High SOX2 Research Articles

Hypomethylation-associated Sox11 upregulation promotes oncogenesis via the PI3K/AKT pathway in OLP-associated OSCC.

Oral lichen planus (OLP) is a particularly prevalent oral disorder with the potential to progress to oral squamous cell carcinoma (OSCC). SRY-box transcription factor 11 (Sox11) has been reported to serve as a prognostic marker for various cancers. However, the role and mechanism of Sox11 in OLP-related OSCC are unknown. Our results indicated that Sox11 was highly expressed, and that Sox11 promoter methylation was significantly reduced in OLP-associated OSCC tissues. High Sox11 expression and Sox11 promoter hypomethylation indicate a poor patient prognosis. According to invivo and invitro experiments, the knockdown of Sox11 inhibited proliferation, invasion, and migration while driving its apoptotic death in OSSC cells; Sox11 overexpression exerted the opposite effect as Sox11 knockdown. Mechanistically, knockdown of Sox11 inhibited PI3K/AKT and glycolysis pathway, and overexpression of Sox11 enhanced the PI3K/AKT and glycolysis pathways in OSCC cells. In addition, we demonstrated that Sox11 overexpression accelerated the progression of OSCC, at least in part by promoting PI3K/AKT pathway activation. In conclusion, our data indicated that the DNA hypomethylation-associated upregulation of Sox11 could promote oncogenic transformation via the PI3K/AKT pathway in OLP-associated OSCC. Therefore, Sox11 might be a reliable biomarker for predicting the progression of precancerous oral tissues.

A Comprehensive Understanding of Post-Translational Modification of Sox2 via Acetylation and O-GlcNAcylation in Colorectal Cancer.

Aberrant expression of the pluripotency-associated transcription factor Sox2 is associated with poor prognosis in colorectal cancer (CRC). We investigated the regulatory roles of major post-translational modifications in Sox2 using two CRC cell lines, SW480 and SW620, derived from the same patient but with low and high Sox2 expression, respectively. Acetylation of K75 in the Sox2 nuclear export signal was relatively increased in SW480 cells and promotes Sox2 nucleocytoplasmic shuttling and proteasomal degradation of Sox2. LC-MS-based proteomics analysis identified HDAC4 and p300 as binding partners involved in the acetylation-mediated control of Sox2 expression in the nucleus. Sox2 K75 acetylation is mediated by the acetyltransferase activity of CBP/p300 and ACSS3. In SW620 cells, HDAC4 deacetylates K75 and is regulated by miR29a. O-GlcNAcylation on S246, in addition to K75 acetylation, also regulates Sox2 stability. These findings provide insights into the regulation of Sox2 through multiple post-translational modifications and pathways in CRC.

Cancer stem cell biomarkers SOX2 and Oct4 in cervical cancer patients undergoing chemoradiotherapy.

Cancer stem cell biomarkers SRY (sex-determining region Y)-box 2 (SOX2) and octamer-binding transcription factor 4 (Oct4) account for radioresistance in cervical squamous cell cancers (CSCCs). Their clinical implications are limited and contradictory. In this prospective cohort study, we recruited patients with FIGO IB2-IVA CSCC treated with primary chemoradiotherapy on regular follow-up. Tissue biopsy specimens were evaluated for SOX2 and Oct4 expression by immunohistochemistry, quantified by a product of proportion and intensity scores. A total of 59 patients were included. Most had a moderately differentiated (81%), keratinizing (59%) CSCC, and ≥FIGO stage IIB disease (95%). SOX2 expression (high:low 21:38 patients) and Oct4 expression (high:low 4:55 patients) had a significant interrelation (p=0.005, odds ratio (95% CI) - 1.23 (1.004-1.520)). At a median follow-up of 36 months, the 3-year overall survival (OS) was 60% and 53% for low and high SOX2 expression (p=0.856), and 54% and 100% for low and high Oct4 expression (p=0.114). The 3-year disease-frese survival (DFS) was 65% and 50% in the low and high SOX2 expression (p=0.259), and 59% and 75% for low and high Oct4 expression (p=0.598). SOX2 expression was the only variable significantly associated with a lower OS and DFS on regression analysis. Our study demonstrated a trend toward improved OS and DFS with low SOX2 and high Oct4 expression in CSCC patients undergoing chemoradiotherapy.

Significance of OCT3/4 and SOX2 antigens expression by leukemic blast cells in adult acute leukemia

ObjectiveThis study aimed to address the prognostic impact of SOX2 and OCT3/4 expression on adult acute leukemia patients’ outcomes.MethodsSOX2 and OCT3/4 expression by blast cells were evaluated by flow cytometry in 80 acute leukemia patients and 8 healthy controls.ResultsBaseline SOX2 and OCT3/4 expression were significantly higher in both ALL (P = < 0.001, P = 0.005 respectively) and AML patients (P < 0.001, P = 0.003 respectively) as compared to control, and decline at complete remission (CR) and elevated again at relapse. High SOX2 and OCT3/4 levels were significantly correlated with the presence of adverse risk stratification parameters.ConclusionOur findings indicated that both SOX2 and OCT3/4 could serve as biomarkers that could improve risk stratification of acute leukemia patients. Also, both SOX2 and OCT3/4 might be a therapeutic target, especially in resistant acute leukemia.

Characterizing chromosome 3p/q genes as biomarkers of treatment response in squamous cell carcinoma of the lung and head and neck.

e18048 Background: There is an urgent need to improve treatment options for lung squamous cell carcinoma (LUSC) and head and neck squamous cell carcinoma (HNSCC). Immunotherapy (IO) is used in both diseases, but response rates are ~20% to monotherapy. Chromosome alterations in 3p/3q are frequently found in both LUSC and HNSCC. Here we examined the association of expression of Chromosome 3p/3q genes with treatment outcomes and immune microenvironment. Methods: 3833 LUSC and 1386 HNSCC biopsies were analyzed by next-generation sequencing (592, NextSeq; WES, WTS NovaSeq). Selected Chr 3p ( DLEC1, FOXP1, LTF) and Chr 3q ( SOX2) genes were classified by above (-H, high) or below (-L, low) median RNA expression. HPV status inferred by staining of p16 by IHC. Real world median overall survival (mOS) was obtained from insurance claims and calculated from tissue collection or first IO treatment to last contact using Kaplan-Meier estimates. Immune cell infiltration was estimated based on RNA deconvolution method Quantiseq. Statistical significance was determined by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q &lt; 0.05). Results: High LTF ( LTF-H) was associated with improved OS in both LUSC (mOS: 559 vs 349 days; HR: 0.7, 95% CI (0.6-0.7)) and HNSCC (mOS: 567 vs 473 days; HR: 0.8, 95% CI (0.7-0.9)) (p &lt; 0.01). LTF-H was also associated with improved post-IO survival in both LUSC (Pembro, mOS: 532 vs 349 days; HR: 0.8, 95% CI (0.6-0.9)) and HNSCC (Nivo, mOS: 797 vs 604 days; HR: 0.5, 95% CI (0.2-0.9)) (p &lt; 0.05). Interestingly, this improved OS was specific to HPV+ HNSCC patients (Nivo, Pembro mOS: 1210 vs 473 days; HR: 0.39, 95% CI (0.22-0.69) (p &lt; 0.01)) and not HPV- HNSCC patients (Nivo, Pembro mOS: 313 vs 336 days; HR 0.98, 95% CI (0.664-1.47) (p = 0.95)). LTF-H LUSC and HNSCC had increased IFNy score (-0.24 vs -0.30; -0.16 vs -0.23, p &lt; 0.05) and immune cell infiltration of B cells (median cell fraction: 6.9% vs 5.8%; 6.9% vs 5.3%), M2 Mφ (5.7% vs 5.1%; 4.3% vs 3.8%), NK cells (3.1% vs 2.8%; 3.3% vs 2.7%), CD4 T cells (1.7% vs 1%; 1.7% vs 1%), CD8 T cells (1.5% vs 1%; 1.5% vs 1%) and Tregs (3.1% vs 2.4%; 4.1% vs 3.5%) compared to LTF-L tumors, respectively (all p &lt; 0.05). Additionally, high DLEC1 was associated with improved OS in LUSC (mOS: 484 vs 392 days; HR: 0.8, 95% CI (0.8-0.9)) and HNSCC (mOS: 594 vs 448 days; HR: 0.7, 95% CI (0.6-0.9) (p &lt; 0.01)). FOXP1 expression did not correlate with different survival in LUSC or HNSCC. High SOX2 expression was associated with an improved OS in LUSC (mOS: 526 vs 352 days; HR: 0.7, 95% CI (0.7-0.8)) and HNSCC (mOS: 634 vs 404 days; HR: 0.7, 95% CI (0.6-0.8)) (p &lt; 0.01). Conclusions: Our data suggest a strong association between LTF expression and differential immune cell infiltration and improved overall survival. Future studies interrogating additional Chr 3q/3p alterations may provide further information of the prognostic implications of LTF in LUSC and HNSCC.

SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry

The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC.

Association of wnt signalling with metachronous colonic polyp risk.

232 Background: Following colorectal polypectomy, 20-50% of patients develop metachronous polyps, and a proportion have increased colorectal cancer (CRC) risk. However, there are currently no molecular biomarkers for predicting metachronous polyp risk. Constitutive activation of the Wnt signalling cascade is a hallmark of polyp development and carcinogenesis, therefore biomarkers from this pathway were investigated for association with detection of metachronous polyps. Methods: A retrospective study was performed on a tissue microarray (TMA) of left sided colonic polyps from 279 patients undergoing screening polypectomy (May’09-Dec’16) followed by surveillance colonoscopy (up to 6 years). Mutational analysis was performed using the GPOL cancer plus panel, protein expression by Immunohistochemistry and RNA-sequencing by TempO-Seq (BioClavis). Log rank statistics determined associations with time to detection of metachronous polyp. Index polyp number, histology and size were compared to metachronous lesion outcome using χ2/ANOVA and multivariate polynomial regression identified independent predictors of advanced future lesions. Results: APC (91%), KRAS (30%) and SOX9 (23%) were the most frequently mutated genes and APC and SOX9 are both implicated in Wnt signalling. Mutations in APC and co-mutations in SOX9 with ARID1 were associated with a shorter time to detection of metachronous polyps. Neither variant classification nor location of mutations were associated with metachronous polyp detection. Luminal epithelial cells with high expression of E-Cadherin or SOX9 were significantly associated with earlier detection of metachronous polyps or CRC (HR 2.3, 95%CI 1.6-3.3: p&lt;0.001 and: HR 2.0, 95%CI 1.3-3.0; p=0.001 respectively). By χ2/ANOVA analysis, E-Cadherin and SOX9 expression was associated with detection of metachronous polyp (p&gt;0.001, p=0.037 respectively). On multivariate regression, number of polyps (HR 1.2, 95%CI 1.1-1.3; p&lt;0.001), and E-Cadherin expression (HR 2.1, 95%CI 1.5-3; p&lt;0.001), independently predicted metachronous lesions. Gene set enrichment analysis (GSEA) was used to explore differential biology between high and low E-Cadherin or SOX9 expression. For E-Cadherin, all seven immune-annotated MSigDB hallmarks had negative enrichment, however Wnt--catenin signaling was positively enriched (NES=1.50, p-adj&lt;0.1). The top signature enriched for SOX9 was ‘NFB signaling via TNF (NES=1.70, p-adj&lt;0.001). The LGR5 stemness signature was enriched in both high E-Cadherin (NES=1.97 p-adj&lt;0.0001) and high SOX9 (NES=1.48, p-adj&lt;0.0001) groups. Conclusions: Wnt signalling-associated protein expression within index polyp tissue is valuable for predicting metachronous polyp risk. In addition, expression of E-Cadherin and SOX9 in colonic polyps are linked to immune and stemness signatures, suggesting immune and stemness biology may be an underlying driver of metachronous polyp development.

SOX2-high cancer cells exhibit an aggressive phenotype, with increases in stemness, proliferation and invasion, as well as higher metabolic activity and ATP production.

Cancer stem cells (CSCs) are responsible for cancer recurrence, treatment failure and metastatic dissemination. As such, the elimination of CSCs represents one of the most important approaches for the future of cancer treatment. Among other properties, CSCs show the activation of particular cell signalling pathways and the over-expression of certain transcription factors, such as SOX2. Herein, we describe a new model system to isolate stem-like cancer cells, based on the functional transcriptional activity of SOX2. Briefly, we employed a SOX2-enhancer-GFP-reporter system to isolate cancer cells with high SOX2 transcriptional activity by FACS sorting. The over-expression of SOX2 in this sub-population was validated by Western blot analysis and flow cytometry. SOX2-high cancer cells showed CSCs features, such as greater mammosphere forming ability, validating that this sub-population was enriched in CSCs. To further explore the model, we analysed other stemness characteristics in MCF7 and MDA-MB-231 breast cancer cell lines, corroborating that SOX2-high cells were more metabolically active, proliferative, migratory, invasive, and drug-resistant. SOX2-high MDA-MB-231 cells also showed a loss of E-cadherin expression, and increased Vimentin expression, consistent with an epithelial-mesenchymal transition (EMT). Therefore, endogenous SOX2 transcriptional activity and protein levels are mechanistically linked to aggressive phenotypic behaviours and energy production in CSCs.

Geometrical analysis identified morphological features of hydrogel-induced cancer stem cells in synovial sarcoma model cells

Cancer stem cells (CSCs) has been a key target to cure cancer patients completely. Although many CSC markers have been identified, they are frequently cancer type-specific and those expressions are occasionally variable, which becomes an obstacle to elucidate the characteristics of the CSCs. Here we scrutinized the relationship between stemness elevation and geometrical features of single cells. The PAMPS hydrogel was utilized to create the CSCs from mouse myoblast C2C12 and its synovial sarcoma model cells. qRT-PCR analysis confirmed the significant increase in expression levels of Sox2, Nanog, and Oct3/4 on the PAMPS gel, which was higher in the synovial sarcoma model cells. Of note, the morphological heterogeneity was appeared on the PAMPS gel, mainly including flat spreading, elongated spindle, and small round cells, and the Sox2 expression was highest in the small round cells. To examine the role of morphological differences in the elevation of stemness, over 6,400 cells were segmented along with the Sox2 intensity, and 12 geometrical features were extracted at single cell level. A nonlinear mapping of the geometrical features by using uniform manifold approximation and projection (UMAP) clearly revealed the existence of relationship between morphological differences and the stemness elevation, especially for C2C12 and its synovial sarcoma model on the PAMPS gel in which the small round cells possess relatively high Sox2 expression on the PAMPS gel, which supports the strong relationship between morphological changes and the stemness elevation. Taken together, these geometrical features can be useful for morphological profiling of CSCs to classify and distinguish them for understanding of their role in disease progression and drug discovery.

SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma.

Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with SOX9 -high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High SOX9 mRNA level, but not increased expression of EpCAM mRNA or K19 mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High SOX9 mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased SOX9 mRNA and can be used to predict prognosis in HCC cases.

Clinicopathological and prognostic significance of SOX9 expression in gastric cancer patients: A meta-analysis.

Background:SOX9 is a potential prognostic marker in gastric cancer (GC) patients. This meta-analysis aimed to highlight the clinicopathological and prognostic implications of SOX9 expression in GC patients.Methods:A systematic literature search was conducted to identify relevant studies by the electronic literature databases (PubMed, Web of Science, EMBASE and Chinese databases). Review Manager version 5.4 was employed to evaluate the pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CIs).Results:Seventeen studies with a total of 2893 GC patients were enrolled in this meta-analysis. The analysis with ten articles clarified that higher expression of SOX9 was observed in GC cancers than that of normal gastric samples (OR = 16.26; 95% CI: 8.16 to 32.42; P < .00001). Consequently, the results also showed that SOX9 expression was closely associated with age (OR = 1.34; 95% CI: 1.04–1.72; P = .03), tumor size (OR = 0.67; 95% CI: 0.49–0.91; P = .01), histological differentiation (OR = 0.62; 95% CI: 0.36–1.06; P = .002), tumor stage (OR = 0.48; 95% CI: 0.20–1.12; P = .04), lymph node metastasis (OR = 0.36; 95% CI: 0.19–0.67; P = .0010) and advanced TNM stage (OR = 0.46; 95% CI: 0.30–0.70; P = .0003), but not significantly related to gender, distant metastasis and vascular invasion. Furthermore, high SOX9 expression could significantly indicate poorer overall survival (OS) (HR = 1.40; 95% CI: 1.14–1.72; P = .001).Conclusion:SOX9 overexpression might be related to poor prognosis and could serve as a potential predictive marker of poor clinicopathological prognosis factor in GC patients.

The expression of Beta-Catenin and Sox2 in adenocarcinoma and adenomatous polyps of the colon and their association with clinicopathological parameters

Objective: Our aim was to investigate the immunohistochemical expression of β-catenin and Sox-2 in adenomatous polyps and adenocarcinoma of colon and also to evaluate the effects of these markers in adenoma-carcinoma sequence and their association with clinicopathological parameters.&#x0D; Methods: Fifty-six tubular adenomas with low grade dysplasia (TALGD), 53 tubular adenomas with high grade dysplasia (TAHGD), 44 tubulovillous adenomas (TVA), 29 villous adenomas (VA) and 60 adenocarcinomas were included in the study. The nuclear staining of Sox2 was evaluated as well as both nuclear and cytoplasmic stainings of β-catenin. A semiquantitative scoring was performed. The results were compared between the groups and the relationship of the results with clinicopathological parameters was evaluated.&#x0D; Results: Nuclear and cytoplasmic β-catenin expressions of the adenocarcinomas were higher than polyps. The expressions in the VA and TVA polyp groups were higher than the expressions in TAHGD and TALGD, respectively. Membranous β-catenin expression in the adenocarcinoma was higher than the polyps except VA. The evaluation between polyp groups with respect to membranous β-catenin staining revealed a statistically significantly difference in favor of VA compared with TVA, TAHGD and TALGD; in favor of TAHGD compared with TVA, in favor of TVA compared with TALGD while it was found statistically significantly higher in TAHGD than TALGD. &#x0D; Conclusion: The results regarding β-catenin expression of the polyp groups were consistent with the literature. There was a positive correlation between β-catenin expression (nuclear and cytoplasmic) and malignancy. High Sox2 expressions were found correlated with malignancy potential. Large sampling size investigations to be supported by further molecular studies are needed to clarify the effect of Sox2 expression in the sequence of adenoma-carcinoma comprehensively.

Abstract LB035: Understanding the mechanism of neuropilin2 upregulation in advanced prostate cancer

Abstract Background: Prostate cancer management involves administering Androgen Deprivation Therapy (ADT). Patients with advanced form of the disease become resistant to ADT and progress to a lethal phenotype called Castration Resistant Prostate Cancer (CRPC). Neuropilin-2 is upregulated in advanced prostate cancer. It has been implicated in decreasing the overall survival of such patients by inducing therapy-resistance. Significance: Understanding how NRP2 is differentially expressed will uncover molecular pathways that can be targeted to develop a specific treatment strategy for better management of patients. Experimental Design: We checked NRP2 expression in different prostate cancer cell lines {LNCaP, C4-2 and C4-2 P53/RB1 null cells (DKD cells)} and the level of methylation of the NRP2 promoter in these cells by pyrosequencing. We demethylated the NRP2 promoter by treatment with 5’Azacytidine and checked NRP2 mRNA expression. We analyzed the NRP2 promoter activity under demethylated conditions by transfecting cells with a demethylated NRP2 promoter construct using a GLuc dual-luciferase assay. Using Biobase we found DNA sequences for binding of transcription factors within the NRP2 promoter. RNA-Seq, RT-PCR was performed to identify potential transcription factors of NRP2(highly expressed in DKD cells). To validate SOX2 as a transcription factor for NRP2, we tested its binding to NRP2 promoter by ChIP-q-PCR. Requirement of SOX2 in transcribing NRP2 mRNA in C4-2 and DKD cells was tested by both knocking down or ectopically expressing SOX2. To determine whether demethylation of NRP2 promoter is a prerequisite for SOX2 binding, SOX2 was overexpressed in LNCaP cells following 5’Azacytidine and monitored the change in the NRP2 expression. Results: NRP2 expression was low in LNCaP cells. It steadily increased in C4-2 cells with a steep rise in the DKD cells. Pyrosequencing showed a high level of DNA methylation in LNCaP cells compared to C4-2 cells. On treatment with 5’Azacytidine, NRP2 mRNA expression was upregulated in the LNCaP cells and it significantly rose in the C4-2 cells. Our dual-luciferase assay showed us that in C4-2 cells, the promoter activity of NRP2 upon demethylation went up causing a significant rise in Luciferase expression. RNA-seq and RT-PCR analysis showed high SOX2 levels in DKD cells indicating that SOX2 might play a role in elevating NRP2 expression in these cells. ChIP q-PCR indicated enriched binding of SOX2 in the NRP2 promoter in DKD cells. On silencing SOX2 in DKD cells, the expression of NRP2 was decreased. Analogous to this finding, overexpressing SOX2 in C4-2 cells caused significant rise in NRP2 expression, whereas in LNCaP cells, there was no change. Demethylation of NRP2 promoter and simultaneous overexpression of SOX2 in LNCaP lead to a significant increase in NRP2 mRNA suggesting the requirement of demethylated NRP2 promoter for SOX2 function. Conclusion: The differential expression of NRP2 in advanced prostate cancer is a two-step process of initial demethylation of the DNA in the NRP2 promoter region, followed by binding of SOX2 Citation Format: Sanika Bodas, Ridwan Islam, Sreyashi Bhattacharya, Juhi Mishra, Dipanwita Das, Michael Muders, Samikshan Dutta, Benjamin A. Teply, Kaustubh Datta. Understanding the mechanism of neuropilin2 upregulation in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB035.

The Relationship of SRY Determining Region Y Box 2 (SOX2) Immunohistochemical Expression with Stromal and Intratumoral TILs (Tumor Infiltrating Lymphocytes) in Patients with Ovarian Serous Tumors

Background: Ovarian serous tumors are the most common epithelial tumors in premenopausal and postmenopausal, 60% of the most common cases are ovarian cystadenoma, 25% of low grade and highgrade serous carcinoma. Tumor infiltrating lymphocytes (TILs) is used to predict the prognosis some solid tumors. SRY (sex determining region Y)-box 2 (SOX2) is a transcription factor. High SOX2 in ovarian tumors associated with reduced disease-free survival. Research Objective: To determine the relationship between SOX2 expression and TILs in patients with a diagnosis of ovarian serous tumor at the Anatomic Pathology Laboratory, USU Medical Faculty and RSUP. H. Adam Malik Medan. Materials and Methods: 39 samples histopathological slides with a diagnosis of ovarian serous tumor, slide review was performed and TILs assessed and then SOX2 immunohistochemical staining and then analyzed for correlation between variables using Eta test (p<0.001) and Somer'sd test (p=0.120). Results: The highest expression of SOX2 high was in the highgrade serous carcinoma subtype in 9 (23.1%) cases. Most cases were also found in low SOX2 expression with low iTILs in 20 (51.3%) cases and low SOX2 expression with low sTILs in 16 (41.0%) cases. There was a significant relationship between subtypes and SOX2 expression (p < 0.001) and the Somers'd correlation showed no significant relationship between SOX2 and TILs (p = 0.120). Conclusion: In this study, there was a correlation between tumor subtypes and SOX2 expression and there was no correlation between SOX2 expression and TILs in ovarian serous tumors.

High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML.

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.

Truncating SOX9 Alterations Are Heterozygous Null Alleles in Genome-Stable Colorectal Cancer.

Truncating SOX9 Alterations Are Heterozygous Null Alleles in Genome-Stable Colorectal Cancer.

Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor.

BackgroundThymic epithelial tumors (TETs) are rare tumors originating from the thymic epithelial cells. SOX9, a member of the family of SOX (SRY-related high-mobility group box) genes, has been considered as an oncogene and therapeutic target in various cancers. However, its role in TETs remains uncertain.MethodsUsing the immunohistochemistry method, the expression of SOX9 was analyzed in TETs tissues, including 34 thymoma (8 cases with type A, 6 with type AB, 6 with type B1, 9 with type B2, and 5 with type B3 thymomas) and 20 thymic cancer tissues and the clinicopathologic and prognostic significances were evaluated. Further bioinformatics analysis of gene expression profiles of thymomas with high and low SOX9 expressions and the corresponding survival analyses were based on the thymoma cases identified in The Cancer Genome Atlas (TCGA) database, with the median expression level of SOX9 selected as cutoff.ResultsImmunohistochemistry staining showed that SOX9 was highly expressed in the nuclei of the epithelial cells of the Hassall’s corpuscles and of the TET tumor cells. SOX9 expression was significantly associated with histological type and high expression indicated unfavorable clinical outcomes of thymomas. Bioinformatics analysis revealed that genes positively associated with SOX9 expression were mapped in proteoglycans in cancer, cell adhesion molecules, and molecules involved in extracellular matrix-receptor interaction and the TGF-β signaling pathway, and that genes negatively associated with SOX9 expression were mapped in molecules involved in primary immunodeficiency, the T cell receptor signaling pathway, Th17 cell differentiation, PD-L1 expression, and the PD-1 checkpoint pathway in cancer. In addition, SOX9 expression was positively associated with POU2F3 and TRPM5 expressions, the master regulators of tuft cells, suggesting that high SOX9 expression might be associated with the tuft cell phenotype of thymomas. Moreover, high SOX9 expression was associated with immune dysregulation of thymoma, and M2 macrophage significantly dominated in the high SOX9 expression group.ConclusionSOX9 may serve as a diagnostic and prognostic marker for TETs. Notably, high SOX9 expression in TETs may indicate a tuft cell phenotype and an immune suppressive microenvironment of thymomas.

High SOX2 expression as an indicator of the potential involvement of cancer stem cells in the development of cervical cancer among females with HPV infection

High SOX2 expression as an indicator of the potential involvement of cancer stem cells in the development of cervical cancer among females with HPV infection

Design and Characterization of a Cell-Penetrating Peptide Derived from the SOX2 Transcription Factor.

SOX2 is an oncogenic transcription factor overexpressed in nearly half of the basal-like triple-negative breast cancers associated with very poor outcomes. Targeting and inhibiting SOX2 is clinically relevant as high SOX2 mRNA levels are positively correlated with decreased overall survival and progression-free survival in patients affected with breast cancer. Given its key role as a master regulator of cell proliferation, SOX2 represents an important scaffold for the engineering of dominant-negative synthetic DNA-binding domains (DBDs) that act by blocking or interfering with the oncogenic activity of the endogenous transcription factor in cancer cells. We have synthesized an interference peptide (iPep) encompassing a truncated 24 amino acid long C-terminus of SOX2 containing a potential SOX-specific nuclear localization sequence, and the determinants of the binding of SOX2 to the DNA and to its transcription factor binding partners. We found that the resulting peptide (SOX2-iPep) possessed intrinsic cell penetration and promising nuclear localization into breast cancer cells, and decreased cellular proliferation of SOX2 overexpressing cell lines. The novel SOX2-iPep was found to exhibit a random coil conformation predominantly in solution. Molecular dynamics simulations were used to characterize the interactions of both the SOX2 transcription factor and the SOX2-iPep with FGF4-enhancer DNA in the presence of the POU domain of the partner transcription factor OCT4. Predictions of the free energy of binding revealed that the iPep largely retained the binding affinity for DNA of parental SOX2. This work will enable the future engineering of novel dominant interference peptides to transport different therapeutic cargo molecules such as anti-cancer drugs into cells.

Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11.

Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment. SIGNIFICANCE: This study uncovers a SOX2-SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.