Sex-determining Region Y-box 2 Expression Research Articles

Gene Expression of SOX2, OCT4, and Nanog by Small Molecule Compound VC6TFZ on Peripheral Blood Mononuclear Cell

Peripheral blood mononuclear cells are a potential source of cells to be induced into pluripotent stem cells because the collection procedure is easy, minimally invasive, and can be stored in a frozen form. Small molecule compound VC6TFZ consisting of valproic acid (VPA), CHIR990210 (CHIR), 616452, Tranylcypromine, Farsokline, 3-deazaneplanocin (DZnep) and TTNPB has been shown to induce pluripotency in mouse fibroblasts, but this has not been proven in peripheral blood cells. This chemical reprogramming strategy has the potential to be used in producing the desired functional cell types for clinical applications. This study aims to determine whether the small molecule compound VC6TFZ can induce pluripotency of peripheral blood mononuclear cells to become induced pluripotent stem cells. Mononuclear cells were isolated from peripheral venous blood by density gradient centrifugation method. The cells are grouped into 4 groups. Group 1 was the control group, which was not exposed to the small molecule. Groups 2-4 were experimental groups exposed to different doses of the small molecule VC6TFZ. Identification of induced pluripotent stem cells was carried out by identifying colony morphology and pluripotent gene expression of Octamer-binding transcription factor-4 (OCT4), Sex-determining region Y-box 2 (SOX2), and Nanog using Real-Time Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Colonies with a round shape, large, cobble stone like, and clear boundaries resembling pluripotent stem cell colonies appeared on the 9th day of the induction process. OCT4 and Nanog gene expression were significantly increased in the treatment group compared to the control.

Circular RNA from phosphodiesterase 4D can attenuate chondrocyte apoptosis and matrix degradation under OA milieu induced by IL-1β via circPDE4D/miR-4306/SOX9 Cascade

Background Phosphodiesterase 4D (PDE4D) is a novel molecular therapeutic agent for human diseases, including Alzheimer’s disease, ischemic stroke, asthma, and cancers. Circular RNA from PDE4D (circPDE4D; ID hsa_circ_0072568) was one of the most downregulated circRNAs in OA patients. However, its precise role in OA-related chondrocytes was largely unknown. Methods Expressions of circPDE4D, microRNA (miR)-4306, and sex-determining region Y-box 9 (SOX9) were measured by quantitative real-time PCR; protein levels of SOX9 and proteins related to apoptosis and extracellular matrix (ECM) were detected by Western blotting. Cell apoptosis was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, 5-ethynyl-2′-deoxyuridine and Annexin V-fluorescein isothiocyanate apoptosis assays. MiR-4306 response elements were predicted by bioinformatics algorithm and identified using dual-luciferase reporter, RNA immunoprecipitation, and biotin-coupled miRNA capture assays. Results CircPDE4D was markedly downregulated in OA cartilages and interleukin (IL)-1β-stressed human normal chondrocytes (HNC). Ectopic expression of circPDE4D rescued cell viability, proliferation, and expressions of B-cell lymphoma/leukemia-2 (Bcl-2) and Collagen type II α1 in IL-1β-insulted HNC, and meanwhile declined apoptosis rate and levels of Bcl-2-associated X protein, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1, matrix metalloproteinase-13, ADAM metallopeptidase with thrombospondin type 1 motif 5, IL-6, and IL-8. CircPDE4D and SOX9 were competing endogenous RNAs (ceRNAs) for miR-4306, and circPDE4D could positively regulate SOX9 expression via miR-4306. Conclusion CircPDE4D and miR-4306 were important regulators in regulating IL-1β-induced HNC apoptosis and matrix degradation via regulating the key transcription factor SOX9, suggesting a novel circPDE4D/miR-4306/SOX9 ceRNA pathway in OA-related chondrocyte dysfunction.

Glucocorticoids inhibit the maturation of committed osteoblasts via SOX2.

During bone formation, mesenchymal progenitor cells mature into bone-forming osteoblasts after undergoing several stages of differentiation. Impaired bone formation is a predominant finding in glucocorticoid (GC)-induced osteoporosis (GIO). Osteoblasts at different stages of maturation can be affected by excessive endogenous or therapeutic GCs. Sex-determining region Y-box 2 (SOX2) is normally expressed in immature osteoblasts, but its overexpression can suppress osteoblast differentiation. This study aimed to evaluate whether GC affects SOX2 expression in osteoblasts, and whether SOX2 contributes to GC-induced inhibition of osteoblast differentiation. Treatment with GCs such as dexamethasone (Dex) or hydrocortisone enhanced SOX2 expression. Silencing SOX2 improved inhibition of GC-induced osteoblast differentiation, whereas SOX2 overexpression decreased mineralized nodule formation and RUNX2 and Osterix expression in MC3T3-E1 cells. On the contrary, when C3H10T1/2 uncommitted mesenchymal stem cells were subjected to SOX2 overexpression, RUNX2 expression increased. As a mechanism of Dex-induced SOX2 upregulation in preosteoblasts, we found that the STAT3 pathway or GC receptor (GR) is involved, using a GR antagonist, STAT3 regulators, and chromatin immunoprecipitation assays. Moreover, mice treated with Dex for 4 weeks showed a notable increase in SOX2 expression in the bones and an increased ratio of procollagen type 1 N-terminal propeptide to osteocalcin in the plasma than in control mice. This study demonstrated that GC enhances SOX2 expression in vitro in osteoblast and in vivo in the mice bone, which affects bone-forming activity differently depending on the differentiation stage of osteoblast-lineage cells. Our results provide new insights into prevention and treatment against impaired bone formation in GIO.

EP459: Rare clinical gene variant of SOX9: Acampomelic campomelic dysplasia

eP459: Rare clinical gene variant of SOX9: Acampomelic campomelic dysplasia

SOX9 contributes to the progression of ductular reaction for the protection from chronic liver injury.

The transcription factor sex-determining region Y-box 9 (SOX9) is a biliary epithelial marker ectopically expressed in hepatocytes (SOX9 + hepatocytes). SOX9 + hepatocytes are believed to function in ductular reaction (DR), recognized as an essential phenomenon related to liver regeneration; however, the functional role of SOX9 and clinical implications of SOX9 + hepatocytes in DR progression are unclear. Human and mouse liver samples were subjected to immunohistochemical and gene functional analyses to investigate the functional role of SOX9 and the clinical significance of SOX9 + hepatocytes. SOX9 + hepatocytes were observed in a bile duct ligation (BDL) mouse model. Forced Sox9 expression in mouse hepatocytes by hydrodynamic injection converted them into cholangiocyte-like cells. DR progression was slower in liver epithelium-specific Sox9-knockout BDL mice than in wild-type BDL mice. SOX9 + hepatocytes were also observed in rare pediatric liver disease biliary atresia (BA). In patients with BA who underwent liver transplantation (LT), the median number of SOX9 + hepatocytes at LT was significantly lower than that at Kasai portoenterostomy (KP) performed prior to LT (P < 0.001). The high SOX9 + hepatocyte group at KP demonstrated significantly better native liver survival rates than the low SOX9 + hepatocyte group at a cut-off of 390 cells/mm2 (P = 0.019, log-rank test). Ectopic expression of SOX9 in hepatocytes of chronically injured livers may exert protective effects in DR progression. To our knowledge, this is the first study showing that SOX9 + hepatocyte count at KP can be a promising biomarker to predict native liver survival after KP in patients with BA.

ROS Promote Hypoxia-Induced Keratinocyte Epithelial-Mesenchymal Transition by Inducing SOX2 Expression and Subsequent Activation of Wnt/β-Catenin.

We previously showed that wound-induced hypoxia is related to keratinocyte migration. The ability of keratinocytes within wound healing to undergo epithelial to mesenchymal transition (EMT) contributes significantly to the acquisition of migratory properties. However, the effect of hypoxia on keratinocyte EMT on wound healing and the potential mechanism are poorly documented. This study first demonstrated that reactive oxygen species (ROS) appear to be an essential signalling mediator in keratinocytes with increased EMT and migration subjected to hypoxic conditions. Next, we showed that the expression of sex-determining region Y-box 2 (SOX2), a stemness-associated molecule, is ROS-dependent under hypoxia and that SOX2 inhibition in keratinocytes dramatically prevented hypoxia-induced EMT and migration. In addition, β-catenin was found to be a potential molecular target of SOX2, and the activation of Wnt/β-catenin was required for hypoxia-induced EMT and migration. Using an in vitro skin culture model and an in vivo skin wound model, our study further reinforced the critical role of ROS in inducing EMT through SOX2 expression and subsequent activation of Wnt/β-catenin, allowing for rapid reepithelialization of the wound area. Taken together, our findings reveal a previously unknown mechanism by which hypoxia promotes wound healing by promoting reepithelialization through the production of ROS, inducing keratinocyte EMT and migration via the enhancement of SOX2 and activation of Wnt/β-catenin.

Retraction to 'DDP-resistant ovarian cancer cells-derived exosomal microRNA-30a-5p reduces the resistance of ovarian cancer cells to DDP'.

Exosomes carrying microRNAs (miRNAs) have been demonstrated to play critical roles in the regulation of development, growth and metastasis of cancer. Bioinformatic predictions identified differentially expressed SRY-box 9 (SOX9) in OC, and the regulatory miRNA miR-139-5p. Here, we aim to evaluate the function of exosomal miR-139-5p in the sensitivity of ovarian cancer (OC) cells to cis-diamminedichloroplatinum(II) (DDP). Expression pattern of miR-139-5p and SOX9 in ovarian cancer cells (SKOV3) and DDP-resistant cells (SKOV3/DDP) was identified using reverse transcription quantitative polymerase chain reaction and western blot analysis. The relationship between miR-139-5p and SOX9 was validated using a dual-luciferase reporter assay. SKOV3/DDP cell line was developed and introduced with miR-30a-5p mimic to analyse the effects of miR-30a-5p on resistance to DDP. The in vitro and in vivo effects of exosomal miR-30a-5p on resistance of SKOV3 cells to DDP were assessed in a co-culture system of exosomes and OC cells as well as in tumour-bearing nude mice. High expression of SOX9 and low expression of miR-30-5p were witnessed in OC. Furthermore, miR-30-5p, a downregulated miRNA in SKOV3/DDP cells, increased the rate of cell apoptosis and enhanced the sensitivity of SKOV3/DDP cells to DDP by targeting SOX9. Moreover, exosomes carrying miR-30a-5p were identified to sensitize SKOV3/DDP cells to DDP both in vitro and in vivo. These data together supported an important conclusion that DDP-resistant OC cell-derived exosomal miR-30a-5p enhanced cellular sensitivity to DDP, highlighting a potential strategy to overcome drug resistance.

SOX2 as a prognostic marker and a potential molecular target in cervical cancer: A meta-analysis.

Sex determining region Y-box 2 (SOX2) has been reported as a potential therapeutic target for cancer. However, the role of SOX2 in cervical cancer remains largely undetermined. This study was performed to evaluate the correlation of SOX2 with clinical characteristics and prognosis in cervical cancer. Multiple databases were systematically searched for eligible publications. The combined odds ratios (ORs) or hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were used to assess the effect sizes. A total of 17 studies with 1906 participants were identified. SOX2 expression was higher in cervical cancer than in the normal control group (OR = 10.83, 95% CI = 6.64-17.67, P < 0.001), while no significant difference was observed between cervical cancer and cervical intraepithelial neoplasia. SOX2 expression was not associated with age, tumor stage, and lymph node metastasis, but was correlated with tumor grade (grade 2-3 vs. grade 1: OR = 4.59, 95% CI = 2.76-7.62, P < 0.001) and tumor size (≥4 cm vs. ≤4 cm: OR = 1.66, 95% CI = 1.05-2.60, P = 0.028). Based on multivariate Cox analysis, SOX2 expression was not correlated with overall survival, but was closely associated with poor recurrence-free survival (HR = 5.83, 95% CI = 1.35-25.16, P = 0.018) and progress-free survival HR = 2.29, 95% CI = 1.01-5.19, P = 0.046). SOX2 may serve as a novel prognostic factor and a promising molecular target for cervical cancer.

Human Papilloma Virus and Cancer Stem Cell markers in Oral Epithelial Dysplasia-An Immunohistochemical Study.

ObjectivesTo study the correlation between the putative cancer stem cell (CSC) markers aldehyde dehydrogenase 1 (ALDH1), cluster of differentiation 44 (CD44), sex-determining region Y-box 2 (SOX2), and octamer-binding protein 4 (OCT4) and human papilloma virus (HPV) infection using p16, the surrogate marker of HPV in oral epithelial dysplasia (OED) and normal mucosa.MethodsFive sections each from 40 histopathologically diagnosed cases of different grades of OED and 10 cases of normal oral mucosa without dysplasia were immunohistochemically stained with p16, ALDH1, CD44, SOX2, and OCT4, respectively.ResultsExpression of ALDH1 and SOX2 was significantly increased in OED cases, whereas CD44 and OCT4 expression was increased in normal mucosa. P16-positive OED cases showed upregulation of ALDH1 and OCT4 expression as compared to p16-negative cases, while CD44 and SOX2 expression was downregulated in p16-positive OED cases; however, the results were not statistically significant.ConclusionThe present study indicated a suggestive link between p16 and cancer stem cell marker expression in HPV-associated OED, and that p16 has a significant role in CSC progression in OED. This is the first study to evaluate the expression of putative CSC markers in HPV-associated OED. However, low study numbers are a potential limiting factor in this study.

Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression

Cancer-associated fibroblasts (CAFs) have important roles in promoting cancer development and progression. We previously reported that high expression of sex-determining region Y (SRY)-box9 (SOX9) in oral squamous cell carcinoma (OSCC) cells was positively correlated with poor prognosis. This study developed three-dimensional (3D) in vitro models co-cultured with OSCC cells and CAFs to examine CAF-mediated cancer migration and invasion in vitro and in vivo. Moreover, we performed an immunohistochemical analysis of alpha-smooth muscle actin and SOX9 expression in surgical specimens from 65 OSCC patients. The results indicated that CAFs promote cancer migration and invasion in migration assays and 3D in vitro models. The invading OSCC cells exhibited significant SOX9 expression and changes in the expression of epithelial–mesenchymal transition (EMT) markers, suggesting that SOX9 promotes EMT. TGF-β1 signalling inhibition reduced SOX9 expression and cancer invasion in vitro and in vivo, indicating that TGF-β1-mediated invasion is dependent on SOX9. In surgical specimens, the presence of CAFs was correlated with SOX9 expression in the invasive cancer nests and had a significant impact on regional recurrence. These findings demonstrate that CAFs promote cancer migration and invasion via the TGF-β/SOX9 axis.

Long non-coding RNA PROX1-AS1 knockdown upregulates microRNA-519d-3p to promote chemosensitivity of retinoblastoma cells via targeting SOX2

ABSTRACT Objective Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) participate in tumor progression, while the role of PROX1-antisense RNA1 (PROX1-AS1) sponging miR-519d-3p in retinoblastoma (RB) remains largely unknown. We aim to explore the effect of the PROX1-AS1/miR-519d-3p/sex determining region Y-box 2 (SOX2) in chemosensitivity of RB cells. Methods Expression of PROX1-AS1, miR-519d-3p and SOX2 in RB tissues and cells was determined. The drug-resistant cell lines were established and respectively intervened with PROX1-AS1 or miR-519d-3p expression to explore their roles in drug resistance and malignant behaviors of the drug-resistant cells. The binding relationships between PROX1-AS1 and miR-519d-3p, and between miR-519d-3p and SOX2 were evaluated. Results PROX1-AS1 and SOX2 were upregulated while miR-519d-3p was downregulated in RB tissues and cells, especially in drug-resistant cells. The PROX1-AS1 inhibition or miR-519d-3p elevation suppressed the drug resistance, proliferation, migration and invasion, and promoted apoptosis of the drug-resistant RB cells. Moreover, PROX1-AS1 sponged miR-519d-3p and miR-519d-3p targeted SOX2. Conclusion PROX1-AS1 knockdown upregulates miR-519d-3p to promote chemosensitivity of RB cells via targeting SOX2.

SOX2 and Bcl-2 as a Novel Prognostic Value in Hepatocellular Carcinoma Progression.

Sex-determining region Y-box 2 (SOX2) is a stem cell transcription factor and a major regulator of self-renewal and pluripotency of cancer stem cells (CSCs). In many types of cancer, SOX2 is dysregulated due to overexpression associated with tumor progression and low survival rate. Many HCC cases encounter recurrence and metastasis which might be due to CSCs and also apoptosis. Since little is known about the expression pattern of SOX2 and apoptotic genes in HCC, we aimed to determine the prognostic significance of SOX2, Bax, and Bcl-2 in clinicopathological features, tumor progression, and survival rate of the HCC patients. The expression of SOX2, Bax, and Bcl-2 were evaluated using qRT-PCR in 53 formalin-fixed, paraffin-embedded tissues (FFPE) of patients and 44 controls. Correlation of these genes was analyzed with clinicopathological features and tumor progression. The correlationship between SOX2 expression and ALBI grade as prognostic indicators were calculated. Survival rates were determined by Kaplan–Meier survival curves. SOX2 and Bcl-2 were remarkably overexpressed in HCC patients compared to controls (p = 0.04 and p = 0.003, respectively). A significant association was found for both SOX2 and Bcl-2 overexpression with TNM staging (p = 0.02, p = 0.04) and tumor grading (p = 0.01, p = 0.003), respectively. A significant correlation was observed: patients with SOX2 overexpression had a lower 5-year overall survival rate (p = 0.04); however, there was no significant association between Bcl-2 and survival (p = 0.5). Collectively, overexpression of SOX2 and Bcl-2, alone or combined, may be a potential marker to evaluate prognosis and response to HCC treatment.

MicroRNA-200a inhibits TGF-β-induced epithelial-mesenchymal transition in human ovarian carcinoma cells by downregulating SOX4 expression

IntroductionThe microRNA-200 (miR-200) family and sex-determining region Y-box 4 (SOX4) could regulate EMT phenotypes, which is important to the process of tumor pathological. This study explored the association of miR-200a with SOX4 in transforming growth factor (TGF)-β-induced EMT of OC cells.Material and methodsFor the in vitro experiments, hunam CO cells subjected to TGF-β was used to induce EMT; the activity of miR-200a was selectively inhibited or overexpressioned by miR-200a inhibitor and mimics, respectively. Small interfering RNAs against SOX4 (si-SOX4) were used to inhibit SOX4 expression in human OC cell lines.ResultsDecreased miR-200a and increased SOX4 levels were detected in patients with OC and these changes were closely related to the International Federation of Gynaecology and Obstetrics stage, ovarian tumor biomarker CA125 level, lymph node status and tumor size. The TGF-β-treated cells increased the miR-200a level, decreased the SOX4 level and prompted EMT properties, including a reduction in epithelial marker (e-cadherin), induction in interstitial markers (vimentin and n-cadherin), and enhancement of proliferation, migration and invasion. The OC cells were transducted with miR-200a mimic and the overexpression cells were subsequently treated with TGF-β, decreased SOX4 expression and EMT properties were detected. Also, in miR-200a inhibited cells, TGF-β increased SOX4 expression and EMT properties. Moreover, SOX4 silencing weakened the effect of the miR-200a inhibitor.ConclusionsOverall, these results provide a link between miR-200a and SOX4 in OC pathogenesis and indicate that miRNA-200a inhibits EMT by downregulating SOX4 expression in human OC cells.

The Prognostic Value of Sex-Determining Region Y-Box 2 and CD8+ Tumor-Infiltrating Lymphocytes in Limited-Stage Small-Cell Lung Cancer

Background: Sex-determining region Y-box 2 (SOX2) is a transcriptional factor that drives embryonic stem cells to neuroendocrine cells in lung development and is highly expressed in small-cell lung cancer (SCLC). However, the prognostic role of SOX2 and its relationship with tumor-infiltrating lymphocytes (TILs) has not been determined in SCLC. Herein, we assessed the expression of SOX2 and CD8+ TILs to obtain insights into the prognostic role of SOX2 and CD8+ TILs in limited-stage (LS)-SCLC. Methods: A total of 75 patients with LS-SCLC was enrolled. The SOX2 expression and CD8+ TILs were evaluated by immunohistochemistry. Results: High SOX2 and CD8+ TIL levels were identified in 52 (69.3%) and 40 (53.3%) patients, respectively. High SOX2 expression was correlated with increased density of CD8+ TILs (p = 0.041). Unlike SOX2, high CD8+ TIL numbers were associated with significantly longer progression-free survival (PFS; 13.9 vs. 8.0 months, p = 0.014). Patients with both high SOX2 expression and CD8+ TIL numbers (n = 29, 38.7%) had significantly longer PFS and overall survival (OS) compared to those from the other groups (median PFS 19.3 vs. 8.4 months; p = 0.002 and median OS 35.7 vs. 17.4 months; p = 0.004, respectively). Multivariate Cox regression analysis showed that the combination of high SOX2 expression and CD8+ TIL levels was an independent good prognostic factor for OS (HR = 0.471, 95% CI, 0.250–0.887, p = 0.02) and PFS (HR = 0.447, 95% CI, 0.250–0.801, p = 0.007) in SCLC. Conclusions: Evaluation of the combination of SOX2 and CD8+ TIL levels may be of a prognostic value in LS-SCLC.

Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma

SOX9 (Sex-determining region Y Box 9) is a well-characterized transcription factor that is a marker for progenitor cells in various tissues. In the liver, cells delineated by SOX9 are responsible for regenerating liver parenchyma when cell proliferation is impaired following chronic injury. However, whether these SOX9+ cells play a role in liver carcinogenesis has not been fully understood, although high SOX9 expression has been linked to poor survival outcome in liver cancer patients. To address this question, we developed a liver cancer mouse model (PtenloxP/loxP; Sox9-CreERT+; R26RYFP) where tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome ten) is deleted in SOX9+ cells following tamoxifen injection. In this paper, we employ lineage-tracing to demonstrate the tumorigenicity potential of the Pten-, SOX9+ cells. We show that these cells are capable of giving rise to mixed-lineage tumors that manifest features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA). Our results suggest that PTEN loss induces the transformation of SOX9+ cells. We further show that to activate these transformed SOX9+ cells, the presence of liver injury is crucial. Liver injury, induced by hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or high-fat diet (HFD), substantially increases tumor incidence and accelerates liver carcinogenesis from SOX9+ cells in Pten null mice but not in control mice. We further examine the mechanisms underlying tumor formation in this model to show that concurrent with the induction of niche signal (i.e., Wnt signaling), liver injury significantly stimulates the expansion of tumor-initiating cells (TICs). Together, these data show that (1) SOX9+ cells have the potential to become TICs following the primary transformation (i.e. Pten deletion) and that (2) liver injury is necessary for promoting the activation and proliferation of transformed SOX9+ cells, resulting in the genesis of mixed-lineage liver tumors.

Prognostic and diagnostic value of SOX9 in cirrhotic and noncirrhotic hepatocellular carcinoma.

BackgroundThis study was designed to explore the prognostic and diagnostic value of Sex-Determining Region Y-Box 9 (SOX9) in cirrhotic hepatocellular carcinoma HCC (CHCC) and noncirrhotic hepatocellular carcinoma (NCHCC).MethodsSOX9 tissue expression was detected using data from The Cancer Genome Atlas (TCGA) database and our cohort. The Kaplan-Meier method was used to analyze differences in survival between high/low SOX9 expression groups. Univariate analysis and multivariate analysis were used to identify independent risk factors associated with overall survival (OS). Receiver operating characteristic (ROC) curve and area under the curve (AUC) were utilized for evaluation of the diagnostic efficacy of SOX9.ResultsSOX9 was found to exhibit differential expression between HCC and adjacent normal tissues but not between CHCC and NCHCC, which was confirmed by RNA sequencing, quantitative real-time polymerase chain reaction and immunohistochemical staining. Kaplan-Meier survival analysis and multivariate analysis revealed that high SOX9 expression was closely related to the OS in NCHCC but not that in CHCC. In CHCC and NCHCC, SOX9 expression was positively associated with serum α-fetoprotein levels. The AUC of SOX9 in differentiating HCC and adjacent normal tissues in CHCC and NCHCC was 0.77 and 0.78, respectively, and no significant difference was found between them.ConclusionsHigh SOX9 expression may aid prognostic evaluation in NCHCC but not in CHCC. SOX9 expression was not different between CHCC and NCHCC, but it has reliable and comparable diagnostic value in both CHCC and NCHCC.

TNF Alpha-Induced SOX2 Expression Promotes Hepatic Steatois in Diet-Induced Obesity Model

Diet-induced obesity can cause metabolic or inflammatory damage on liver. Nonalcoholic fatty liver disease (NAFLD) begins with the fat accumulation in hepatocyte, but can lead to hepatocellular carcinoma (HCC). Sex-determining region Y-box 2 (SOX2) is a critical transcription factor involving regeneration and pluripotency. The expression level of Sox2 is correlated with progression of HCC, and anti-inflammatory effects of Sox2 in mesenchymal stem cells have been found. However, the expression of Sox2 by inflammatory cytokines in hepatocyte in NAFLD or the role of SOX2 in fat accumulation has been rarely reported. Here, we found that high-fat diet feeding, with or without high fructose in drinking water, significantly upregulated SOX2 in the livers of mice. In vitro, treatment with free fatty acids (FFAs) and fructose increased SOX2 expression in FL83B cells compared with the vehicle-treated group. Furthermore, overexpression or knockdown of SOX2 in FL83B cells promoted or suppressed, respectively, triglyceride synthesis and lipid accumulation after FFAs stimulation. The expression levels of several lipogenesis-related molecules were found to be altered by SOX2 expression. In addition, among several cytokines, only the treatment of tumor necrosis factor-alpha (TNFα) increased the SOX2 expression compared with the vehicle-treated control. Further, upregulation of (TNFα) by FFA/fructose was observed, and TNFα and FFA/fructose induced SOX2 expression was abolished by pretreatment of a TNFα inhibitor. Collectively, our findings suggest that TNFα-SOX2 signaling pathway in hepatocyte may be one of targets for early prevention of the development of NAFLD.

SOX2 promotes chemoresistance, cancer stem cells properties, and epithelial\u2013mesenchymal transition by \u03b2-catenin and Beclin1/autophagy signaling in colorectal cancer

Sex-determining region Y-box2 (SOX2), a master regulator of embryonic and induced pluripotent stem cells, drives cancer stem cells (CSCs) properties, fuels tumor initiation, and contributes to tumor aggressiveness. Our previous study has demonstrated the oncogenic role of SOX2 in colorectal cancer (CRC). In this study, we sought to elucidate the underlying mechanisms. Cell function experiments were performed to detect chemoresistance, proliferation, stemness, migration, and invasion in vitro. Chromatin immunoprecipitation, co-immunoprecipitation, luciferase reporter assay, and immunofluorescence were performed to explore the regulation of ABCC2, β-catenin, and Beclin1 by SOX2. The carcinogenic role of SOX2-β-catenin/Beclin1-ABCC2 axis in vivo was analyzed by CRC tissues and xenograft models. Here, we reported that SOX2 sustained chemoresistance by transcriptional activation of ABCC2 expression. Suppressing either β-catenin or autophagy signaling curbed SOX2-driven chemoresistance, stemness, and epithelial–mesenchymal transition (EMT). Mechanistically, SOX2 combined with β-catenin and increased its nuclear expression and transcriptional activity. Transcriptional activation of Beclin1 expression by SOX2 consequently activating autophagy and inducing malignant phenotype. Furthermore, overexpression of β-catenin or Beclin1 facilitated ABCC2 expression. The clinical analyses showed that high expression of ABCC2 and Beclin1 were positively correlated with SOX2 and were associated with poor prognosis in CRC patients. Finally, xenograft models revealed that inhibition of SOX2 expression and autophagy restrained tumor growth and chemoresistance in vivo. Conclusively, we demonstrated a novel mechanism by which the SOX2-β-catenin/Beclin1/autophagy signaling axis regulates chemoresistance, stemness, and EMT in CRC. Our findings provide novel insights into CRC carcinogenesis and may help develop potential therapeutic candidates for CRC.

Up-regulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas

BackgroundPituitary adenomas are benign brain tumors that cause considerable morbidity and neurological symptoms. SOX9 as a regulatory transcriptional mediator affects normal and tumor cell growth with an undefined role in pituitary adenomas pathogenesis. Thus, in the present study, the expression pattern of SOX9 in GH-secreting pituitary tumors and normal pituitary tissues is investigated.MethodsThe SOX9 gene expression level was evaluated in 60 pituitary tissues including different types of GH-secreting adenomas and normal pituitary tissues through Real-Time PCR. The protein level of SOX9 was assessed using immunohistochemistry. The correlations of SOX9 gene and protein expression level with the patient’s clinical and pathological features were considered.ResultsThe SOX9 over-expression was detected in GH-secreting adenomas tumor tissues compared to normal pituitary tissues which were accompanied by overexpression of SOX9 protein in tumor tissues. The over-expression of SOX9 had a significant impact on GH-secreting adenomas tumor incidence with the odds ratio of 8.4 and the diagnostic value of SOX9 was considerable. The higher level of SOX9 expression was associated with invasive and macro tumors in GH-secreting pituitary adenoma patients. The positive correlation of SOX9 gene and protein level was observed and the tumor size and tumor invasive features were valuable in predicting SOX9 expression level in GH-producing pituitary tumors.ConclusionThe study provided the first shreds of evidence regarding the expression pattern of SOX9 in the GH- secreting pituitary adenomas at both gene and protein levels which may emphasize the possible involvement of SOX9 as a mediator in pituitary adenoma tumor formation also open up new intrinsic molecular mechanism regarding pituitary adenoma pathogenesis.

Programming changes of hippocampal miR-134-5p/SOX2 signal mediate the susceptibility to depression in prenatal dexamethasone-exposed female offspring.

Depression is a neuropsychiatric disorder and has intrauterine developmental origins. This study aimed to confirm the depression susceptibility in offspring rats induced by prenatal dexamethasone exposure (PDE) and to further explore the intrauterine programming mechanism. Wistar rats were injected with dexamethasone (0.2 mg/kg·d) subcutaneously during the gestational days 9-20 and part of the offspring was given chronic stress at postnatal weeks 10-12. Behavioral results showed that the adult PDE female offspring was susceptible to depression, accompanied by increased hippocampal miR-134-5p expression and decreased sex-determining region Y-box 2 (SOX2) expression, as well as disorders of neural progenitor cells proliferation and hippocampal neurogenesis. The PDE female fetal rats presented consistent changes with the adult offspring, accompanied by the upregulation of glucocorticoid receptor (GR) expression and decreased sirtuin 1 (SIRT1) expression. We further found that the H3K9ac level of the miR-134-5p promoter was significantly increased in the PDE fetal hippocampus, as well as in adult offspring before and after chronic stress. In vitro, the changes of GR/SIRT1/miR-134-5p/SOX2 signal by dexamethasone were consistent with in vivo experiments, which could be reversed by GR receptor antagonist, SIRT1 agonist, and miR-134-5p inhibitor. This study confirmed that PDE led to an increased expression level as well as H3K9ac level of miR-134-5p by activating the GR/SIRT1 pathway in the fetal hippocampus and then inhibited the SOX2 expression. The programming effect mediated by the abnormal epigenetic modification could last from intrauterine to adulthood, which constitutes the intrauterine programming mechanism leading to hippocampal neurogenesis disorders and depression susceptibility in female offspring. Intrauterine programming mechanism for the increased depressive susceptibility in adult female offspring by prenatal dexamethasone exposure (PDE). GR, glucocorticoid receptor; SIRT1, sirtuin 1; SOX2, sex-determining region Y-box 2; NPCs, neuroprogenitor cells; H3K9ac, histone 3 lysine 9 acetylation; GRE, glucocorticoid response element.