Jmjd2c maintains the ALDHbri+ cancer stemness with transcription factor SOX2 in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LSCC) is a deadly cancer in the world. Histone demethylase Jmjd2c is a key epigenetic regulator in various tumors, while the molecular mechanism underlying Jmjd2c regulatory in LSCC is still unclear. We used the aldehyde dehydrogenasebright (ALDHbri+) subtype as a research model for cancer stem cells (CSCs) in LSCC and detected the sphere formation ability and the proportion of ALDHbri+ CSCs with Jmjd2c interference and caffeic acid (CA) treatment. Additionally, we carried out bioinformatic analysis on the expression file of Jmjd2c RNAi mice and performed western blotting, qRT-PCR, Co-IP and GST pull-down assays to confirm the bioinformatic findings. Moreover, we generated Jmjd2c-silenced and Jmjd2c-SOX2-silenced ALDHbri+ tumor-bearing BALB/c nude mice to detect the effects on tumor progression. The results showed that Jmjd2c downregulation inhibited the sphere formation and the proportion of ALDHbri+ CSCs. The SOX2 decreased expression significantly in Jmjd2c RNAi mice, and they were positively co-expressed according to the bioinformatic analysis. In addition, SOX2 expression decreased in Jmjd2c shRNA ALDHbri+ CSCs, Jmjd2c and SOX2 proteins interacted with each other. Furthermore, Jmjd2c interference revealed significant blocking effect, and Jmjd2c-SOX2 interference contributed even stronger inhibition on ALDHbri+ tumor progression. The Jmjd2c and SOX2 levels were closely related to the development and prognosis of LSCC patients. This study indicated that Jmjd2c played key roles on maintaining ALDHbri+ CSC activity in LSCC by interacting with transcription factor SOX2. Jmjd2c might be a novel molecule for therapeutic targets and biomarkers in the diagnosis and clinical treatment of lung cancer.

Evaluation of the Effects of Opium on the Expression of SOX2 and OCT4 in Wistar Rat Bladder.

BACKGROUND: Bladder cancer is a malignancy greatly affected by behavioral habits. The aim of this study was to examine the effect of opium on changes in the expression of OCT4 and SOX2 in the bladder tissue of rats. METHOD: Thirty six rats were divided into six groups: 24 rats in the addicted group received morphine and opium for 4 months with 12 rats in the control group. Blood testing was done for the evaluation of CBC, MDA, and TAC. The bladder tissue was removed and checked by histopathological examination. All total RNA was extracted, then cDNAs were synthesized and the OCT4 and SOX2 gene expressions were evaluated by Real-time PCR. RESULTS: The OCT4 mRNA expression level in the opium group of rats was significantly increased compared to the control group (13.5 and 6.8 fold in males and females respectively). Also, in the morphine group, similar augmentation was detected (3.8 and 6.7 fold in males and females respectively). The SOX2 mRNA over-expression level was seen in the morphine group of both genders as compared to the control group (3.7 and 4.2 fold in male and female respectively) but in the opium group, enhancement of mRNA level was seen only in males (6.6 fold). Opium increases both OCT4 and SOX2 expression more than morphine in male rats, but in female rats, SOX2 is increased more by morphine. CONCLUSION: Over expression of OCT4 and SOX2 was observed in rats treated with opium and morphine. Increased OCT4 and SOX2 expression was seen in opium-treated male rats, but in female rats, SOX2 was increased more by morphine.

Clinicopathological significance of cancer stem cell marker CD44/SOX2 in esophageal squamous cell carcinoma (ESCC) patients and construction of a nomogram to predict overall survival.

Background: Esophageal squamous cell carcinoma (ESCC), a prevalent malignancy within the upper gastrointestinal system, is characterized by its unfavorable prognosis and the absence of specific indicators for outcome prediction and high-risk case identification. In our research, we examined the expression levels of cancer stem cells (CSCs), markers CD44/SOX2 in ESCC, scrutinized their association with clinicopathological parameters, and developed a predictive nomogram model. This model, which incorporates CD44/SOX2, aims to forecast the overall survival (OS) of patients afflicted with ESCC. Methods: Immunohistochemistry was utilized to detect the expression levels of CD44 and SOX2 in both cancerous and paracancerous tissues of 68 patients with ESCC. The correlation between CD44/SOX2 expression and clinicopathological parameters was subsequently analyzed. Factors impacting the prognosis of ESCC patients were assessed through univariate and multivariate Cox regression analyses. Leveraging the results of these multivariate regression analyses, a nomogram prognostic model was established to provide individualized predictions of ESCC patient survival outcomes. The predictive accuracy of the nomogram prognostic model was evaluated using the consistency index (C-index) and calibration curves. Results: The expression levels of CD44 were markedly elevated in the tumor tissues of ESCC patients. Similarly, SOX2 was significantly overexpressed in the tumor tissues of ESCC patients. The positive expression of SOX2 in ESCC demonstrated a strong correlation with both the pathological T-stage and the presence of carcinoembryonic antigen. CD44 and SOX2 co-positive expression was significantly associated with the pathological T-stage and tumor node metastasis (TNM) stage. Furthermore, ESCC patients exhibiting CD44-positive expression in their tumor tissue generally had a more adverse prognosis. The co-expression of CD44 and SOX2 resulted in a grimmer prognosis compared to patients with other combinations. Multivariate Cox regression analysis identified the co-expression of CD44 and SOX2, the pathological T-stage, and lymph node metastasis as independent prognostic indicators for ESCC patients. The three identified variables were subsequently incorporated into a nomogram for predicting OS. The C-index of the measurement model and the area under the curve of the subjects' work characteristics showed good individual prediction. This prognostic model stratified patients into low- and high-risk categories. Analysis revealed that the 5-year OS rate was significantly higher in the low-risk group compared to the high-risk group. Conclusions: Elevated CD44 levels, indicative of CSC presence, are intimately linked with the oncogenesis of ESCC and are strongly predictive of unfavorable patient outcomes. Concurrently, the SOX2 gene exhibits a heightened expression in ESCC, markedly accelerating tumor progression and fostering more extensive disease infiltration. The co-expression of CD44 and SOX2 correlates significantly with ESCC patient prognosis, serving as a reliable, independent prognostic marker. Our constructed nomogram, incorporating CD44/SOX2 expression, enhances the prediction of OS and facilitates risk stratification in ESCC patients.

Maturation of type I and type II rat vestibular hair cells in vivo and in vitro.

Vestibular sensory epithelia contain type I and type II sensory hair cells (HCI and HCII). Recent studies have revealed molecular markers for the identification of these cells, but the precise composition of each vestibular epithelium (saccule, utricle, lateral crista, anterior crista, posterior crista) and their postnatal maturation have not been described in detail. Moreover, in vitro methods to study this maturation are not well developed. We obtained total HCI and HCII counts in adult rats and studied the maturation of the epithelia from birth (P0) to postnatal day 28 (P28). Adult vestibular epithelia hair cells were found to comprise ∼65% HCI expressing osteopontin and PMCA2, ∼30% HCII expressing calretinin, and ∼4% HCII expressing SOX2 but neither osteopontin nor calretinin. At birth, immature HCs express both osteopontin and calretinin. P28 epithelia showed an almost adult-like composition but still contained 1.3% of immature HCs. In addition, we obtained free-floating 3D cultures of the epithelia at P1, which formed a fluid-filled cyst, and studied their survival and maturation in vitro up to day 28 (28 DIV). These cultures showed good HC resiliency and maturation. Using an enriched medium for the initial 4 days, a HCI/calretinin+-HCII ratio close to the in vivo ratio was obtained. These cultures are suitable to study HC maturation and mature HCs in pharmacological, toxicological and molecular research.

Dissecting SOX2 expression and function reveals an association with multiple signaling pathways during embryonic development and in cancer progression.

SRY (Sex Determining Region) box 2 (SOX2) is an essential transcription factor that plays crucial roles in activating genes involved in pre- and post-embryonic development, adult tissue homeostasis, and lineage specifications. SOX2 maintains the self-renewal property of stem cells and is involved in the generation of induced pluripotency stem cells. SOX2 protein contains a particular high-mobility group domain that enables SOX2 to achieve the capacity to participate in a broad variety of functions. The information about the involvement of SOX2 with gene regulatory elements, signaling networks, and microRNA is gradually emerging, and the higher expression of SOX2 is functionally relevant to various cancer types. SOX2 facilitates the oncogenic phenotype via cellular proliferation and enhancement of invasive tumor properties. Evidence are accumulating in favor of three dimensional (higher order) folding of chromatin and epigenetic control of the SOX2 gene by chromatin modifications, which implies that the expression level of SOX2 can be modulated by epigenetic regulatory mechanisms, specifically, via DNA methylation and histone H3 modification. In view of this, and to focus further insights into the roles SOX2 plays in physiological functions, involvement of SOX2 during development, precisely, the advances of our knowledge in pre- and post-embryonic development, and interactions of SOX2 in this scenario with various signaling pathways in tumor development and cancer progression, its potential as a therapeutic target against many cancers are summarized and discussed in this article.

Blastocyst-like Structures in the Peripheral Retina of Young Adult Beagles.

In this immunohistological study on the peripheral retina of 3-year-old beagle dogs, excised retina specimens were immunostained with antibodies against nestin, Oct4, Nanog, Sox2, CDX2, cytokeratin 18 (CK 18), RPE65, and YAP1, as well as hematoxylin and DAPI, two nuclear stains. Our findings revealed solitary cysts of various sizes in the inner retina. Intriguingly, a mass of small round cells with scant cytoplasms was observed in the cavity of small cysts, while many disorganized cells partially occupied the cavity of the large cysts. The small cysts were strongly positive for nestin, Oct4, Nanog, Sox2, CDX2, CK18, and YAP1. RPE65-positive cells were exclusively observed in the tissue surrounding the cysts. Since RPE65 is a specific marker of retinal pigment epithelial (RPE) cells, the surrounding cells of the peripheral cysts were presumably derived from RPE cells that migrated intraretinally. In the small cysts, intense positive staining for nestin, a marker of retinal stem cells, seemed to indicate that they were derived from retinal stem cells. The morphology and positive staining for markers of blastocyst and RPE cells indicated that the small cysts may have formed structures resembling the blastocyst, possibly caused by the interaction between retinal stem cells and migrated RPE cells.

The multifaceted role of SOX2 in breast and lung cancer dynamics.

Breast and lung cancers are leading causes of death among patients, with their global mortality and morbidity rates increasing. Conventional treatments often prove inadequate due to resistance development. The alteration of molecular interactions may accelerate cancer progression and treatment resistance. SOX2, known for its abnormal expression in various human cancers, can either accelerate or impede cancer progression. This review focuses on examining the role of SOX2 in breast and lung cancer development. An imbalance in SOX2 expression can promote the growth and dissemination of these cancers. SOX2 can also block programmed cell death, affecting autophagy and other cell death mechanisms. It plays a significant role in cancer metastasis, mainly by regulating the epithelial-to-mesenchymal transition (EMT). Additionally, an imbalanced SOX2 expression can cause resistance to chemotherapy and radiation therapy in these cancers. Genetic and epigenetic factors may affect SOX2 levels. Pharmacologically targeting SOX2 could improve the effectiveness of breast and lung cancer treatments.

[Retracted] MicroRNA­336 directly targets Sox­2 in osteosarcoma to inhibit tumorigenesis.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell cell migration and invasion assay data in Fig. 3C and D, and the tumour images shown in Fig. 4A were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had already been published. In addition, certain of the data panels shown in Fig. 3C were overlapping, such that the data from the same original source had been selected to represent the results from allegedly differently performed experiments. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 15: 4217­4224, 2017; DOI: 10.3892/mmr.2017.6493].

Exploring the role of SOX 2 and OCT 4 in the pathogenesis of gliomatosis peritonei: the clinicopathological profile of eleven cases.

Objective: Gliomatosis peritonei (GP) is a rare entity characterized by multiple mature glial tissue implants in association with ovarian teratomas in the peritoneum and omentum. To date, only 100 cases have been published. Not much is known about the origin, clinicopathological profile or prognosis of GP. SOX2 and OCT4 are recently recognized markers of embryonic stem cell differentiation. Here, the role of SOX2 and OCT4 in the pathogenesis of 11 cases of GP are reported and clinicopathological factors are described. Material and Methods: This was a retrospective study of six years duration (2017-2022). All the cases of GP were retrieved from archives, the diagnosis was confirmed and clinicopathological factors were noted. Immunohistochemical (IHC) investigation for glial fibrillary acid protein (GFAP) and S100 was noted wherever available. IHC for SOX2 and OCT4 was performed using an avidin-biotin technique. Results: There were 11 cases of GP identified. The median age was 29 years and 1/11 cases had nodal gliomatosis as well. There were eight cases of immature teratoma and three cases of mature cystic teratoma. SOX2 was positive in all foci of GP, while OCT4 was negative. These foci were also positive for GFAP and S100. Conclusion: A possibility of GP should be considered as a differential, clinically and radiologically, in cases of omental nodularity. Adequate sampling at the time of surgery is essential to rule out metastasis or growing teratoma syndrome. SOX2, a stem cell marker inducing neural differentiation, may play a crucial role in the development of GP in association with other transcription factors.

Oncogenic Role of SATB2 In Vitro: Regulator of Pluripotency, Self-Renewal, and Epithelial-Mesenchymal Transition in Prostate Cancer.

Special AT-rich sequence binding protein-2 (SATB2) is a nuclear matrix protein that binds to nuclear attachment regions and is involved in chromatin remodeling and transcription regulation. In stem cells, it regulates the expression of genes required for maintaining pluripotency and self-renewal and epithelial-mesenchymal transition (EMT). In this study, we examined the oncogenic role of SATB2 in prostate cancer and assessed whether overexpression of SATB2 in human normal prostate epithelial cells (PrECs) induces properties of cancer stem cells (CSCs). The results demonstrate that SATB2 is highly expressed in prostate cancer cell lines and CSCs, but not in PrECs. Overexpression of SATB2 in PrECs induces cellular transformation which was evident by the formation of colonies in soft agar and spheroids in suspension. Overexpression of SATB2 in PrECs also resulted in induction of stem cell markers (CD44 and CD133), pluripotency-maintaining transcription factors (cMYC, OCT4, SOX2, KLF4, and NANOG), CADHERIN switch, and EMT-related transcription factors. Chromatin immunoprecipitation assay demonstrated that SATB2 can directly bind to promoters of BCL-2, BSP, NANOG, MYC, XIAP, KLF4, and HOXA2, suggesting SATB2 is capable of directly regulating pluripotency/self-renewal, cell survival, and proliferation. Since prostate CSCs play a crucial role in cancer initiation, progression, and metastasis, we also examined the effects of SATB2 knockdown on stemness. SATB2 knockdown in prostate CSCs inhibited spheroid formation, cell viability, colony formation, cell motility, migration, and invasion compared to their scrambled control groups. SATB2 knockdown in CSCs also upregulated the expression of E-CADHERIN and inhibited the expression of N-CADHERIN, SNAIL, SLUG, and ZEB1. The expression of SATB2 was significantly higher in prostate adenocarcinoma compared to normal tissues. Overall, our data suggest that SATB2 acts as an oncogenic factor where it is capable of inducing malignant changes in PrECs by inducing CSC characteristics.

Dexamethasone-tamoxifen combination exerts synergistic therapeutic effects in tamoxifen-resistance breast cancer cells.

Tamoxifen (TAM) is a key player in estrogen receptor-positive (ER+) breast cancer (BC); however, ∼30% of patients experience relapse and a lower survival rate due to TAM resistance. TAM resistance was related to the over expression of SOX-2 gene, which is regulated by the E2F3 transcription factor in the Wnt signaling pathway. It was suggested that SOX-2 overexpression was suppressed by dexamethasone (DEX), a glucocorticoid commonly prescribed to BC patients. The aim of the present study is to explore the effect of combining DEX and TAM on the inhibition of TAM-resistant LCC-2 cells (TAMR-1) through modulating the E2F3/SOX-2-mediated Wnt signaling pathway. The effect of the combination therapy on MCF-7 and TAMR-1 cell viability was assessed. Drug interactions were analyzed using CompuSyn and SynergyFinder softwares. Cell cycle distribution, apoptotic protein expression, gene expression levels of SOX-2 and E2F3, and cell migration were also assessed. Combining DEX with TAM led to synergistic inhibition of TAMR-1 cell proliferation and migration, induced apoptosis, reduced SOX-2 and E2F3 expression and was also associated with S and G2-M phase arrest. Therefore, combining DEX with TAM may present an effective therapeutic option to overcome TAM resistance, by targeting the E2F3/SOX-2/Wnt signaling pathway, in addition to its anti-inflammatory effect.

RNA methylation machinery and m6A target genes as circulating biomarkers of ulcerative colitis and Crohn's disease: Correlation with disease activity, location, and inflammatory cytokines.

Accurate diagnosis of ulcerative colitis (UC) and Crohn's disease (CD), the main subtypes of inflammatory bowel disease (IBD), has been challenging due to the constraints of the current techniques. N6-methyl adenosine (m6A) regulators have evolved as key players in IBD pathogenesis; however, their relation to its clinical setting is largely unexplored. This study investigated the potential of selected RNA methylation machinery and m6A target genes as serum biomarkers of UC and CD, their predictive and discriminating capabilities, and their correlations with laboratory data, interleukin (IL)-6, interferon-γ, disease activity scores, and pathological features. Fifty UC and 45 CD patients, along with 30 healthy volunteers were enlisted. The mRNA expression levels of the m6A writers methyltransferase-like 3 (METTL3) and Wilms-tumor associated protein (WTAP), and the reader YTH domain family, member 1 (YTHDF1), along with the m6A candidate genes sex determining region Y-box 2 (SOX2), hexokinase 2 (HK2), and ubiquitin-conjugating enzyme E2 L3 (UBE2L3) were upregulated in UC patients, whereas only METTL3, HK2, and UBE2L3 were upregulated in CD patients versus controls. Serum WTAP (AUC = 0.94, 95 %CI = 0.874-1.006) and HK2 (AUC = 0.911, 95 %CI = 0.843-0.980) expression levels showed excellent diagnostic accuracy for UC, METTL3 showed excellent diagnostic accuracy for CD (AUC = 0.91, 95 %CI = 0.828-0.992), meanwhile, WTAP showed excellent discriminative power between the two diseases (AUC = 0.91, 95 %CI = 0.849-0.979). Multivariate logistic analysis unveiled the association of METTL3 and UBE2L3 expression with the risk of CD and UC diagnosis, respectively, controlled by age and sex as confounders. Remarkable correlations were recorded between the gene expression of studied m6A regulators and targets in both diseases. Among UC patients, serum METTL3 and WTAP were correlated with UC extent/type, while WTAP was correlated with IL-6. Among CD patients, serum METTL3 and HK2 were correlated with CD activity index (CDAI) and CD location. In conclusion, m6A regulators and target genes are distinctly expressed in UC and CD clinical samples, correlate with disease activity and extent/location, and could serve as a novel approach to empower the diagnosis and stratification of IBD subtypes.

Prognostic role of SOX2 and STAT3 expression on circulating T lymphocytes and CD44+/CD24neg cells in the locally advanced and metastatic breast cancer.

BACKGROUND: Breast cancer (BC) is associated with a continuous increase in incidence, with high mortality rates in several countries. CD44, STAT3, and SOX2 are related to regulating of somatic cell division, tumorigenesis, and metastasis in BC. METHODS: A cross-sectional study was carried out at the Hospital de Cancer de Pernambuco (HCP) between 2017 and 2018. Fifty-one women with locally advanced (LA) and 14 with metastatic BC were included in the study. RESULTS: High CD44+/CD24neg and CD44+/CD24neg/SOX2+ levels in Luminal B (LB), HER2+, and triple-negative breast cancer (TNBC) compared with controls (p < 0.05). Low CD44+/CD24negSTAT3+ levels in LB, HER2+, and TNBC compared with controls (p < 0.05). High T lymphocytes, and low STAT3 + T, and SOX2 + T levels in BC patients (p < 0.05). High SOX2 + T levels in patients with axillary lymph node-negative (N0) compared with the axillary lymph node-positives (N1 and N2 groups; p < 0.05). High SOX2 + T levels in N1 compared to N2 (p < 0.05). High T lymphocytes and low SOX2 + T levels in the LA tumor compared to metastatic disease (p = 0.0007 and p = 0.02, respectively). High CD44 + /CD24negSTAT3+, and T lymphocyte levels in TNBC patients with LA tumor compared to metastatic (p < 0.05). Low STAT3 + T levels in TBNC patients with LA tumor compared to metastatic (p = 0.0266). CONCLUSION: SOX2 and STAT3 expression on circulating T lymphocytes and CD44 + /CD24neg cells in peripheral blood have prognostic roles in breast cancer. SOX2 and STAT3 expression are potential predictive biomarkers of disease progression in breast cancer regardless of tumor subtype.

Targeting m6A mRNA demethylase FTO alleviates manganese-induced cognitive memory deficits in mice.

Manganese (Mn) induced learning and memory deficits through mechanisms that are not fully understood. In this study, we discovered that the demethylase FTO was significantly downregulated in hippocampal neurons in an experimental a mouse model of Mn exposure. This decreased expression of FTO was associated with Mn-induced learning and memory impairments, as well as the dysfunction in synaptic plasticity and damage to regional neurons. The overexpression of FTO, or its positive modulation with agonists, provides protection against neurological damage and cognitive impairments. Mechanistically, FTO interacts synergistically with the reader YTHDF3 to facilitate the degradation of GRIN1 and GRIN3B through the m6A modification pathway. Additionally, Mn decreases the phosphorylation of SOX2, which specifically impairs the transcriptional regulation of FTO activity. Additionally, we found that the natural compounds artemisinin and apigenin that can bind molecularly with SOX2 and reduce Mn-induced cognitive dysfunction in mice. Our findings suggest that the SOX2-FTO-Grins axis represents a viable target for addressing Mn-induced neurotoxicity and cognitive impairments.

Neuromesodermal specification during head-to-tail body axis formation.

The anterior-to-posterior (head-to-tail) body axis is extraordinarily diverse among vertebrates but conserved within species. Body axis development requires a population of axial progenitors that resides at the posterior of the embryo to sustain elongation and is then eliminated once axis extension is complete. These progenitors occupy distinct domains in the posterior (tail-end) of the embryo and contribute to various lineages along the body axis. The subset of axial progenitors with neuromesodermal competency will generate both the neural tube (the precursor of the spinal cord), and the trunk and tail somites (producing the musculoskeleton) during embryo development. These axial progenitors are called Neuromesodermal Competent cells (NMCs) and Neuromesodermal Progenitors (NMPs). NMCs/NMPs have recently attracted interest beyond the field of developmental biology due to their clinical potential. In the mouse, the maintenance of neuromesodermal competency relies on a fine balance between a trio of known signals: Wnt/ß-catenin, FGF signalling activity and suppression of retinoic acid signalling. These signals regulate the relative expression levels of the mesodermal transcription factor Brachyury and the neural transcription factor Sox2, permitting the maintenance of progenitor identity when co-expressed, and either mesoderm or neural lineage commitment when the balance is tilted towards either Brachyury or Sox2, respectively. Despite important advances in understanding key genes and cellular behaviours involved in these fate decisions, how the balance between mesodermal and neural fates is achieved remains largely unknown. In this chapter, we provide an overview of signalling and gene regulatory networks in NMCs/NMPs. We discuss mutant phenotypes associated with axial defects, hinting at the potential significant role of lesser studied proteins in the maintenance and differentiation of the progenitors that fuel axial elongation.

lncRNA Biomarkers of Glioblastoma Multiforme.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

Stem Cell Markers in Neoplasms and their Relationship with Progression-free and Overall Survival in Patients with Recurrence.

BACKGROUND: Gliomas account for 30% of primary brain tumors in adults, and despite the scientific progress in the field, recurrence is prevalent. Glioma Stem Cells (GSCs) can generate tumor cells in vivo and in vitro and they are associated with treatment resistance, tumor progression, and recurrence. Furthermore, the expression of SOX transcription factors (SOX1, SOX2, SOX9) in these cells is responsible for maintaining an oncogenic genotype and is associated with an aggressive tumor phenotype. The relationship between SOX transcription factors and their prognostic role in recurrent gliomas has not been described in detail. Therefore, we set out to describe the relationship between SOX expression and Progression-free Survival (PFS) and Overall Survival (OS) in patients with recurrent gliomas. METHODS: In this observational study, we have retrospectively analyzed 69 patients, of which 20 met the inclusion criteria. The clinical, radiological, and histopathological findings have been described, and survival analysis has been performed according to SOX expression for PFS and OS. RESULTS: We found SOX1, SOX2, and SOX9 to show a non-statistically significant trend with increasing histopathological grade, co-expressed with Ki67, a cell proliferation factor. CONCLUSION: There has been found an inversely proportional correlation between the degree of immunopositivity of SOX1 and OS. A higher SOX1 immunopositivity could predict a worse clinical prognosis. There has also been found an interaction between a pluripotent genotype (GSC) and cell proliferation.

Long Noncoding RNA SOX2OT Ameliorates Sepsis-Induced Myocardial Injury by Inhibiting Cellular Pyroptosis Through Mediating the EZH2/Nrf-2/NLRP3 Signaling Pathway.

Objective: Cellular pyroptosis is a pro-inflammatory mode of programmed cell death that has been identified in recent years, and studies have shown that the LncRNA SOX2OT regulates myocardial injury during sepsis, but the exact regulatory mechanism is unclear. The aim of this study was to assess the role of SOX2OT in regulating cardiomyocyte injury during sepsis cardiomyopathy. Methods: Rat cardiomyocytes, C57BL/6 mice, and transgenic mice were divided into four groups: control, LPS, LPS+ knockout LncRNA SOX2OT, and LPS+ overexpression LncRNA SOX2OT. Inflammatory factor levels were detected by qPCR. Associated proteins and gene expression were detected by Western blotting and qPCR. Dual luciferase was used to detect the target genes of SOX2OT. Nrf2 and EZH2 knockdown and overexpression cell lines were established, and the expression of related genes was detected by qPCR. Results: Results In this study, we found that SOX2OT knockdown exacerbated LPS-induced levels of inflammatory factors and procalcitoninogen (PCT), and increased the expression of pyroptosis-related proteins and LDH. The results of dual luciferase reporter gene assay showed that EZH2 is the target gene of SOX2OT, and overexpression of SOX2OT decreased the expression of EZH2; we also found that knockdown of EZH2 in H9c2 cells decreased the expression of Nrf2, which was positively correlated with the expression level of NLRP3. Further in vivo results showed that overexpression of SOX2OT attenuated SIMD (sepsis-induced myocardial dysfunction), as evidenced by improved myocardial structural integrity and reduced inflammatory cell infiltration. The expression of pyroptosis-related proteins and LDH was significantly increased in the mice in the LPS group; this effect was reversed by overexpression of SOX2OT, and potentiated by knockdown of SOX2OT. Conclusion: Our data reveal a novel mechanism by which SOX2OT inhibits cardiomyocyte sepsis through the EZH2/Nrf-2/NLRP3 pathway, thereby attenuating septic myocardial injury, which may contribute to the development of new therapeutic strategies.

The transcription factor sex-determining region Y-box 2 (SOX2) in bladder cancer.

Sex-determining region Y-box 2 (SOX2) is a transcription factor with a central role in embryologic development. SOX2 is also an oncogene in several cancer types. Prior work by our group has shown SOX2 activity associates with cell cycle dysregulation in early-stage bladder cancer. The present study was thus undertaken to broadly investigate SOX2 in bladder cancer, with emphasis on associations with tumor stage, clinical outcomes, and tumorigenicity. Gene expression was quantified by immunohistochemistry in an established tissue microarray (n=303 cystectomy specimens, all stages) and whole tissue sections of noninvasive papillary urothelial carcinoma (n=25). Gene expression by RNA sequencing was evaluated in non-muscle invasive and muscle-invasive cohorts from publicly available repositories. By immunohistochemistry, SOX2 was expressed in 40% of whole tissue sections of noninvasive papillary carcinoma, which correlated with SOX2 expression by RNA sequencing (r=0.6, P=0.001, Spearman correlation). Expression tended to be focal (median H-score =6). SOX2 was expressed in only 9% of TMA cases, consistent with focal expression. SOX2 expression was substantially higher in muscle-invasive compared with noninvasive papillary urothelial carcinoma by RNA sequencing (P<0.001, Wilcoxon rank sum test). SOX2 expression associated with stage progression in lamina-propria invasive cancers (hazard ratio =2, P=0.05, Cox model, binary, RNA sequencing) but not noninvasive papillary cancers (P=0.5, Cox model, binary, RNA sequencing). SOX2 expression did not associate with overall survival in muscle-invasive carcinoma. Activity of SOX2 in bladder cancer was tested in vivo using murine allografts created with MB49 cells that express human SOX2 (MB49-SOX). MB49-SOX allografts expressed this protein focally by immunohistochemistry, much like human tumors. Compared with controls, MB49 allografts demonstrated larger tumor size (P=0.03, Wilcoxon rank sum test) and higher tumor burden in mesenteric metastases (P=0.009, Wilcoxon rank sum test). Though SOX2 expression is focal within tumors, it may drive tumorigenesis, increase growth rate, and promote aggressive features of bladder cancer, particularly stage progression of early-stage disease.

Early neural specification of stem cells is mediated by a set of SOX2-dependent neural-associated enhancers.

SOX2 is a transcription factor involved in the regulatory network maintaining the pluripotency of embryonic stem cells in culture as well as in early embryos. In addition, SOX2 plays a pivotal role in neural stem cell formation and neurogenesis. How SOX2 can serve both processes has remained elusive. Here, we identified a set of SOX2-dependent neural-associated enhancers required for neural lineage priming. They form a distinct subgroup (1,898) among 8,531 OCT4/SOX2/NANOG-bound enhancers characterized by enhanced SOX2 binding and chromatin accessibility. Activation of these enhancers is triggered by neural induction of wild-type cells or by default in Smad4-ablated cells resistant to mesoderm induction and is antagonized by mesodermal transcription factors via Sox2 repression. Our data provide mechanistic insight into the transition from the pluripotency state to the early neural fate and into the regulation of early neural versus mesodermal specification in embryonic stem cells and embryos.