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Objective(s): Sox11, one of the SoxC family members, is an important transcription factor during neural development and neurogenesis. However, there is no report about its function in neural apoptosis. This research aims to examine the function of Sox11 in surgical brain injury (SBI).Materials and Methods: We used 90 Sprague-Dawley rats to develop the SBI models and the siRNA of Sox11 to study the roles of Sox11. Western blot, real-time PCR, immunofluorescence, neuron apoptosis and necrosis, brain edema, and neurological score were determined.Results: The gene and protein amount of Sox11, compared with the Sham group, were increased after SBI, which reached a peak at 12 hr. In addition, following the application of siRNAs, the amount of Sox11 protein was significantly less than that in the SBI group. On the other hand, neuronal apoptosis, necrosis, and brain edema were significantly increased, while neurological scores were decreased.Conclusion: These findings demonstrate the role of Sox11 following nerve injury induced by SBI. Inhibition of Sox11 with siRNA may lead to neuronal injury and cell death, aggravating secondary brain injury after SBI.

De novo germline variants of the SRY‐related HMG‐box 11 gene (SOX11) have been reported to cause Coffin–Siris syndrome‐9 (CSS‐9), a rare congenital disorder associated with multiple organ malformations, including ear anomalies. Previous clinical and animal studies have found that intragenic pathogenic variant or haploinsufficiency in the SOX11 gene could cause inner ear malformation, but no studies to date have documented the external ear malformation caused by SOX11 deficiency. Here, we reported a Chinese male with unilateral microtia and bilateral sensorineural deafness who showed CSS‐like manifestations, including dysmorphic facial features, impaired neurodevelopment, and fingers/toes malformations. Using trio‐based whole‐exome sequencing, a de novo missense variant in SOX11 (NM_003108.4: c.347A>G, p.Y116C) was identified and classified as pathogenic variant as per American College of Medical Genetics guidelines. Moreover, a systematic search of the literature yielded 12 publications that provided data of 55 SOX11 intragenic variants affecting various protein‐coding regions of SOX11 protein. By quantitatively analyzing phenotypic spectrum information related to these 56 SOX11 variants (including our case), we found variants affecting different regions of SOX11 protein (high‐mobility group [HMG] domain and non‐HMG regions) appear to influence the phenotypic spectrum of organ malformations in CSS‐9; variants altering the HMG domain were more likely to cause the widest range of organ anomalies. In summary, this is the first report of CSS with external ear malformation caused by pathogenic variant in SOX11, indicating that the SOX11 gene may be not only essential for the development of the inner ear but also critical for the morphogenesis of the external ear. In addition, thorough clinical examination is recommended for patients who carry pathogenic SOX11 variants that affect the HMG domain, as these variants may cause the widest range of organ anomalies underlying this condition. [ABSTRACT FROM AUTHOR]

Cyclin D1 protein-positive diffuse large B cell lymphoma (DLBCL) has an immunophenotype of CD5(−) cyclin D1(+) SOX11(−), and most cases lack a CCND1 rearrangement and have a gene expression profile of DLBCL. Rarely, cyclin D1 protein-positive DLBCL harbors a CCND1 rearrangement, and some genetic copy number features typical of mantle cell lymphoma (MCL) have been detected. Since gene expression studies have not been performed, whether such CCND1-rearranged cases represent cyclin D1 protein-positive DLBCL or CD5/SOX11 double-negative pleomorphic MCL remains unclear. To date, no cases of CD5/SOX11 double-negative MCL have been reported. In this study, we collected eight cases initially diagnosed as cyclin D1 protein-positive DLBCL, including four with a CCND1 rearrangement and four without. Immunohistochemically, all four CCND1-rearranged cases had >50% of tumor cells positive for cyclin D1 protein, whereas only one (25%) non-rearranged case had >50% positive tumor cells. Analysis of genome-wide copy number, mutational, and gene expression profiles revealed that CCND1-rearranged cases were similar to MCL, whereas CCND1-non-rearranged cases resembled DLBCL. Despite the SOX11 negativity by immunohistochemistry, CCND1-rearranged cases had a notable trend (P = 0.064) of higher SOX11 mRNA levels compared to non-rearranged cases. Here, we show for the first time that CCND1 rearrangement could be useful for identifying CD5/SOX11 double-negative pleomorphic MCL in cases diagnosed as cyclin D1 protein-positive DLBCL. Cases with >50% cyclin D1 protein-positive tumor cells immunohistochemically and higher SOX11 mRNA levels are more likely to have a CCND1 rearrangement, and fluorescence in situ hybridization can be used to detect the rearrangement. [ABSTRACT FROM AUTHOR]

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 in vivo and in vitro 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. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) refers to the malignancy of squamous cells in the head and neck region. Ranked as the seventh most common cancer worldwide, HNSCC has a very low survival rate, highlighting the importance of finding therapeutic targets for the disease. Integrins are cell surface receptors that play a crucial role in mediating cellular interactions with the extracellular matrix (ECM). Within this protein family, Integrin αV (ITGAV) has received attention for its important functional role in cancer progression. In this study, we first demonstrated the upregulation of ITGAV expression in HNSCC, with higher ITGAV expression levels correlating with significantly lower overall survival, based on TCGA (the Cancer Genome Atlas) and GEO datasets. Subsequent in vitro analyses revealed an overexpression of ITGAV in highly invasive HNSCC cell lines UM1 and UMSCC-5 in comparison to low invasive HNSCC cell lines UM2 and UMSCC-6. In addition, knockdown of ITGAV significantly inhibited the migration, invasion, viability, and colony formation of HNSCC cells. In addition, chromatin immunoprecipitation (ChIP) assays indicated that SOX11 bound to the promoter of ITGAV gene, and SOX11 knockdown resulted in decreased ITGAV expression in HNSCC cells. In conclusion, our studies suggest that ITGAV promotes the progression of HNSCC cells and may be regulated by SOX11 in HNSCC cells.

Head and neck squamous cell carcinoma (HNSCC) refers to the malignancy of squamous cells in the head and neck region. Ranked as the seventh most common cancer worldwide, HNSCC has a very low survival rate, highlighting the importance of finding therapeutic targets for the disease. Integrins are cell surface receptors that play a crucial role in mediating cellular interactions with the extracellular matrix (ECM). Within this protein family, Integrin αV (ITGAV) has received attention for its important functional role in cancer progression. In this study, we first demonstrated the upregulation of ITGAV expression in HNSCC, with higher ITGAV expression levels correlating with significantly lower overall survival, based on TCGA (the Cancer Genome Atlas) and GEO datasets. Subsequent in vitro analyses revealed an overexpression of ITGAV in highly invasive HNSCC cell lines UM1 and UMSCC-5 in comparison to low invasive HNSCC cell lines UM2 and UMSCC-6. In addition, knockdown of ITGAV significantly inhibited the migration, invasion, viability, and colony formation of HNSCC cells. In addition, chromatin immunoprecipitation (ChIP) assays indicated that SOX11 bound to the promoter of ITGAV gene, and SOX11 knockdown resulted in decreased ITGAV expression in HNSCC cells. In conclusion, our studies suggest that ITGAV promotes the progression of HNSCC cells and may be regulated by SOX11 in HNSCC cells. [ABSTRACT FROM AUTHOR]

Background: Speech and language skills are important for social interaction and learning. This study characterised the communication abilities of verbal individuals with SOX11 syndrome using a standardised parent/carer questionnaire, the Children's Communication Checklist (CCC‐2). Method: Thirteen parent/carers of verbal individuals (aged 5–19 years) diagnosed with SOX11 syndrome completed the CCC‐2. In order to contextualise findings, responses were compared to norms and to data from Noonan syndrome, a relatively well‐known genetic diagnosis associated with communication impairment. Results: For all individuals, the CCC‐2 composite score indicated significant communication difficulties. Language structure (speech, syntax, semantics and coherence), pragmatic language (inappropriate initiation, stereotyped language use of context and non‐verbal communication) and autistic features (social relations and interests) scores were lower than typically developing norms. Subscale comparisons revealed relative difference in use of context compared to other pragmatic domains (stereotyped language and inappropriate initiation). Individual scores showed substantial variation, particularly in regard to language structure profile. Differences were more pronounced than for Noonan syndrome, specifically in domains of speech, syntax, non‐verbal communication and social relations. Conclusions: SOX11 syndrome is associated with communication impairment. It is important to assess communication abilities as part of the management of individuals with SOX11 syndrome and understand individual strengths and difficulties in order to provide targeted support. [ABSTRACT FROM AUTHOR]

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) is a rare lymphoid neoplasm, usually occurring in the pediatric/young-adult age. Despite this, subsets of cases occur in elderly patients and express CD5, possibly entering the differential diagnosis with adult aggressive lymphomas, such as blastoid/pleomorphic mantle cell lymphoma (MCL-B/P). To better characterize the clinical-pathological features and differential diagnosis of LBCL-IRF4, we conducted a multi-centric study on 12 cases, focusing on CD5, Cyclin D1, and SOX11 expression. While most cases had typical presentation, adult-to-elderly age at diagnosis and unusual anatomic locations were reported in 3/12 (25.0%) and 2/12 (16.7%) patients, respectively. Histologically, CD5 was positive in 4/12 (33.3%) cases, Cyclin D1 was invariably negative, and SOX11 was weakly/partially expressed in 1/12 (8.3%) case. In conclusion, LBCL-IRF4 can have unconventional clinical presentations that may challenge its recognition. Although CD5 is frequently expressed, negativity for Cyclin D1 and SOX11 contributes to the differential diagnosis with MCL-B/P. [ABSTRACT FROM AUTHOR]

Background: Neuropathic pain, a complex condition originating from nervous system damage, remains a significant clinical challenge due to limited understanding of its underlying mechanisms. Recent research highlights the SOX11 transcription factor, known for its role in nervous system development, as a crucial player in neuropathic pain development and maintenance. This study investigates the role of the SOX11-ARID1A-SOCS3 pathway in neuropathic pain modulation within the spinal cord. Methods and results: Using a spinal nerve ligation (SNL) model in mice, we observed a significant upregulation of Sox11 in the spinal cord dorsal horn post-injury. Intrathecal administration of Sox11 shRNA mitigated SNL-induced neuropathic pain behaviors, including mechanical allodynia and heat hyperalgesia. Further, we demonstrated that Sox11 regulates neuropathic pain via transcriptional control of ARID1A, with subsequent modulation of SOCS3 expression. Knockdown of ARID1A and SOCS3 via shRNA resulted in alleviation of Sox11-induced pain sensitization. Additionally, Sox11 overexpression led to an increase in ARID1A binding to the SOCS3 promoter, enhancing chromatin accessibility and indicating a direct regulatory relationship. These findings were further supported by in vitro luciferase reporter assays and chromatin accessibility analysis. Conclusions: The SOX11-ARID1A-SOCS3 pathway plays a pivotal role in the development and maintenance of neuropathic pain. Sox11 acts as a master regulator, modulating ARID1A, which in turn influences SOCS3 expression, thereby contributing to the modulation of neuropathic pain. These findings provide a deeper understanding of the molecular mechanisms underlying neuropathic pain and highlight potential therapeutic targets for its treatment. The differential regulation of this pathway in the spinal cord and dorsal root ganglia (DRG) underscores its complexity and the need for targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Pitt‐Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12‐year‐old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin‐Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an intermediate-grade B-cell lymphoma, representing 2.8% of all non-Hodgkin lymphomas in the US. It is associated with t(11;14)(q13; q23), which leads to the overexpression of cyclin D1, consequently promoting cell proliferation. MCL usually expresses CD19, CD20, CD43, surface immunoglobulins, FMC7, BCL2, cyclin D1, CD5, and SOX11. Herein is a case of a 67-year-old male, referred to our facility with shortness of breath, anemia (hemoglobin of 5.3 g/dL), thrombocytopenia (12 × 109/L), and leukocytosis (283 × 109/L). A peripheral blood smear showed marked lymphocytosis with blastoid morphology. Morphologic examination of the bone marrow biopsy revealed a diffuse sheet of blastoid cells expressing CD20 and CD10, but without CD5 or cyclin D1. Given these features, a differential diagnosis of diffuse large B-cell lymphoma (DLBCL) with germinal center derivation, high-grade follicular lymphoma, and Burkitt lymphoma was considered, with the latter not favored due to morphology. Additional studies revealed positive SOX11, and fluorescence in situ hybridization (FISH) studies detected t(11;14). These additional studies supported diagnosis of the blastoid variant of MCL. In conclusion, we present a unique and challenging case of MCL without cyclin D1 or CD5, but with an expression of CD10 and SOX11, along with t(11;14). Pathologists should explicitly consider the blastoid variant of MCL when dealing with mature B-cell neoplasms with blastoid morphology in adults, and utilize a broad panel of ancillary studies, including FISH and SOX11. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a fatal malignancy that has limited treatment options. This study focused on the potential therapeutic effects of curcumin (CUR) and berberine (BBR) on the miR-221/SRY-box transcription factor 11 (SOX11) axis in HCC. We investigated the combined effects of CUR and BBR on HEPG2 and Huh7 cell survival and miR-221 expression using Cell Counting Kit-8 assays and RTqPCR, respectively. Western blotting was used to detect changes in the apoptosis-related caspase-3/9 protein levels. We performed bioinformatics analysis and dual-luciferase assays and measured apoptotic protein levels to assess the role of the miR-221/SOX11 axis in mediating the effects of CUR-BBR. Both CUR and BBR suppressed HCC cell growth in a dose-dependent manner, with the most potent combined effect observed at a 2:1 ratio. CUR-BBR treatment significantly downregulated miR-221 expression, and miR-221 overexpression partially reversed the CUR-BBR-mediated decrease in cell survival. In addition, SOX11 was found to be a direct target of miR-221. CUR-BBR treatment upregulated SOX11 expression, and overexpression of SOX11 restored the inhibitory effects of CUR-BBR on cell growth, migration, and invasion and promoted apoptosis in the presence of miR-221. Furthermore, CUR-BBR activated pro-apoptotic proteins caspase-3/9 through the miR-221/SOX11 axis. The combined effect of CUR-BBR played an important role in inhibiting the growth of HCC cells. This combined effect was achieved by regulating the miR-221/SOX11 axis and activating the synthesis of pro-apoptotic proteins. Our findings highlight a promising combined therapeutic approach for HCC and underscore the importance of targeting the miR-221/SOX11 axis. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an intermediate-grade B-cell lymphoma, representing 2.8% of all non-Hodgkin lymphomas in the US. It is associated with t(11;14)(q13; q23), which leads to the overexpression of cyclin D1, consequently promoting cell proliferation. MCL usually expresses CD19, CD20, CD43, surface immunoglobulins, FMC7, BCL2, cyclin D1, CD5, and SOX11. Herein is a case of a 67-year-old male, referred to our facility with shortness of breath, anemia (hemoglobin of 5.3 g/dL), thrombocytopenia (12 × 109/L), and leukocytosis (283 × 109/L). A peripheral blood smear showed marked lymphocytosis with blastoid morphology. Morphologic examination of the bone marrow biopsy revealed a diffuse sheet of blastoid cells expressing CD20 and CD10, but without CD5 or cyclin D1. Given these features, a differential diagnosis of diffuse large B-cell lymphoma (DLBCL) with germinal center derivation, high-grade follicular lymphoma, and Burkitt lymphoma was considered, with the latter not favored due to morphology. Additional studies revealed positive SOX11, and fluorescence in situ hybridization (FISH) studies detected t(11;14). These additional studies supported diagnosis of the blastoid variant of MCL. In conclusion, we present a unique and challenging case of MCL without cyclin D1 or CD5, but with an expression of CD10 and SOX11, along with t(11;14). Pathologists should explicitly consider the blastoid variant of MCL when dealing with mature B-cell neoplasms with blastoid morphology in adults, and utilize a broad panel of ancillary studies, including FISH and SOX11.

Background: Ovarian cancer is the leading cause of death from gynecological malignancies, with serous carcinoma being the most common histopathologic subtype. Epithelial–mesenchymal transition (EMT) correlates with increased metastatic potential, whereas the transcription factor SRY-box transcription factor 11 (SOX11) is overexpressed in diverse malignancies. Methods: In the present study, we aimed to evaluate the potential role of the immunohistochemical expression of SOX11 in 30 serous ovarian carcinomas in association with E-cadherin and vimentin expression as well as with patients' clinicopathological data. Results: Most of the examined cases showed concurrent expression of E-cadherin and vimentin, whereas SOX11 was expressed in a minority of the cases (26.7%). Interestingly, the positive cases more frequently had a metastatic disease at the time of diagnosis compared with the negative cases (p = 0.09), an association, however, of marginal significance. Moreover, there was a negative correlation between E-cadherin and SOX11 expression (p = 0.0077) and a positive correlation between vimentin and SOX11 expression (p = 0.0130). Conclusions: The present work, for the first time, provides preliminary evidence of a possible implication of SOX11 overexpression in the promotion of EMT in metastatic serous ovarian cancer, thereby endorsing tumor metastasis. [ABSTRACT FROM AUTHOR]

Histological identification of dispersed glioma cells in small biopsies can be challenging, especially in tumours lacking the IDH1 R132H mutation or alterations in TP53. We postulated that immunohistochemical detection of proteins expressed preferentially in gliomas (EGFR, MEOX2, CD34) or during embryonal development (SOX11, INSM1) can be used to distinguish reactive gliosis from glioma. Tissue microarrays of 46 reactive glioses, 81 glioblastomas, 34 IDH1-mutant diffuse gliomas, and 23 gliomas of other types were analysed. Glial neoplasms were significantly more often (p < 0.001, χ2) positive for EGFR (34.1% vs. 0%), MEOX2 (49.3% vs. 2.3%), SOX11 (70.5% vs. 20.4%), and INSM1 (65.4% vs. 2.3%). In 94.3% (66/70) of the glioblastomas, the expression of at least two markers was observed, while no reactive gliosis showed coexpression of any of the proteins. Compared to IDH1-mutant tumours, glioblastomas showed significantly higher expression of EGFR, MEOX2, and CD34 and significantly lower positivity for SOX11. Non-diffuse gliomas were only rarely positive for any of the five markers tested. Our results indicate that immunohistochemical detection of EGFR, MEOX2, SOX11, and INSM1 can be useful for detection of glioblastoma cells in limited histological samples, especially when used in combination. [ABSTRACT FROM AUTHOR]

The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development. However, its function in retina regeneration remains elusive. Here we report that Sox11b, a zebrafish Sox11 homolog, regulates the migration and fate determination of Müller glia-derived progenitors (MGPCs) in an adult zebrafish model of mechanical retinal injury. Following a stab injury, the expression of Sox11b was induced in proliferating MGPCs in the retina. Sox11b knockdown did not affect MGPC formation at 4 days post-injury, although the nuclear morphology and subsequent radial migration of MGPCs were altered. At 7 days post-injury, Sox11b knockdown resulted in an increased proportion of MGPCs in the inner retina and a decreased proportion of MGPCs in the outer nuclear layer, compared with controls. Furthermore, Sox11b knockdown led to reduced photoreceptor regeneration, while it increased the numbers of newborn amacrines and retinal ganglion cells. Finally, quantitative polymerase chain reaction analysis revealed that Sox11b regulated the expression of Notch signaling components in the retina, and Notch inhibition partially recapitulated the Sox11b knockdown phenotype, indicating that Notch signaling functions downstream of Sox11b. Our findings imply that Sox11b plays key roles in MGPC migration and fate determination during retina regeneration in zebrafish, which may have critical implications for future explorations of retinal repair in mammals.

M2 macrophages-derived extracellular vesicles (M2-EVs) serve as a tool for the delivery of miRNAs and play an anti-inflammatory role in diseases. This study sought to explore the role of (M2-EVs) in the proliferation and inflammatory responses of IL-1β-stimulated chondrocytes. M2 macrophages were induced and characterized, followed by isolation and characterization of M2-EVs. Chondrocytes were treated with 10 ng/mL IL-1β and co-cultured with M2 macrophages transfected with Cy3-labeled miR-370-3p. Cell viability, TNF (tumor necrosis factor)-α, IL(Interleukin)-18, IL-10, miR-370-3p, and sex-determining region Y-related high-mobility-group box transcription factor 11 (SOX11) mRNA were determined via cell counting assay kit, colony formation, ELISA, and qRT-PCR. The binding relationship between miR-370-3p and SOX11 was testified via the dual-luciferase assay. The functional rescue experiment was designed to confirm the role of SOX11. M2-EVs improved chondrocyte viability and colony formation, lowered TNF-α and IL-18, and elevated IL-10. M2-EVs delivered miR-370-3p into chondrocytes to upregulate miR-370-3p. Upregulation of miR-370-3p in M2-EVs enhanced the protective role of M2-EVs in chondrocytes. miR-370-3p inhibited SOX11 transcription. SOX11 overexpression attenuated the protective role of M2-EVs in chondrocytes. Overall, our findings suggested that M2-EVs promote proliferation and suppress inflammatory responses in IL-1β-stimulated chondrocytes via the miR-370-3p/SOX11 axis. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common disorders that disrupt the quality of life of millions of people. These two chronic diseases cause damage to the joint cartilage and surrounding tissues of more than 220 million people worldwide. Sex-determining region Y-related (SRY) high-mobility group (HMG) box C, SOXC, is a superfamily of transcription factors that have been recently shown to be involved in various physiological and pathological processes. These include embryonic development, cell differentiation, fate determination, and autoimmune diseases, as well as carcinogenesis and tumor progression. The SOXC superfamily includes SOX4, SOX11, and SOX12, all have a similar DNA-binding domain, i.e., HMG. Herein, we summarize the current knowledge about the role of SOXC transcription factors during arthritis progression and their potential utilization as diagnostic biomarkers and therapeutic targets. The involved mechanistic processes and signaling molecules are discussed. SOX12 appears to have no role in arthritis, however SOX11 is dysregulated and promotes arthritic progression according to some studies but supports joint maintenance and protects cartilage and bone cells according to others. On the other hand, SOX4 upregulation during OA and RA was documented in almost all studies including preclinical and clinical models. Molecular details have indicated that SOX4 can autoregulate its own expression besides regulating the expression of SOX11, a characteristic associated with the transcription factors that protects their abundance and activity. From analyzing the currently available data, SOX4 seems to be a potential diagnostic biomarker and therapeutic target of arthritis. [ABSTRACT FROM AUTHOR]

The transcription factor SOX11 is a tumor-associated antigen with low expression in normal cells, but overexpression in glioblastoma (GBM). So far, conventional surgery, chemotherapy, and radiotherapy have not substantially improved the dismal prognosis of relapsed/refractory GBM patients. Immunotherapy is considered a promising strategy against GBM, but there is a fervent need for better immunotargets in GBM. To this end, we performed an in silico prediction study on SOX11, which primarily yielded ten promising HLA-A*0201-restricted peptides derived from SOX11. We defined a novel peptide FMACSPVAL, which had the highest score according to in silico prediction (6.02 nM by NetMHC-4.0) and showed an exquisite binding affinity to the HLA-A*0201 molecule in the peptide-binding assays. In the IFN-γ ELISPOT assays, FMACSPVAL demonstrated a high efficiency for generating SOX11-specific CD8+ T cells. Nine out of thirty-two healthy donors showed a positive response to SOX11, as assessed by the ELISPOT assays. Therefore, this novel antigen peptide epitope seems to be promising as a target for T cell-based immunotherapy in GBM. The adoptive transfer of in vitro elicited SOX11-specific CD8+ T cells constitutes a potential approach for the treatment of GBM patients. [ABSTRACT FROM AUTHOR]

Coffin‐Siris syndrome (CSS, OMIM#135900) is a rare congenital disorder associated with neurodevelopmental and dysmorphic features. The primary cause of CSS is pathogenic variants in any of 9 BAF chromatin‐remodeling complex encoding genes or the genes SOX11 and PHF6. Herein, we performed whole‐exome sequencing (WES) and a series of analyses of growth‐related, auditory, and radiological findings in two probands with syndromic sensorineural hearing loss and inner ear malformations who exhibited distinctive facial features, intellectual disability, growth retardation, and fifth finger malformation. Two de novo variants in the SOX11 gene (c.148A>C:p.Lys50Asn; c.811_814del:p.Asn271Serfs*10) were detected in these probands and were identified as pathogenic variants as per ACMG guidelines. These probands were diagnosed as having CSS based upon clinical and genetic findings. This is the first report of CSS caused by variants in SOX11 gene in Chinese individuals. Deleterious SOX11 variants can result in sensorineural hearing loss with inner ear malformation, potentially extending the array of phenotypes associated with these pathogenic variants. We suggest that both genetic and clinical findings be considered when diagnosing syndromic hearing loss. [ABSTRACT FROM AUTHOR]

Background: Syndromic intellectual disability (ID) with accompanying primary microcephaly is a group of rare neurodevelopmental disorders exhibiting extreme genetic and clinical heterogeneity. This layered heterogeneity can partially be resolved by unbiased genetic approaches targeting the genome with next generation sequencing (NGS) technologies, including exome sequencing (ES). Objective: This study was performed to dissect the clinical and genetic features in five distinct IDM cases. Methods: Singleton or trio ES approach followed by in-depth variant analysis using alternative inheritance models was performed. Results: We have identified biallelic loss of function variants in genes WDR62 and AP4M1 in three families, together with de novo missense variants in genes SOX11 and TRIO in two families. ES based haplotype analysis in two cases upon identification of an identical WDR62 variant in the homozygous state in two cases was suggestive of a small shared haplotype of 0.1 Mb. Additionally, we have shown a paternal origin for the de novo variant in TRIO via a polymorphic tag SNP, which enlightens the mutational mechanism for this variant. Conclusion: In populations with high parental consanguinity, an autosomal recessive inheritance pattern for data analysis is usually the most obvious choice. Therefore, heterozygous variants may be overlooked in standard NGS analyses in consanguineous families. Our findings underlie the importance of using multiple inheritance models in NGS data analysis. [ABSTRACT FROM AUTHOR]

Simple Summary: The transcription factor SOX11 is a member of the SRY box-containing family. Recently, SOX11 research has shifted from embryogenesis to cancer development. Nevertheless, the roles of SOX11 in different cancer types remain controversial. Here, we systematically explored the characteristics of SOX11 by multiple omics analyses. Aberrant SOX11 expression has been observed in many types of human malignant tumors. Moreover, SOX11 expression could serve as an indicator of survival outcomes, tumor progression and cellular immune infiltration. Our work highlights the diverse role of SOX11 in different types of tumors, which points out several directions for future prospective studies on SOX11 in cancer. SRY-box transcription factor 11 (SOX11), as a member of the SOX family, is a transcription factor involved in the regulation of specific biological processes and has recently been found to be a prognostic marker for certain cancers. However, the roles of SOX11 in cancer remain controversial. Our study aimed to explore the various aspects of SOX11 in pan-cancer. The expression of SOX11 was investigated by the Genotype Tissue-Expression (GTEX) dataset and the Cancer Genome Atlas (TCGA) database. The protein level of SOX11 in tumor tissues and tumor-adjacent tissues was verified by human pan-cancer tissue microarray. Additionally, we used TCGA pan-cancer data to analyze the correlations among SOX11 expression and survival outcomes, clinical features, stemness, microsatellite instability (MSI), tumor mutation burden (TMB), mismatch repair (MMR) related genes and the tumor immune microenvironment. Furthermore, the cBioPortal database was applied to investigate the gene alterations of SOX11. The main biological processes of SOX11 in cancers were analyzed by Gene Set Enrichment Analysis (GSEA). As a result, aberrant expression of SOX11 has been implicated in 27 kinds of cancer types. Aberrant SOX11 expression was closely associated with survival outcomes, stage, tumor recurrence, MSI, TMB and MMR-related genes. In addition, the most frequent alteration of the SOX11 genome was mutation. Our study also showed the correlations of SOX11 with the level of immune infiltration in various cancers. In summary, our findings underline the multifaceted role and prognostic value of SOX11 in pan-cancer. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Long non-coding RNA LINC01296 has been shown to predict the invasiveness and poor outcomes of patients with NB. Our study validated its prognostic value and investigated the biological function and potential mechanism of LINC01296 regulating NB. Results illuminated that LINC01296 expression was significantly correlated with unfavorable prognosis and malignant clinical features according to the public NB database. We identified that silencing LINC01296 repressed NB cell proliferation and migration and promoted apoptosis. Moreover, LINC01296 knockdown inhibited tumor growth in vivo. The opposite results were observed through the dCas9 Synergistic Activation Mediator System (dCas9/SAM) activating LINC01296. Mechanistically, we revealed that LINC01296 could directly bind to nucleolin (NCL), forming a complex that activated SRY-box transcription factor 11 (SOX11) gene transcription and accelerated tumor progression. In conclusion, our findings uncover a crucial role of the LINC01296-NCL-SOX11 complex in NB tumorigenesis and may serve as a prognostic biomarker and effective therapeutic target for NB.

Background: Ovarian cancer is the leading cause of death from gynecological malignancies, with serous carcinoma being the most common histopathologic subtype. Epithelial–mesenchymal transition (EMT) correlates with increased metastatic potential, whereas the transcription factor SRY-box transcription factor 11 (SOX11) is overexpressed in diverse malignancies. Methods: In the present study, we aimed to evaluate the potential role of the immunohistochemical expression of SOX11 in 30 serous ovarian carcinomas in association with E-cadherin and vimentin expression as well as with patients’ clinicopathological data. Results: Most of the examined cases showed concurrent expression of E-cadherin and vimentin, whereas SOX11 was expressed in a minority of the cases (26.7%). Interestingly, the positive cases more frequently had a metastatic disease at the time of diagnosis compared with the negative cases (p = 0.09), an association, however, of marginal significance. Moreover, there was a negative correlation between E-cadherin and SOX11 expression (p = 0.0077) and a positive correlation between vimentin and SOX11 expression (p = 0.0130). Conclusions: The present work, for the first time, provides preliminary evidence of a possible implication of SOX11 overexpression in the promotion of EMT in metastatic serous ovarian cancer, thereby endorsing tumor metastasis.

Abstract Background Synaptophysin (SYN), chromogranin A (CGA), CD56 and insulinoma-associated protein 1 (INSM1) are proposed neuroendocrine (NE) markers used for diagnosis of pulmonary NE tumors. These NE markers have been identified in subsets of non-NE tumors requiring differential diagnosis, thus we sought to explore new NE markers. Methods We evaluated the immunohistochemical expression of SOX11, a transcription factor involved in neurogenesis, in pulmonary NE tumors and large cell carcinomas (LCCs). Results We found that SOX11 showed a sensitivity similar to INSM1 and CGA, and less than SYN and CD56 in small cell lung carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). While SOX11 is more specific than the other four markers for diagnosis of high-grade neuroendocrine carcinomas (HG-NECs) because 1) None of LCCs (0/63), the most challenging non-NE tumor type for differential diagnosis due to overlapped morphology with LCNECs displayed SOX11 positivity. While expression of at least one of SYN, CGA, CD56 or INSM1 was identified in approximately 60% (18/30) of LCCs. 2) SOX11 was only expressed in 1 of 37 carcinoid tumors in contrast to diffuse expression of SYN, CGA, CD56 and INSM1. In HG-NECs, we noticed that SOX11 was a good complementary marker for SCLC diagnosis as it was positive in 7 of 18 SYN−/CGA−/CD56− SCLCs and 3 of 8 SYN−/CGA−/CD56−/INSM1− SCLCs, and SOX11 positivity in 4 of 6 SYN−/CGA−/CD56− cases previously diagnosed as LCCs with NE morphology provides additional evidence of NE differentiation for reclassification into LCNECs, which was further confirmed by electromicroscopical identification of neurosecretory granules. We also found SOX11 expression cannot predict the prognosis in patients with HG-NECs. Conclusions Therefore, SOX11 is a useful complementary transcriptional NE marker for diagnosis and differential diagnosis of SCLC and LCNEC.

Abstract Background Non-small cell lung cancer (NSCLC) is still one of the diseases with the highest mortality and morbidity, and lung adenocarcinoma (LUAD) accounts for more than half of all NSCLC cases in most countries. miRNA can be used as a potential biological marker and treatment for lung adenocarcinoma. However, the effect of miR-937-3p to the invasion and metastasis of LUAD cells is not clear. Methods miRNA microarray is used to analyze the expression of miRNA in lung adenocarcinoma tissue. Transwell migration, Wound-healing assay and Western blot analysis are used to analyze cell migration, invasion and epithelial-mesenchymal transition (EMT) capabilities. Tube formation is used to assess angiogenesis ability. In addition, dual luciferase reporter gene detection is used to identify the potential binding between miRNA and target mRNA. In vivo experiments were performed on male NOD/SCID nude mice by tail vein injection to establish a transplanted tumor model. The CHIP experiment is used to verify the transcription factors of miRNA. Result In our study, miR-937-3p was high-regulated in LUAD cell lines and tissues, and its expression level was related to tumor progression. We found that miR-937-3p high-expression has an effect on cell invasion and metastasis. In molecular mechanism, miR-937-3p causes SOX11 reduction by directly binding to the 3′-UTR of SOX11.In addition, MYC affects miR-937-3p transcription by binding to its promoter region. Conclusions Our research shows that miR-937-3p is mediated by MYC and can control the angiogenesis, invasion and metastasis of LUAD by regulating SOX11, thereby promoting the progress of LUAD. We speculate that miR-937-3p can be used as a therapeutic target and potential biomarker for LUAD.

Background: Colorectal cancer (CRC) is one of the most common malignant tumors and the fourth leading cause of cancer death worldwide. Constitutive activation of the PI3K/AKT signaling pathway is a hallmark of colon tumor growth. CATSPER1 gene encodes a pore-forming and pH-sensing subunit of the CatSper Ca2+—permeable channel, a sperm-specific calcium channel essential for hyperactivated motility and male fertility. However, the function of CATSPER1 outside the male reproductive system is unclear. Objective: This study was designed to explore whether CatSper exerted its functional role in the progress of CRC, and investigate the possible mechanisms. Methods: Microarray data (GSE146587) from 6 patients diagnosed with stage III CRC post-surgery was analyzed by Limma R package. The Kaplan Meier plotter (KM plotter) database was used to assess the relevance of CATSPER1 mRNA expression to the overall survival (OS) rates in CRC. Western blot, real-time PCR and luciferase reporter assays were used to determine the SOX11-CATSPER1 axis in CRC cells. Clustered regularly interspaced short palindromic repeats (CRISPR)–based gene editing was used to generate CATSPER1 knockout (KO) CRC cells. The proliferation of CRC cells was determined by BrdU incorporation and colony formation assays. The effect of CATSPER1 on CRC tumor growth in vivo was investigated in a mice tumor xenograft model. Results: Here, we show that CATSPER1 expression was significantly up-regulated in CRC and elevated CATSPER1 was associated with poor overall survival (OS). Moreover, the transcription factor SOX11 (SRY-related high-mobility-group (HMG) box 11) activated CATSPER1 transcription in CRC cells. Functionally, we showed that CATSPER1 promoted CRC cells proliferation both in vitro and in vivo. At the molecular level, we demonstrated that CATSPER1 might maintain CRC malignant process partly through the activation of the PI3K/AKT signaling pathway. Conclusion: Increased CATSPER1 expression facilitates CRC cells proliferation, suggesting that targeting CATSPER1 might represent a promising strategy for colon cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Inactivating TP53 mutations in mantle cell lymphoma (MCL) are associated with poor prognosis. While next-generation sequencing (NGS) is the gold standard for assessing TP53 , p53 immunohistochemistry (IHC) is an orthogonal means of evaluating TP53 status that has not been well characterized in MCL. In this single tertiary care center laboratory study, we aimed to evaluate the concordance of p53 IHC with the TP53 status in cases of MCL in hopes of evaluating if the former could act as an accurate, timely and cost-effective way of risk stratifying these patients., Methods: A total of 47 cases of MCL that had TP53 NGS performed were included in this study. The main objective was to correlate NGS findings with p53 IHC results. Secondary objectives included assessment of possible associations between TP53 status and other variables (demographics, unique histopathological and IHC features). The turn-around time and cost for NGS and p53 IHC were also compared., Results: Thirteen out of 47 (28%) cases were TP53 -mutated by NGS. p53 IHC showed good concordance with NGS, with moderate to high sensitivity (11/13, 85%) and excellent specificity (34/34, 100%). Secondary objectives revealed increased SOX11-negative status in TP53 -mutated cases (3/13, 23% vs. 1/29, 3%, P = 0.045). The cost and turn-around time of NGS were approximately of 30- and sixfold those of p53 IHC, respectively., Conclusion: p53 IHC shows good concordance with NGS in MCL, with high specificity and moderate sensitivity for identifying inactivating TP53 mutations. Based on our findings, p53 IHC may be an efficient and cost-effective tool in risk stratification of MCL., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright 2024, Elsharawi et al.)

Context: SOX11 variants cause Coffin-Siris Syndrome (CSS), characterized by developmental delay, hypogonadotropic hypogonadism (HH), skeletal and facial defects., Objective: To examine the contribution of SOX11 variants to the pathogenesis of Idiopathic Hypogonadotropic Hypogonadism (IHH), a disorder caused by hypothalamic GnRH deficiency., Setting: The Reproductive Endocrine Unit and the Pediatric Endocrinology Division, Massachusetts General Hospital., Patients or Other Participants: A cohort of 1810 unrelated IHH probands., Interventions: Exome sequencing data from the entire cohort were examined for SOX11 rare single nucleotide variants (SNVs) [minor allele frequency in the gnomAD database <0.1%]. Rare SOX11 variant association testing was performed between the IHH and gnomAD population. Phenotyping of individuals harboring pathogenic/likely pathogenic SNVs (determined by the ACMG criteria) was performed., Main Outcomes/results: Four pathogenic SOX11 SNVs were identified in 5 IHH probands. The IHH cohort was enriched for SOX11 protein truncating SNVs (frameshift/nonsense) across the entire protein (2 SNVs in 3 IHH cases [p.S303X (de-novo); p.S345Afs*13]; p 0.0004981) and for SOX11 missense SNVs within the SOX11-high-mobility group (HMG) domain (2 SNVs in 2 IHH cases p.G84D[de-novo]; p.P114S; p=0.00313922). The phenotypic spectrum of SOX11 variant carriers revealed additional endocrine defects including anosmic and normosmic forms of IHH, growth-hormone deficiency, pituitary and hypothalamic structural defects, and hypothyroidism. A pathogenic SOX11 SNV was also identified in a patient with functional HH (FHH, p.R100Q). CSS-associated features were present in 4/5 probands., Conclusions: Deleterious SOX11 variants cause IHH and other pituitary hormone deficiencies, suggesting that the human SOX11-associated disorder may stem from both hypothalamic and pituitary level defects., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Histological identification of dispersed glioma cells in small biopsies can be challenging, especially in tumours lacking the IDH1 R132H mutation or alterations in TP53. We postulated that immunohistochemical detection of proteins expressed preferentially in gliomas (EGFR, MEOX2, CD34) or during embryonal development (SOX11, INSM1) can be used to distinguish reactive gliosis from glioma. Tissue microarrays of 46 reactive glioses, 81 glioblastomas, 34 IDH1-mutant diffuse gliomas, and 23 gliomas of other types were analysed. Glial neoplasms were significantly more often (p < 0.001, χ2) positive for EGFR (34.1% vs. 0%), MEOX2 (49.3% vs. 2.3%), SOX11 (70.5% vs. 20.4%), and INSM1 (65.4% vs. 2.3%). In 94.3% (66/70) of the glioblastomas, the expression of at least two markers was observed, while no reactive gliosis showed coexpression of any of the proteins. Compared to IDH1-mutant tumours, glioblastomas showed significantly higher expression of EGFR, MEOX2, and CD34 and significantly lower positivity for SOX11. Non-diffuse gliomas were only rarely positive for any of the five markers tested. Our results indicate that immunohistochemical detection of EGFR, MEOX2, SOX11, and INSM1 can be useful for detection of glioblastoma cells in limited histological samples, especially when used in combination.

The phenotypic spectrum of SOX11‐related Coffin‐Siris syndrome (CSS) is expanding with reports of new associations. SOX11 is implicated in neurogenesis and inner ear development. Cochlear nerve deficiency, absence or hypoplasia, is commonly associated with cochlear canal stenosis or with CHARGE syndrome, a monogenic condition that affects inner ear development. SOX11 is a transcription factor essential for neuronal identity, highly correlated with the expression of CHD7, which regulates SOX11. We present two unrelated probands, each with novel de novo SOX11 likely pathogenic variants and phenotypic manifestations of CSS including global developmental delay, growth deficiency, and hypoplastic nails. They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI. SOX11 is implicated in sensory neuron survival and maturation. It is highly expressed in the developing inner ear. Homozygous ablation of SOX11 in a mouse model resulted in a reduction in sensory neuron survival and decreased axonal growth. A heterozygous knockout mice model had hearing impairment with grossly normal inner ear structures like the two probands reported. We propose cochlear nerve deficiency as a new phenotypic feature of SOX11‐related CSS. Magnetic resonance imaging is useful in delineating the cochlear nerve deficiency and other CSS‐related brain malformations. [ABSTRACT FROM AUTHOR]

SOX11 is a transcription factor belonging to the sex determining region Y-related high-mobility group box family that plays a vital role in early embryogenesis and neurogenesis. De novo variants in SOX11 have been initially reported to cause a rare neurodevelopmental disorder, mainly referred to Coffin-siris syndrome 9 (CSS9, OMIM# 615866) which is characterized with growth deficiency, intellectual disability (ID), microcephaly, coarse facies, and hypoplastic nails of the fifth fingers and/or toes. A recent large-scale cohort study suggests that SOX11 variation would result in a clinically and molecularly distinct disease from CSS. Here, we describe three unrelated Chinese cases with variable phenotype, mainly involving developmental delay, ID, short statute, microcephaly, facial deformities (i.e., prominent forehead, arched eye brow, flat nasal bridge, broad nose and short philtrum), and cryptorchidism. Whole-exome sequencing (WES) revealed three novel heterozygous variants in the SOX11 gene, including two missense variants of c.337T>C (p.Y113H) and c.425C>G (p.A142G), and one nonsense variant of c.820A>T (p. K142*). Luciferase reporting assay shows that the two missense variants impair the transcriptional activity of the SOX11 target gene GDF5. Additionally, WES uncovered a 4,300 kb deletion involving the region of 1q24.2-q25.1 (hg19,chr1:169,433,149-173,827,682) in patient 1, which also contributes to the condition of the patient. In summary, this is the first report of Chinese cases with de novo variants of SOX11. Our study partially supports the previous observation that the phenotype caused by SOX11 variants somewhat differs from classical CSS. [ABSTRACT FROM AUTHOR]

Simple Summary: Mantle cell lymphoma (MCL) is associated with poor response to anthracycline-based chemotherapy, and high-dose cytarabine offers a durable response. Recently, multiple targeted therapies have been approved for the treatment of MCL, highlighting the role of the tumor microenvironment (TME) in the expansion and resistance of the disease. We review herein the TME in MCL and the different therapeutic strategies of treatment. Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive treatment and are ideal candidates for novel targeted therapies (such as BTK, proteasome or BCL2 inhibitors, Immunomodulatory Drugs (IMiDs), bispecific antibodies, or CAR-T cell therapy). On the bench side, several studies aiming to integrate the tumor within its ecosystem highlighted a critical role of the tumor microenvironment (TME) in the expansion and resistance of MCL. This led to important insights into the role of the TME in the management of MCL, including potential targets and biomarkers. Indeed, targeted agents often have a combined mechanism of action on the tumor B cell but also on the tumor microenvironment. The aim of this review is to briefly describe the current knowledge on the biology of the TME in MCL and expose the results of the different therapeutic strategies integrating the TME in this disease. [ABSTRACT FROM AUTHOR]

Advances in CRISPR-Cas9 genome editing technology have strengthened the role of zebrafish as a model organism for genetics and developmental biology. These tools have led to a significant increase in the production of loss-of-function mutant zebrafish lines. However, the generation of precisely edited knock-in lines has remained a significant challenge in the field due to the decreased efficiency of homology directed repair (HDR). In this study, we overcame some of these challenges by combining available design tools and synthetic, commercially available CRISPR reagents to generate a knock-in line carrying an in-frame MYC epitope tag at the sox11a locus. Zebrafish Sox11a is a transcription factor with critical roles in organogenesis, neurogenesis, craniofacial, and skeletal development; however, only a few direct molecular targets of Sox11a have been identified. Here, we evaluate the knock-in efficiency of various HDR donor configurations and demonstrate the successful expression and localization of the resulting knock-in allele. Our results provide an efficient, streamlined approach to knock-in experiments in zebrafish, which will enable expansion of downstream experimental applications that have previously been difficult to perform. Moreover, the MYC-Sox11a line we have generated will allow further investigation into the function and direct targets of Sox11a. • Commercially available CRISPR knock-in reagents allow for ease of use and application. • Increased germline transmission of knock-in allele compared to previous reports. • Detection and validation of MYC-Sox11a expression patterns in brain and retina. [ABSTRACT FROM AUTHOR]

Abstract Background Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers. As reported, long non-coding RNAs (lncRNAs) induce various biological behaviors in cancers. LncRNA PCGEM1 prostate-specific transcript (PCGEM1) is reported to exert carcinogenic effect on certain cancers. Our research aimed to explore the role of PCGEM1 in NSCLC. Methods We enrolled forty NSCLC patients to explore PCGEM1 expression in clinical NSCLC tissues. Colony formation assay, CCK-8, Transwell assay were conducted to reveal cell proliferation, viability, migration and invasion. Luciferase reporter assay, RNA pull down, and RIP assay were performed to investigate the downstream axis of PCGEM1. Results PCGEM1 was significantly upregulated in NSCLC cells and tissues. Subsequently, in vitro loss-of-function experiments illustrated the carcinogenic role of PCGEM1 in NSCLC through promoting viability, proliferation, migration, and invasion. MiR-590-3p was confirmed to be a downstream gene of PCGEM1. Furthermore, SRY-box transcription factor 11 (SOX11) was verified to be a target of miR-590-3p. Additionally, rescue experiments indicated that miR-590-3p inhibitor or pcDNA3.1/SOX11 rescued the impacts of downregulated PCGEM1 on NSCLC cell proliferation, viability, migration and invasion. Conclusions LncRNA PCGEM1 aggravated proliferative and migrative abilities in NSCLC via the miR-590-3p/SOX11 axis.

Transcription factors (TFs) as SRY-Box transcription factor 11 (SOX11) and B-cell lymphoma/leukemia 11A (BCL11A) role in breast cancer (BC) as well as their effect on epithelial cadherin (E-cadherin) membrane protein which is a metastasis suppressor is a question that must be addressed. Among the thirty-nine BC patients were invasive ductal carcinoma (IDC), twenty females with benign fibroadenomas and/or fibrocystic changes and nineteen healthy control. We quantified SOX11, E-cadherin and BCL11A serum levels in Egyptian women with BC and determined their cut-off values. The correlation between SOX11, E-cadherin and BCL11A sera levels and cancer antigen (CA15.3) as well as carcino-embryonic antigen (CEA) were assessed and quantified by ELISA. Finally, we explored the association between SOX11, E-cadherin levels, and BCL11A as potential markers according to histo- and clinicopathological characteristics and hormones receptors. Significant increase in E-cadherin serum levels in the cancerous than the non-cancerous group (p  0.05). A significant decrease in SOX11 and BCL11A serum levels (p < 0.05) was detected in the non-cancerous group than the cancerous group. In addition, a decrease in SOX11 levels was observed in the later stage of BC cases, while earlier stage BC cases were associated with an increase in SOX11. In addition to the significant positive correlation (p < 0.05) between SOX11 and BCL11A proteins in blood suggesting a common inter-regulatory pathway. SOX11 has an excellent area under the curve (AUC) either solely or combined with CA15.3. Earlier stages in BC were associated with an increase in SOX11 serum levels (p < 0.05).

Long noncoding RNA (lncRNA) has been shown to be involved in the development of osteoarthritis (OA), an age-related bone and joint disease. However, the function and possible molecular mechanism of lncRNA myocardial infarction-associated transcript (MIAT) in lipopolysaccharide (LPS)-induced chondrocytes injury model remain unexplored. Cell viability and apoptosis were detected by methyl thiazolyl tetrazolium (MTT) and flow cytometry, respectively. Western blot was used to detect protein expression. The concentrations of inflammatory factors were estimated by enzyme-linked immunosorbent assay (ELISA). Abundances of MIAT, microRNA-488-3p (miR-488-3p), and sex determining region Y-related HMG-box 11 (SOX11) were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to analyze the interaction between miR-488-3p and MIAT or SOX11. LPS caused chondrocytes injury by reducing cell activity and increasing apoptosis rate and inflammatory factor secretions. Higher levels of MIAT and SOX11 and lower miR-488-3p were observed in LPS-treated C28/I2 cells. Importantly, knockdown of MIAT attenuated the LPS-induced cell injury by targeting miR-488-3p, and miR-488-3p overexpression weakened the LPS-induced cell injury by targeting SOX11. Additionally, repression of MIAT inactivated the LPS-induced NF-κB signaling pathway by decreasing SOX11 and increasing miR-488-3p. Knockdown of MIAT alleviated the LPS-induced chondrocytes injury by inhibiting the NF-κB signaling pathway mediated by the miR-488-3p/SOX11 axis.

Background and Objective: To detect the mRNA and protein levels of Zinc-finger protein382 (ZNF382) in human hepatocellular carcinoma (HCC) tissues and cell lines and investigate its effects on the cellular processes of HCC cells in vitro. Methods: Quantitative PCR and Immunoblot assays were respectively conducted to detect the alteration of ZNF382 mRNA and protein levels in HCC human tissues and cell lines. MTT, FCM, wound closure, and transwell assays were performed to detect the effects of ZNF382 on HCC cell proliferation, apoptosis, and motility of HCC cells in vitro. Immunoblot assays were then performed to detect the effects of ZNF382 on the expression of Signal Transducer and Activator of Transcription 3 (STAT3) and SOX11 in HCC cells, and the rescue assays were conducted to confirm the conclusion. Results: We found ZNF382 was low expression in human HCC tissues and cell lines. ZNF382 suppressed the proliferation and stimulated the apoptosis of HCC cells. Additionally, ZNF382 inhibited the motility of HCC cells in vitro. Mechanically, ZNF382 mediated STAT3/SOX11, and therefore affected the proliferation, apoptosis, and motility of HCC cells. Conclusion: We showed the abnormal low expression of ZNF382 in human HCC tissues and cell lines, and confirmed the effects of ZNF382 on HCC cellular processes. We thought ZNF382 was a tumor suppressor in HCC.

Non-alcoholic steatohepatitis (NASH) is the clinically aggressive variant of non-alcoholic fatty liver disease. Hippo pathway dysregulation can contribute to NASH development and progression. The use of probiotics is effective in NASH management. Our aim is to investigate the efficacy of kefir Milk in NASH management via modulation of hepatic mRNA-miRNA based panel linked to NAFLD/NASH Hippo signaling and gut microbita regulated genes which was identified using bioinformatics tools. Firstly, we analyzed mRNAs (SOX11, SMAD4 and AMOTL2), and their epigenetic regulator (miR-6807) followed by validation of target effector proteins (TGFB1, IL6 and HepPar1). Molecular, biochemical, and histopathological, analyses were used to evaluate the effects of kefir on high sucrose high fat (HSHF) diet -induced NASH in rats. We found that administration of Kefir proved to prevent steatosis and development of the inflammatory component of NASH. Moreover, Kefir improved liver function and lipid panel. At the molecular level, kefir down-regulated the expression of miR 6807-5p with subsequent increase in the expression of SOX 11, AMOTL2 associated with downregulated SMAD4, resulting in reduction in the expression of the inflammatory and fibrotic markers, IL6 and TGF-b1 in the treated and prophylactic groups compared to the untreated rats. In conclusion, Kefir suppressed NASH progression and improved both fibrosis and hepatic inflammation. The produced effect was correlated with modulation of SOX11, SMAD4 and AMOTL2 mRNAs) - (miR-6807- 5p) - (TGFB, IL6 and, HepPar1) expression. [ABSTRACT FROM AUTHOR]

A 68-year-old male presents with generalized lymphadenopathy and fever of short duration. Axillary lymph node excision was performed and was sent for histopathological evaluation. Microscopic evaluation of the submitted lymph node revealed diffuse proliferation of intermediate-sized atypical lymphoid cells with round nuclei, irregular membranes, finely dispersed chromatin, and inconspicuous nucleoli. Mitotic figures were frequently seen. Immunohistochemical evaluation revealed diffuse expression of CD20, CD5, CD10, B-cell lymphoma 2 (Bcl2), and B-cell lymphoma 6 (Bcl6). Atypical lymphoid cells were negative for cyclin D1; however, showed diffuse and strong nuclear expression of SOX11. MIB1 proliferation index was high (Ki67: 90%-95%). Based on morphological features and immunohistochemical findings a diagnosis of "cyclin D1 negative aggressive blastoid variant of mantle cell lymphoma (MCL)" was offered. The classic morphology of MCL is seen in 90% of cases, while the remaining (∼10%) are considered as variants. A blastoid variant is an aggressive subtype that can lack expression of CD5 as well as cyclin D1, but instead expresses CD10, Bcl6, and CD23. SOX11 expression is seen in 90% cases of MCL and in almost 100% cases of cyclin D1 negative MCL. The current case highlights the unusual morphologic and aggressive variant of MCL and a significant role of SOX11 in its diagnosis. [ABSTRACT FROM AUTHOR]

Recent studies have shown that the downregulation of miR-145-5p in prostate cancer (PCa) is significantly associated with poor differentiation and prognosis. We aimed to investigate the biological role of miR-145-5p in the neuroendocrine differentiation (NED) of PCa. In this study, TheCancer Genome Atlas was used to identify the association of miR-145-5p with PCa. The functions of miR-145-5p were evaluated using the Cell Counting Kit-8 (CCK-8) assay and cell cycle analysis. We validated changes in cell cycle control by testing the expression of cyclin-related genes by western blot. The luciferase reporter assay was performed to test miR-145-5p-targeting genes and direct transcriptional targets of SOX11. The expression of miR-145-5p was found to be significantly downregulated in castration-resistant PCa, and this was correlated with higher Gleason score and prostate-specific antigen. We confirmed these results using PC3 and LNCaP cell lines depicted a gradual decline of miR-145-5p while the cells were cultured under androgen depletion conditions. Moreover, the knockdown of miR-145-5p significantly promoted NED and proliferation of LNCaP cells, whereas overexpression of miR-145-5p significantly inhibited NED and proliferation of LNCaP cells. Mechanistically, we found that SOX11 was a direct target of miR-145-5p, which regulates MYCN might mediate induction of NED and proliferation of LNCaP cells. Furthermore, knockdown of miR-145-5p promoted tumor growth in vivo. Our findings suggest that miR-145-5p can inhibit NED and tumor growth by targeting SOX11 , which regulates the expression of MYCN , and that this could be a novel therapeutic strategy for preventing the progression of PCa. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of microRNA-182 (miR-182) on hepatocellular carcinoma (HCC) and its mechanisms of action. Methods: Sixty-five HCC tissues and matched adjacent tissues were obtained, and miR-182 and sexdetermining region on the Y Chromosome (SRY)-related HMG box 11 (SOX11) expression were quantified using reverse transcription-polymerase chain reaction (RT-PCR). SOX11-positive cells were identified by immunohistochemistry and the correlation between SOX11 and miR-182 expression was analyzed by Spearman correlation analysis. Huh-7 cells were transfected with the miR-182 mimic, the miR-182 inhibitor, and/or si-SOX11, and cell proliferation was measured by cell counting kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry. Luciferase reporter assay was used to investigate the putative target gene of miR-182. A xenograft nude mouse model was established by transfection with miR-182 antagomir, while tumor volume and weight were calculated. SOX11, cleaved caspase-3, cleaved poly (ADP ribose) polymerase (PARP), B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X (Bax) protein levels were analyzed by western blot. Results: MiR-182 expression increased and SOX11 expression was decreased in HCC tissues (p < 0.05). Luciferase reporter assay data confirmed that miR-182 directly targets SOX11. Inhibition of miR-182 repressed proliferation and Bcl-2 expression, but increased protein expression of cleaved caspase-3, cleaved RAPP, and Bax in Huh-7 cells (p < 0.05). In addition, suppression of SOX11 reversed the effects of miR-182 on cell proliferation and apoptosis. The miR-182 antagomir decreased tumor growth and miR-182 expression but increased SOX11 expression in vivo (p < 0.05). Conclusion: MiR-182 and SOX11 may be novel therapeutic targets for HCC patients. [ABSTRACT FROM AUTHOR]

Recent studies have shown that the downregulation of miR-145-5p in prostate cancer (PCa) is significantly associated with poor differentiation and prognosis. We aimed to investigate the biological role of miR-145-5p in the neuroendocrine differentiation (NED) of PCa. In this study, TheCancer Genome Atlas was used to identify the association of miR-145-5p with PCa. The functions of miR-145-5p were evaluated using the Cell Counting Kit-8 (CCK-8) assay and cell cycle analysis. We validated changes in cell cycle control by testing the expression of cyclin-related genes by western blot. The luciferase reporter assay was performed to test miR-145-5p-targeting genes and direct transcriptional targets of SOX11. The expression of miR-145-5p was found to be significantly downregulated in castration-resistant PCa, and this was correlated with higher Gleason score and prostate-specific antigen. We confirmed these results using PC3 and LNCaP cell lines depicted a gradual decline of miR-145-5p while the cells were cultured under androgen depletion conditions. Moreover, the knockdown of miR-145-5p significantly promoted NED and proliferation of LNCaP cells, whereas overexpression of miR-145-5p significantly inhibited NED and proliferation of LNCaP cells. Mechanistically, we found that SOX11 was a direct target of miR-145-5p, which regulates MYCN might mediate induction of NED and proliferation of LNCaP cells. Furthermore, knockdown of miR-145-5p promoted tumor growth in vivo. Our findings suggest that miR-145-5p can inhibit NED and tumor growth by targeting SOX11, which regulates the expression of MYCN, and that this could be a novel therapeutic strategy for preventing the progression of PCa.

Background: Non-small cell lung cancer (NSCLC) is still one of the diseases with the highest mortality and morbidity, and lung adenocarcinoma (LUAD) accounts for more than half of all NSCLC cases in most countries. miRNA can be used as a potential biological marker and treatment for lung adenocarcinoma. However, the effect of miR-937-3p to the invasion and metastasis of LUAD cells is not clear. Methods: miRNA microarray is used to analyze the expression of miRNA in lung adenocarcinoma tissue. Transwell migration, Wound-healing assay and Western blot analysis are used to analyze cell migration, invasion and epithelial-mesenchymal transition (EMT) capabilities. Tube formation is used to assess angiogenesis ability. In addition, dual luciferase reporter gene detection is used to identify the potential binding between miRNA and target mRNA. In vivo experiments were performed on male NOD/SCID nude mice by tail vein injection to establish a transplanted tumor model. The CHIP experiment is used to verify the transcription factors of miRNA. Result: In our study, miR-937-3p was high-regulated in LUAD cell lines and tissues, and its expression level was related to tumor progression. We found that miR-937-3p high-expression has an effect on cell invasion and metastasis. In molecular mechanism, miR-937-3p causes SOX11 reduction by directly binding to the 3′-UTR of SOX11.In addition, MYC affects miR-937-3p transcription by binding to its promoter region. Conclusions: Our research shows that miR-937-3p is mediated by MYC and can control the angiogenesis, invasion and metastasis of LUAD by regulating SOX11, thereby promoting the progress of LUAD. We speculate that miR-937-3p can be used as a therapeutic target and potential biomarker for LUAD. [ABSTRACT FROM AUTHOR]

Background: Synaptophysin (SYN), chromogranin A (CGA), CD56 and insulinoma-associated protein 1 (INSM1) are proposed neuroendocrine (NE) markers used for diagnosis of pulmonary NE tumors. These NE markers have been identified in subsets of non-NE tumors requiring differential diagnosis, thus we sought to explore new NE markers. Methods: We evaluated the immunohistochemical expression of SOX11, a transcription factor involved in neurogenesis, in pulmonary NE tumors and large cell carcinomas (LCCs). Results: We found that SOX11 showed a sensitivity similar to INSM1 and CGA, and less than SYN and CD56 in small cell lung carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). While SOX11 is more specific than the other four markers for diagnosis of high-grade neuroendocrine carcinomas (HG-NECs) because 1) None of LCCs (0/63), the most challenging non-NE tumor type for differential diagnosis due to overlapped morphology with LCNECs displayed SOX11 positivity. While expression of at least one of SYN, CGA, CD56 or INSM1 was identified in approximately 60% (18/30) of LCCs. 2) SOX11 was only expressed in 1 of 37 carcinoid tumors in contrast to diffuse expression of SYN, CGA, CD56 and INSM1. In HG-NECs, we noticed that SOX11 was a good complementary marker for SCLC diagnosis as it was positive in 7 of 18 SYN−/CGA−/CD56− SCLCs and 3 of 8 SYN−/CGA−/CD56−/INSM1− SCLCs, and SOX11 positivity in 4 of 6 SYN−/CGA−/CD56− cases previously diagnosed as LCCs with NE morphology provides additional evidence of NE differentiation for reclassification into LCNECs, which was further confirmed by electromicroscopical identification of neurosecretory granules. We also found SOX11 expression cannot predict the prognosis in patients with HG-NECs. Conclusions: Therefore, SOX11 is a useful complementary transcriptional NE marker for diagnosis and differential diagnosis of SCLC and LCNEC. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an aggressive lymphoid malignancy with a poor prognosis. Ubiquitin-specific peptidase 9, X-linked (USP9X), has been associated with multiple physiological pathways and regulates various cellular activities. In this study, we explored the role of USP9X in MCL in vitro and in vivo. USP9X was verified to be increased in peripheral blood mononuclear cells (PBMCs) of MCL patients and MCL cells. Moreover, CCND1 and SOX11 were also upregulated in PBMCs of MCL patients. The positive correlation between USP9X and CCND1, USP9X and SOX11, and CCND1 and SOX11 were identified. Further, USP9X overexpression and knockdown were performed in MCL cells. We proved that USP9X overexpression promoted proliferation and cell cycle and suppressed cell apoptosis in MCL cells. Upregulation of angiogenesis and cell migration were induced by USP9X overexpression in MCL cells. However, the USP9X knockdown showed opposite effects. In addition, USP9X was discovered to decrease Cyclin D1 (CCND1)-mediated SOX11 expression in MCL cells. We demonstrated that SOX11 overexpression reversed USP9X knockdown-mediated angiogenesis in MCL cells. Besides, tumor formation was inhibited by USP9X knockdown in mice in vivo. In conclusion, these results revealed that USP9X promoted tumor angiogenesis in MCL via increasing CCND1-mediated SOX11. [ABSTRACT FROM AUTHOR]

Abstract Long noncoding RNAs play essential roles in colon cancer tumorigenesis. This study aimed to explore the potential function and molecular mechanisms of LINC00961 in colon cancer. qPCR results showed that LINC00961 was downregulated in colon cancer cells and tissues. Functional assays demonstrated that LINC00961 suppressed the migration and invasion of colon cancer cells in vitro. LINC00961 functioned as an endogenous sponge for miR‐223‐3p in colon cancer cells. SOX11 was confirmed as a target gene of miR‐223‐3p. The effect of miR‐223‐3p on colon cancer cells was then investigated. MiR‐223‐3p inhibition enhanced their migration and invasion. The effect of SOX11 on colon cancer cells was studied. SOX11 overexpression inhibited the invasion of colon cancer cells. LINC00961 acted as an anti‐oncogene and upregulated SOX11 expression by functioning as a miR‐223‐3p sponge. This research revealed the molecular mechanism of LINC00961 in colon cancer. LINC00961 might act as a potential diagnostic biomarker and therapeutic target for further clinical treatments.

Objective To investigate whether miR‐141 and the sex determination region of Y chromosome box 11 (SOX11) play roles in steroid‐induced avascular necrosis of the femoral head (SANFH), and to explore whether miR‐141 could target SOX11 to influence the proliferation of bone marrow mesenchymal stem cells (BMSC). Methods Bone marrow mesenchymal stem cells (BMSC) were isolated and cultured from 4‐week‐old Sprague Dawley rats. A flow cytometry assay was performed to identify BMSC. BMSC were divided into two groups: a control group and a dexamethasone (DEX) group. BMSC were transfected by miR‐141 mimic, miR‐141 inhibitor, and SOX11. Real‐time polymerase chain reaction (PCR) assay was performed to investigate the mRNA expression of miR‐141 and SOX11. The results were used to determine the effect of transfection and to verify the expression in each group and the association between miR‐141 and SOX11. Luciferase reporter assay revealed the targeted binding site between miR‐141 and the 3′‐untranslated region of SOX11 mRNA. MTT assays were performed to investigate the proliferation of BMSC in the miR‐141 mimic, miR‐141 inhibitor, and SOX11 groups. Result The results of the flow cytometry assay suggested that cells were positive for CD29 and CD90 while negative for CD45. This meant that the isolated and cultured cells were not hematopoietic stem cells. In addition, cell transfection was successful based on the expression of miR‐141 and SOX11. According to the results of real‐time PCR assay, the mRNA expression of miR‐141 in SANFH was upregulated (4.117 ± 0.042 vs 1 ± 0.027, P

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common disorders that disrupt the quality of life of millions of people. These two chronic diseases cause damage to the joint cartilage and surrounding tissues of more than 220 million people worldwide. Sex-determining region Y-related (SRY) high-mobility group (HMG) box C, SOXC, is a superfamily of transcription factors that have been recently shown to be involved in various physiological and pathological processes. These include embryonic development, cell differentiation, fate determination, and autoimmune diseases, as well as carcinogenesis and tumor progression. The SOXC superfamily includes SOX4, SOX11, and SOX12, all have a similar DNA-binding domain, i.e., HMG. Herein, we summarize the current knowledge about the role of SOXC transcription factors during arthritis progression and their potential utilization as diagnostic biomarkers and therapeutic targets. The involved mechanistic processes and signaling molecules are discussed. SOX12 appears to have no role in arthritis, however SOX11 is dysregulated and promotes arthritic progression according to some studies but supports joint maintenance and protects cartilage and bone cells according to others. On the other hand, SOX4 upregulation during OA and RA was documented in almost all studies including preclinical and clinical models. Molecular details have indicated that SOX4 can autoregulate its own expression besides regulating the expression of SOX11, a characteristic associated with the transcription factors that protects their abundance and activity. From analyzing the currently available data, SOX4 seems to be a potential diagnostic biomarker and therapeutic target of arthritis.