed experiments&#46; Fang Wen&#44; Shuo Wang and Na Lv carried out experiments and analyzed experimental results&#46; Ye Tian wrote the manuscript&#44; Ye Tian and Fang Wen revised the manuscript&#46; All authors approved the final manuscript&#46;</p></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">Funding</span><p id="para0036" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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              "titulo" => "Prognostic analysis"
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              "titulo" => "Cell culture and transfection"
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              "titulo" => "RNA extraction and quantitative reverse transcription-polymerase chain reaction &#40;RT-qPCR&#41; analysis"
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              "titulo" => "Western blot analysis"
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              "titulo" => "Cell counting kit-8 &#40;CCK-8&#41; assay"
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              "titulo" => "Colony formation assay"
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              "titulo" => "Transwell analyses"
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0016"
              "titulo" => "LHX1 expression was a diagnostic biomarker for UCEC"
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            1 => array:2 [
              "identificador" => "sec0017"
              "titulo" => "Upregulation of LHX1 expression levels was correlated with a poorer prognosis of UCEC patients"
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            2 => array:2 [
              "identificador" => "sec0018"
              "titulo" => "Analysis of the functional roles of genes co-expressed with LHX1 in UCEC"
            ]
            3 => array:2 [
              "identificador" => "sec0019"
              "titulo" => "Overexpression of LHX1 enhanced UCEC cell proliferation&#44; invasion&#44; migration&#44; and EMT induction"
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            4 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Knockdown of LHX1 suppressed UCEC cell invasion&#44; migration&#44; proliferation&#44; and EMT induction"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2022-03-15"
    "fechaAceptado" => "2022-08-26"
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          "identificador" => "xpalclavsec1682031"
          "palabras" => array:5 [
            0 => "LHX1"
            1 => "Uterine corpus endometrial carcinoma"
            2 => "Prognosis"
            3 => "EMT induction"
            4 => "Bioinformatics analysis"
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        ]
      ]
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    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara006" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">LHX1 is highly upregulated in the cells and tissues of Uterine Corpus Endometrial Carcinoma &#40;UCEC&#41;&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">Upregulation of LHX1 is correlated with poor prognosis of UCEC patients&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">LHX1 may regulate UCEC progression at least partly by modulating EMT induction&#46;</p></li></ul></p></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objectives</span><p id="spara007" class="elsevierStyleSimplePara elsevierViewall">To investigate the expression of LHX1 and its role as a biomarker in the diagnosis and prognosis of Uterine Corpus Endometrial Carcinoma &#40;UCEC&#41;&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara008" class="elsevierStyleSimplePara elsevierViewall">The Cancer Genome Atlas &#40;TCGA&#41; database was used to detect the expression level of LHX1 in UCEC cells and tissues&#44; and to find out the effect of LHX1 on prognosis&#46; Co-expressed genes were then identified by Spearman correlation analysis&#44; and the protein-protein interaction network was constructed using Cytoscape software&#46; The R &#8220;clusterProfiler&#8221; package was used to conduct Gene Ontology &#40;GO&#41; and Kyoto Encyclopedia of Genes and Genomes &#40;KEGG&#41; pathway enrichment analyses&#46; A series of <span class="elsevierStyleItalic">in vitro</span> experiments were performed to evaluate LHX1 expression and detect UCEC cell proliferation&#44; invasion&#44; and migration&#46; Western blotting was used to determine the effect of LHX1 on expression levels of Epithelial-Mesenchymal Transition &#40;EMT&#41;-related proteins&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara009" class="elsevierStyleSimplePara elsevierViewall">LHX1 was upregulated in UCEC tissues and correlated with poor overall survival and disease-specific survival outcomes&#46; Functional enrichment analysis suggested that genes co-expressed with LHX1 were enriched in cell adhesion&#46; The expression of LHX1 was positively correlated with the expression levels of genes related to EMT induction and invasion&#46; LHX1 can enhance the proliferation&#44; migration&#44; and invasion activities of UCEC cells <span class="elsevierStyleItalic">in vitro</span>&#44; and alter the expression levels of EMT-related proteins&#46;</p></span> <span id="abss0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">LHX1 expression was highly upregulated in UCEC cells and tissues&#44; which was correlated with the prognosis of patients with UCEC&#46; LHX1 may regulate UCEC progression at least in part by modulating EMT induction&#46;</p></span>"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">LHX1 upregulation in UCEC tissues&#46; &#40;A&#41; Comparison of LHX1 expression levels in UCEC tissues and healthy tissues using data obtained from TCGA database &#40;Match TCGA normal and GTEx data&#44; <span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;001&#41;&#46; Individual points correspond to specific samples&#46; &#40;B&#41; Comparison of relative LHX1 expression levels in patients with stage&#160;I&#47;II or stage&#160;III&#47;IV UCEC&#46; &#40;C&#41; Comparison of LHX1 expression levels in patients with histological stage&#160;G1&#47;G2&#160;or&#160;G3&#160;UCEC&#46; &#40;D&#41; Relative LHX1 expression levels in UCEC tissues were significantly associated with the depth of tumor invasion&#46; &#40;E&#41; RT-qPCR and Western blotting were used to assess LHX1 expression levels in different cell lines&#46; Results are expressed as mean&#160;&#177;&#160;SD&#59; &#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;01&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;001&#46; Data are representative of three independent experiments&#46;</p>"
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">LHX1 upregulation is associated with poorer prognostic outcomes of UCEC patients&#46; &#40;A&#41; AUC curves were plotted to assess the relevance of LHX1 expression levels within TCGA cohort&#46; &#40;B&#41; Kaplan-Meier analyses were used to explore the relationship between LHX1 expression levels and Overall Survival &#40;OS&#41; of UCEC patients&#46; &#40;C&#41; Time-dependent ROC curves were used to assess the&#160;1-&#44; 3-&#44; and 5-year survival rates of UCEC patients&#46; &#40;D&#41; The relationship between LHX1 expression levels and disease-specific survival &#40;DSS&#41; of UCEC patients was assessed by Kaplan-Meier curves&#46; &#40;E&#41; Time-dependent ROC curves were used to assess the&#160;1-&#44; 3-&#44; and 5-year DSS of UCEC patients&#46;</p>"
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          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">Analysis of genes co-expressed with LHX1 in UCEC&#46; &#40;A&#41; Genes co-expressed with LHX1 in UCEC were identified and visualized through Cytoscape software&#46; Nodes in red and blue respectively corresponded to positively correlated genes and negatively correlated genes&#46; &#40;B&#41; Biological process terms&#46; &#40;C&#41; Cellular component terms&#46; &#40;D&#41; Molecular function terms&#46; &#40;E&#41; KEGG pathway analysis&#46; &#40;F&#41; A positive correlation was observed between LHX1 expression levels and expression levels of genes related to the EMT and invasion&#46; Altered genes are noted with a red stare&#44; while upregulated and downregulated genes are respectively denoted in yellow and blue&#46;</p>"
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          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">LHX1 overexpression enhances UCEC cell migration&#44; invasion&#44; proliferation&#44; and EMT induction&#46; &#40;A&#41; LHX1 expression was confirmed to be increased via RT-qPCR and Western blotting compared with that in cells treated with the empty pcDNA3&#46;1 vector&#46; &#40;B&#41; CCK-8 assay was used to analyze cellular proliferation&#46; &#40;C&#41; Overexpressed LHX1 enhanced the colony formation capability of HEC-1B cells compared with empty vector transfection&#46; &#40;D&#41; The influence of LHX1 overexpression on HEC-1B cell migration was examined via wound healing assay&#46; &#40;&#215;100&#59; scale bar&#44; 100&#160;&#956;m&#41; &#40;E&#41; Cellular migration and &#40;F&#41; invasion were analyzed and quantified&#46; &#40;&#215;100&#59; scale bar&#44; 100&#160;&#956;m&#41; &#40;G&#41; LHX1 overexpression enhanced the expression of Slug&#44; Snail&#44; Vimentin&#44; and N-cadherin&#44; while inhibited the expression of E-cadherin&#46; Results are expressed as mean&#160;&#177;&#160;SD&#59; &#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;01&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;001&#46; Data are representative of three independent experiments&#46;</p>"
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          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">LHX1 knockdown suppresses UCEC cell migration&#44; proliferation&#44; invasion&#44; and EMT induction&#46; &#40;A&#41; LHX1 expression was markedly reduced in RT-qPCR and Western blot assays following sh1-LHX1&#47;sh2-LHX1 transfection&#46; &#40;B&#41; The CCK-8 assay was used to assess cellular proliferation&#46; &#40;C&#41; The colony formation capability of Ishikawa cells was reduced following LHX1 knockdown relative to sh-NC transfection&#46; &#40;D&#41; Ishikawa cell migration decreased in the wound healing assay following LHX1 knockdown &#40;&#215;100&#59; scale bar&#44; 100&#160;&#956;m&#41;&#46; &#40;E&#41; Cellular migration and &#40;F&#41; invasion were analyzed and quantified&#46; &#40;G&#41; LHX1 knockdown enhanced E-cadherin expression&#44; while reduced the expression levels of Snail&#44; Slug&#44; Vimentin&#44; and N-cadherin&#46; Results are expressed as mean&#160;&#177;&#160;SD&#59; &#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;01&#44; &#42;&#42;&#42;<span class="elsevierStyleItalic">p</span>&#160;&#60;&#160;0&#46;001&#46; Data are representative of three independent experiments&#46;</p>"
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                            1 => "KD Miller"
                            2 => "HE Fuchs"
                            3 => "A&#46; Jemal"
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Article information
ISSN: 18075932
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos