BACKGROUND: Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay (NDD), but its genetic basis has not been fully characterized. This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume (WBDV). METHODS: We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years. We recruited only NDD patients without acquired etiologies or positive genetic results. Cranial magnetic resonance imaging (MRI) and clinical exome sequencing (2742 genes) data were acquired. A genetic burden test was performed, and the results were compared between patients with and without significant WBDV. Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development. RESULTS: We recruited a total of 253 NDD patients. Among them, 26 had significantly decreased WBDV (<-2 standard deviations [SDs]), and 14 had significantly increased WBDV (>+2 SDs). NDD patients with significant WBDV had higher rates of motor development delay (49.8% [106/213] vs . 75.0% [30/40], P  = 0.003) than patients without significant WBDV. Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV. Analyses of the literature further demonstrated that these genes were not randomly identified: burden genes were more related to the brain development than background genes ( P  = 1.656e -9 ). In seven human brain regions related to motor development, we observed burden genes had higher expression before 37-week gestational age than postnatal stages. Functional analyses found that burden genes were enriched in embryonic brain development, with positive regulation of synaptic growth at the neuromuscular junction, positive regulation of deoxyribonucleic acid templated transcription, and response to hormone, and these genes were shown to be expressed in neural progenitors. Based on single cell sequencing analyses, we found TUBB2B gene had elevated expression levels in neural progenitor cells, interneuron, and excitatory neuron and SOX15 had high expression in interneuron and excitatory neuron. CONCLUSION Idiopathic NDD patients with significant brain volume changes detected by MRI had an increased prevalence of motor development delay, which could be explained by the genetic differences characterized herein.
Child ; Humans ; Neurodevelopmental Disorders/epidemiology* ; Genetic Testing ; Phenotype ; Brain/pathology* ; Genetic Background ; SOX Transcription Factors/genetics*

OBJECTIVE: To explore the effect of abnormal miRNA expression on the proliferation of pediatric acute lymphoblastic leukemia (ALL) cells and its related mechanism. METHODS: 15 children with ALL and 15 healthy subjects were collected from the Second Affiliated Hospital of Hainan Medical University from July 2018 to March 2021. MiRNA sequencing was performed on their bone marrow cells, and validated using qRT-PCR. MiR-1294 and miR-1294-inhibitory molecule (miR-1294-inhibitor) were transfected into Nalm-6 cells, and the proliferation of Nalm-6 cells was detected by CCK-8 and colony formation assays. Western blot and ELISA were used to detect apoptosis of Nalm-6 cells. Biological prediction of miR-1294 was performed to find the target gene, which was verified by luciferase reporter assay. Si-SOX15 was transfected into Nalm-6 cells, Western blot was used to detect the expression of Wnt signaling pathway-related proteins and to verify the effect of si-SOX15 on the proliferation and apoptosis of Nalm-6 cells. RESULTS: Compared with healthy subjects, 22 miRNAs were significantly upregulated in bone marrow cells of ALL patients, of which miR-1294 was the most significantly upregulated. In addition, the expression level of SOX15 gene was significantly reduced in bone marrow cells of ALL patients. Compared with the NC group, the miR-1294 group showed increased protein expression levels of Wnt3a and β-catenin, faster cell proliferation, and more colony-forming units, while caspase-3 protein expression level and cell apoptosis were reduced. Compared with the NC group, the miR-1294-inhibitor group showed reduced protein expression levels of Wnt3a and β-catenin, slower cell proliferation, and fewer colony-forming units, while caspase-3 protein expression level was increased and apoptosis rate was elevated. miR-1294 had a complementary base-pair with the 3'UTR region of SOX15 , and miR-1294 directly targeted SOX15 . The expression of miR-1294 was negatively correlated with SOX15 in ALL cells. Compared with the si-NC group, the si-SOX15 group showed increased protein expression levels of Wnt3a and β-catenin, accelerated cell proliferation, and decreased caspase-3 protein expression level and cell apoptosis rate. CONCLUSION MiR-1294 can target and inhibit SOX15 expression, thus activating the Wnt/β-Catenin signaling pathway to promote the proliferation of ALL cells, inhibit cell apoptosis, and ultimately affect the disease progression.
Humans ; Child ; beta Catenin/genetics* ; Wnt Signaling Pathway ; Caspase 3/metabolism* ; Cell Line, Tumor ; MicroRNAs/genetics* ; Cell Proliferation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Apoptosis ; SOX Transcription Factors/metabolism*

BACKGROUND: Recent findings in molecular pathology suggest that genetic translocation and/or overexpression of oncoproteins is important in salivary gland tumorigenesis and diagnosis. We investigated PLAG1, SOX10, and Myb protein expression in various salivary gland neoplasm tissues. METHODS: A total of 113 cases of surgically resected salivary gland neoplasms at the National Cancer Center from January 2007 to March 2017 were identified. Immunohistochemical staining of PLAG1, SOX10, and Myb in tissue samples was performed using tissue microarrays. RESULTS: Among the 113 cases, 82 (72.6%) were benign and 31 (27.4%) were malignant. PLAG1 showed nuclear staining and normal parotid gland was not stained. Among 48 cases of pleomorphic adenoma, 29 (60.4%) were positive for PLAG1. All other benign and malignant salivary gland neoplasms were PLAG1-negative. SOX10 showed nuclear staining. In normal salivary gland tissues SOX10 was expressed in cells of acinus and intercalated ducts. In benign tumors, SOX10 expression was observed in all pleomorphic adenoma (48/48), and basal cell adenoma (3/3), but not in other benign tumors. SOX10 positivity was observed in nine of 31 (29.0%) malignant tumors. Myb showed nuclear staining but was not detected in normal parotid glands. Four of 31 (12.9%) malignant tumors showed Myb positivity: three adenoid cystic carcinomas (AdCC) and one myoepithelial carcinoma with focal AdCC-like histology. CONCLUSIONS: PLAG1 expression is specific to pleomorphic adenoma. SOX10 expression is helpful to rule out excretory duct origin tumor, but its diagnostic value is relatively low. Myb is useful for diagnosing AdCC when histology is unclear in the surgical specimen.
Adenoma ; Adenoma, Pleomorphic ; Antibody-Dependent Cell Cytotoxicity ; Carcinogenesis ; Carcinoma, Adenoid Cystic ; Diagnosis ; Immunohistochemistry ; Oncogene Proteins ; Oncogene Proteins v-myb ; Parotid Gland ; Pathology, Molecular ; Salivary Gland Neoplasms ; Salivary Glands ; SOX Transcription Factors ; Translocation, Genetic

Gene expressions are sex-specific in the sex development of mammals. Different genes express in different phases and tend to change with the time. The functions of some genes, such as SRY, SOX9, SOX8, DAX1, and FGF9, have already been defined in male gonadal morphogenesis. This paper presents a review of the genes involved in the formation of the male gonad in mammals.
Animals ; DAX-1 Orphan Nuclear Receptor ; DNA-Binding Proteins ; genetics ; Gene Expression Regulation, Developmental ; Genitalia, Male ; embryology ; growth & development ; metabolism ; High Mobility Group Proteins ; genetics ; Male ; Mammals ; embryology ; genetics ; growth & development ; Morphogenesis ; genetics ; Receptors, Retinoic Acid ; genetics ; Repressor Proteins ; genetics ; SOX9 Transcription Factor ; Sex-Determining Region Y Protein ; genetics ; Transcription Factors ; genetics

OBJECTIVETo gain insight into the mechanism by which sex-determining region of Y chromosome (SRY)-related high-mobility-group box 2 (SOX2) involved in carcinogenesis and cancer stem cells (CSCs).

DATA SOURCESThe data used in this review were mainly published in English from 2000 to present obtained from PubMed. The search terms were "SOX2," "cancer," "tumor" or "CSCs."

STUDY SELECTIONArticles studying the mitochondria-related pathologic mechanism and treatment of glaucoma were selected and reviewed.

RESULTSSOX2, a transcription factor that is the key in maintaining pluripotent properties of stem cells, is a member of SRY-related high-mobility group domain proteins. SOX2 participates in many biological processes, such as modulation of cell proliferation, regulation of cell death signaling, cell apoptosis, and most importantly, tumor formation and development. Although SOX2 has been implicated in the biology of various tumors and CSCs, the findings are highly controversial, and information regarding the underlying mechanism remains limited. Moreover, the mechanism by which SOX2 involved in carcinogenesis and tumor progression is rather unclear yet.

CONCLUSIONSHere, we review the important biological functions of SOX2 in different tumors and CSCs, and the function of SOX2 signaling in the pathobiology of neoplasia, such as Wnt/β-catenin signaling pathway, Hippo signaling pathway, Survivin signaling pathway, PI3K/Akt signaling pathway, and so on. Targeting towards SOX2 may be an effective therapeutic strategy for cancer therapy.

Gene Expression Regulation, Neoplastic ; Humans ; Neoplasms ; metabolism ; Neoplastic Stem Cells ; metabolism ; SOXB1 Transcription Factors ; metabolism

OBJECTIVETo rapidly detect SOX2 gene using primed in situ labeling (PRINS).

METHODSHuman peripheral blood samples were cultured using an optimized method. Sequence of the SOX2 gene was amplified in situ with biotin-labeled specific primers and processed with a tyramide signal amplification (TSA) biotin system. Subsequently, fluorescence-stained signal was detected by streptavidin-Texas red. For the control group, MCF-10F cells were transfected with Lentivirus hSox2.

RESULTSBy VideoTesT-FISH software analysis, the long arm of chromosome 3 in the experimental group showed a specific red fluorescence signal, whilst the control samples showed no specific signals for SOX2. Transfected MCF-10F cells showed various efficiency of SOX2 gene integration.

CONCLUSIONPRINS utilizes a highly sensitive in situ PCR technique combined with fluorescence labeled oligodeoxynucleotides can synthesize probes in situ, thus greatly reducing the cost of probe and time for detection. It can facilitate identification and classification of induced pluripotent stem cells, and has many potential applications in this prospect.

Humans ; In Situ Hybridization, Fluorescence ; methods ; Male ; Primed In Situ Labeling ; methods ; SOXB1 Transcription Factors ; chemistry

OBJECTIVETo investigate the expression of SOX2 in cervical intraepithelial neoplasia (CIN) and cervical cancer and explore its association with the clinical features.

METHODSSOX2 expressions were examined using immunohistochemical method in 10 normal cervical tissue specimens, 36 cervical intraepithelial neoplasia specimens (including 10 cases of grade I, 12 of grade II, and 14 grade III) and 40 cervical cancer specimens (including 21 cases of stage I and 19 of stage II). The correlation between the immunohistochemical results and the clinical features of the patients was analyzed.

RESULTSSOX2 expression was negative in normal cervical tissues, and was positive in 41.6% of CIN specimens (10.0% in CIN I, 41.7% in CIN II, and 64.3% in CIN III) in 82.5% of cervical cancer specimens (78.2% in stage I and 88.2% in stage II). The patients with cervical cancer had a significantly higher positivity rate of SOX2 than normal control group (P<0.05). The positivity rate of SOX2 increased with the evolution of cervical disease. SOX2 protein expression was significantly correlated with the histological grade and lymph node metastasis (P<0.05), but not with the age or clinical stage of the patients (P<0.05).

CONCLUSIONSOX2 expression may serve as a useful indicator for evaluating metastasis and malignancy of cervical cancer.

Cervical Intraepithelial Neoplasia ; genetics ; metabolism ; pathology ; Humans ; Lymphatic Metastasis ; Neoplasm Grading ; Neoplasm Staging ; SOXB1 Transcription Factors ; genetics ; metabolism

Living organisms are exposed to the geomagnetic field (GMF) throughout their lifespan. Elimination of the GMF, resulting in a hypogeomagnetic field (HMF), leads to central nervous system dysfunction and abnormal development in animals. However, the cellular mechanisms underlying these effects have not been identified so far. Here, we show that exposure to an HMF (<200 nT), produced by a magnetic field shielding chamber, promotes the proliferation of neural progenitor/stem cells (NPCs/NSCs) from C57BL/6 mice. Following seven-day HMF-exposure, the primary neurospheres (NSs) were significantly larger in size, and twice more NPCs/NSCs were harvested from neonatal NSs, when compared to the GMF controls. The self-renewal capacity and multipotency of the NSs were maintained, as HMF-exposed NSs were positive for NSC markers (Nestin and Sox2), and could differentiate into neurons and astrocyte/glial cells and be passaged continuously. In addition, adult mice exposed to the HMF for one month were observed to have a greater number of proliferative cells in the subventricular zone. These findings indicate that continuous HMF-exposure increases the proliferation of NPCs/NSCs, in vitro and in vivo. HMF-disturbed NPCs/NSCs production probably affects brain development and function, which provides a novel clue for elucidating the cellular mechanisms of the bio-HMF response.
Animals ; Cell Proliferation ; physiology ; Female ; Magnetic Fields ; Male ; Mice ; Nestin ; metabolism ; Neural Stem Cells ; cytology ; metabolism ; SOXB1 Transcription Factors ; metabolism

Mesenchymal stem cells (MSCs) are attractive candidates for clinical repair or regeneration of damaged tissues. Oct4 and Sox2, which are essential transcription factors for pluripotency and self-renewal, are naturally expressed in MSCs at low levels in early passages, and their levels gradually decrease as the passage number increases. Therefore, to improve MSC proliferation and stemness, we introduced human Oct4 and Sox2 for conferring higher expansion and differentiation capabilities. The Oct4-IRES-Sox2 vector was transfected into human adipose tissue MSCs (ATMSCs) by liposomal transfection and used directly. Oct4 and Sox2 were successfully transfected into ATMSCs, and we confirmed maintenance of MSC surface markers without alterations in both red fluorescent protein (RFP) (control) and Oct4/Sox2-ATMSCs. Enhanced proliferative activity of Oct4/Sox2-ATMSCs was shown by WST-1 assay, and this result was further confirmed by cell counting using trypan blue exclusion for a long period. In addition, FACs cell cycle analysis showed that there was a reduction in the fraction of Oct4/Sox2-ATMSCs in G1 with a concomitant increase in the fraction of cells in S, compared with RFP-ATMSCs. Increased levels of cyclin D1 were also seen in Oct4/Sox2-ATMSCs, indicating acceleration in the transition of cells from G1 to S phase. Furthermore, Oct4/Sox2-overexpressing ATMSCs showed higher differentiation abilities for adipocytes or osteoblasts than controls. The markers of adipogenic or osteogenic differentiation were also upregulated by Oct4/Sox2 overexpression. The improvement in cell proliferation and differentiation using Oct4/Sox2 expression in ATMSCs may be a useful method for expanding the population and increasing the stemness of ATMSCs.
Adipose Tissue/cytology ; *Cell Differentiation ; *Cell Proliferation ; Cells, Cultured ; Humans ; Mesenchymal Stromal Cells/cytology/*metabolism/physiology ; Octamer Transcription Factor-3/genetics/*metabolism ; SOXB1 Transcription Factors/genetics/*metabolism

Objective To explore the expressions of Sry-related high mobility group box 9(SOX9)and gastrokine-1(GKN1) in gastric cancer tissues and their relationships with clinicopathologic features and prognosis of patients.Methods Immunohistochemistry was used to detect the expressions of SOX9 and GKN1 in 70 cases of gastric cancer tissues and corresponding paracancerous tissues including 27 cases of intestinal metaplasia and 43 cases of normal gastric mucosa. The relationships of SOX9 and GKN1 expressions with clinicopathological features and prognosis were analyzed in gastric cancer tissues.Results The high expression rates of SOX9 in gastric cancer tissues,intestinal metaplasia,and normal gastric mucosa were 92.9%(65/70),77.8%(21/27),and 55.8%(24/43),respectively(=21.722,<0.001). Positive nuclear and cytoplasmic staining was observed. The high nuclear expression rate of SOX9 in gastric cancer tissues was 67.1%,which was significantly higher than those of intestinal metaplasia(37.0%,=0.007)and normal gastric mucosa(23.3%,<0.001). The high cytoplasmic expression rate of GKN1 in normal gastric mucosa was 76.7%,which was significantly higher than those of intestinal metaplasia(44.4%,=0.006)and gastric cancer tissues(37.1%,<0.001). Univariate analysis demonstrated that the nuclear expression of SOX9 in gastric cancer was associated with the degree of tissue differentiation(=0.007),while the cytoplasmic expression of GKN1 was associated with both the degree of tissue differentiation(=0.002)and whether the pathological type was a signet-ring cell carcinoma(=0.009). Furthermore,the nuclear expression of SOX9 was negatively correlated with the expression of GKN1 in gastric cancer(=15.424,<0.001). The 5-year survival rates of patients with high or low nuclear expression of SOX9 were 33.8% and 67.5%,respectively(=0.016).The 5-year survival rates of patients with high or low expression of GKN1 were 60.0% and 35.6%,respectively(=0.044). Further research indicated that 5-year survival rate of patients with high nuclear expression of SOX9 and low expression of GKN1 was 28.8%. Cox multivariate regression analysis showed that TNM stage(stage Ⅱ:=7.435,95%:1.313-42.096,=0.023;stage Ⅲ:=12.214,95%:2.677-55.721,=0.001)and nuclear expression level of SOX9(=3.297,95%:1.199-9.065,=0.021)were independent risk factors for the prognosis of gastric cancer patients.Conclusions Changes in the expressions of SOX9 and GKN1 may be associated with the malignant biological behavior of gastric cancer. SOX9 may be a potential prognostic factor. The combined detection of SOX9 and GKN1 expression and the further study of their molecular mechanism may provide new clues for early diagnosis,targeted therapy,and prognostic prediction of gastric cancer.
Humans ; Immunohistochemistry ; Peptide Hormones ; genetics ; Prognosis ; SOX9 Transcription Factor ; genetics ; Stomach Neoplasms ; diagnosis ; genetics ; Survival Rate