Sry-related High-mobility Group Research Articles

Biological functions and therapeutic potential of SRY related high mobility group box 5 in human cancer

Cancer is a heavy human burden worldwide, with high morbidity and mortality. Identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. Transcription factors, including SRY associated high mobility group box (SOX) proteins, are thought to be involved in the regulation of specific biological processes. There is growing evidence that SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumor microenvironment, and metastasis. SOX5 is a member of SOX Group D of Sox family. SOX5 is expressed in various tissues of human body and participates in various physiological and pathological processes and various cellular processes. However, the abnormal expression of SOX5 is associated with cancer of various systems, and the abnormal expression of SOX5 acts as a tumor promoter to promote cancer cell viability, proliferation, invasion, migration and EMT through multiple mechanisms. In addition, the expression pattern of SOX5 is closely related to cancer type, stage and adverse clinical outcome. Therefore, SOX5 is considered as a potential biomarker for cancer diagnosis and prognosis. In this review, the expression of SOX5 in various human cancers, the mechanism of action and potential clinical significance of SOX5 in tumor, and the therapeutic significance of Sox5 targeting in cancer were reviewed. In order to provide a new theoretical basis for cancer clinical molecular diagnosis, molecular targeted therapy and scientific research.

Fibroblast-like synoviocytes-derived exosomal circFTO deteriorates rheumatoid arthritis by enhancing N6-methyladenosine modification of SOX9 in chondrocytes

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease that causes disability worldwide. Exosomes released by fibroblast-like synoviocytes in RA (RA-FLSs-Exos) play a role in the development of RA, and circular RNAs (circRNAs) are important for RA progression. This study aimed to investigate the molecular mechanisms underlying the effects of RA-FLSs-Exos in RA and identify the potential pathway responsible for these effects.MethodsWe initially conducted microarray analysis to identify dysregulated circRNAs in exosomes associated with RA. We then co-cultured isolated RA-FLSs-Exos with chondrocytes to examine their role in RA. In vivo experiments were performed using collagen-induced arthritis mouse models, and circFTO knockdown was achieved through intra-articular injection of AAV5 vectors.ResultsOur findings revealed increased expression of circFTO in both RA-FLSs-Exos and synovial tissues from patients with RA. Exosomal circFTO hindered chondrocyte proliferation, migration, and anabolism while promoting apoptosis and catabolism. Mechanistically, we discovered that circFTO facilitates the formation of methyltransferases complex to suppress SRY-related high-mobility group box 9 (SOX9) expression with assistance from YTH domain family 2 (YTHDF2) through an m6A-dependent mechanism. Furthermore, inhibition of circFTO improved symptoms of RA in vivo.ConclusionTaken together, our study demonstrates that exosomal circFTO derived from FLSs contributes to the progression of RA by targeting SOX9. These findings highlight a promising target for treating RA.

SOX4 reversibly induces phenotypic changes by suppressing the epithelial marker genes in human keratinocytes.

SOX4 is a transcription factor belonging to the SOX (Sry-related High Mobility Group [HMG] box) family and plays a pivotal role in various biological processes at various stages of life. SOX4 is also expressed in the skin in adults and has been reported to be involved in wound healing, tumor formation, and metastasis. In this study, we investigated the role of SOX4 in keratinocyte phenotypic changes. We generated a SOX4-overexpressing keratinocyte cell line that expresses SOX4 in a doxycycline (DOX)-inducible manner. DOX treatment induced a change from a paving stone-like morphology to a spindle-like morphology under microscopic observation. Comprehensive gene analysis by RNA sequencing revealed increased expression of genes related to anatomical morphogenesis and cell differentiation as well as decreased expression of genes related to epithelial formation and keratinization, suggesting that SOX4 induced EMT-like phenotype in keratinocytes. Differentially expressed genes (DEGs) obtained by RNA-seq were confirmed using qRT-PCR. DOX-treated TY-1 SOX4 showed a decrease in the epithelial markers (KRT15, KRT13, KRT5, and CLDN1) and an increase in the mesenchymal marker FN1. Protein expression changes by Western blotting also showed a decrease in the epithelial marker proteins keratin 15, keratin 13, and claudin 1, and an increase in the mesenchymal marker fibronectin. Removal of DOX from DOX-treated cells also restored the epithelial and mesenchymal markers altered by SOX4. Our results indicate that SOX4 reversibly induces an EMT-like phenotype in human keratinocytes via suppression of epithelial marker genes.

Clinicopathological and Prognostic Significance of SRY-Box Transcription Factor 2 (SOX2) Overexpression in Central Nervous System Tumor: A Meta-Analysis

Background: Central nervous system (CNS) tumors have been recognized as a type of tumor with high progressivity and a five-year survival rate of just 36%. SRY-related high mobility group box-2 (SOX2) is a gene encoding the Sox2 protein which is found to be overexpressed in various CNS tumors and contribute to its progressiveness. This gene contributes to CNS tumors through several signaling pathways, including Shh, Wnt, FGFR, and TGF-β signaling pathways. This meta-analysis aims to evaluate the clinicopathological and prognostic significance of SOX2 overexpression in CNS tumor. Patients and methods: The literature searches on Cochrane Library, PubMed, and ScienceDirect were conducted systematically up to December 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) method to find relevant references. The effect of SOX2 overexpression on clinicopathological characteristics and prognostic value were analyzed using Review Manager 5.4 (Cochrane Collaboration, Oxford, UK). Results: Ten suitable studies with a total of 466 patients with CNS tumors including gliomas (glioblastoma, astrocytoma, oligoastrocytoma, and oligodendrogliomas) and meningiomas, were included. Our analysis shows a significant association between the overexpression of SOX2 with the grade of CNS tumor (OR 7.05; 95%CI: 2.83 to 17.53; I2 = 53%; p< 0.0001) both in gliomas and meningiomas, with gender (OR 2.08; 95%CI: 1.30 to 3.34; I2 = 13%; p = 0.002) especially in non-Asian population, and higher in primary tumor than recurrent tumor (OR 4.31; 95%CI: 1.41 to 13.14; I2 = 13%; p = 0.01). On the prognostic value, SOX2 overexpression insignificantly associates with poor overall survival (HR 1.73; 95%CI: 0.49 to 6.18; I2 = 83%; p = 0.40) Conclusion: SOX2 overexpression suggests a role as a biomarker in predicting the poorer grade of CNS tumors.

Effects of uphill and downhill walking on post-traumatic osteoarthritis development in mice.

Using destabilization of the medial meniscus (DMM) induced models of osteoarthritis (OA), we sought to clarify how flat, uphill, and downhill walking affects OA-related inflammation and articular cartilage degeneration. Thirty-two male C57BL/6J mice of 7 weeks old underwent DMM surgery in their right knee and sham surgery in their left knee, and then were assigned to either the no walking after DMM group or the flat, uphill, or downhill walking after DMM group (n = 8/group). After creating the knee OA model, the mice in the walking groups were subjected to treadmill walking 1 day after surgery, which included walking for 12 m/min, 30 min/day, and 7 days/week, with inclines of 0, 20, or - 20 degrees. Knee joints were harvested at the end of the intervention period. Non-demineralized frozen sections were prepared and samples were examined histologically. Osteoarthritis Research Society International scores were significantly decreased in both the uphill and flat walking groups, compared with the no-walking group. Immunohistochemical staining showed increased levels of aggrecan and Sry-related high mobility group box 9; conversely, decreased levels of Matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 in both the uphill and flat walking groups. Micro-CT results showed higher bone volume fraction in the uphill and flat walking groups than that in the no-walking group. Our findings indicate that flat and uphill walking may prevent the progression of OA. KEY POINTS: Flat and uphill treadmill walking can prevent the development of post-traumatic osteoarthritis in mice. Flat and uphill walking increases anabolic proteins and decreases catabolic proteins and inflammatory cytokines in articular cartilage, resulting in protection against cartilage degeneration. Downhill walking increases catabolic proteins and inflammatory cytokines in cartilage, which has negative effects on articular cartilage. Abstract figure legend This study sought to verify how flat, uphill, and downhill walking affects osteoarthritis development. Mice of the post-traumatic osteoarthritis model were subjected to treadmill walking. Flat and uphill walking increased cartilage anabolic proteins (Sry-related high mobility group box 9 [Sox9] and/or Aggrecan) and decreased catabolic proteins (Matrix metalloproteinase-13 [MMP-13] or A disintegrin and metalloproteinase with thrombospondin motifs 5 [ADAMTS5]), resulting in protection against osteoarthritis development. Downhill walking decreased Sox9 protein levels in cartilage compared to uphill walking. In addition, downhill walking increased MMP-13 levels, suggesting negative effects on articular cartilage. This article is protected by copyright. All rights reserved.

Dual Effects of miR-181b-2-3p/SOX21 Interaction on Microglia and Neural Stem Cells after Gamma Irradiation.

Ionizing radiation induces brain inflammation and the impairment of neurogenesis by activating microglia and inducing apoptosis in neurogenic zones. However, the causal relationship between microglial activation and the impairment of neurogenesis as well as the relevant molecular mechanisms involved in microRNA (miR) remain unknown. In the present study, we employed immunohistochemistry and real-time RT-PCR to study the microglial activation and miRNA expression in mouse brains. Real-time RT-PCR, western blot, ELISA, cell proliferation and cytotoxicity assay were used in BV2 and mouse neural stem cells (NSCs). In the mouse model, we found the acute activation of microglia at 1 day and an increased number of microglial cells at 1, 7 and 120 days after irradiation at postnatal day 3 (P3), day 10 (P10) and day 21 (P21), respectively. In cell models, the activation of BV2, a type of microglial cell line, was observed after gamma irradiation. Real-time RT-PCR analysis revealed a deceased expression of miR-181b-2-3p and an increased expression of its target SRY-related high-mobility group box transcription factor 21 (SOX21) in a dose- and time-dependent fashion. The results of the luciferase reporter assay confirmed that SOX21 was the target of miR-181b-2-3p. Furthermore, SOX21 knockdown by siRNA inhibited the activation of microglia, thereby suggesting that the direct interaction of 181b-2-3p with SOX21 might be involved in radiation-induced microglial activation and proliferation. Interestingly, the gamma irradiation of NSCs increased miR-181b-2-3p expression but decreased SOX21 mRNA, which was the opposite of irradiation-induced expression in BV2 cells. As irradiation reduced the viability and proliferation of NSCs, whereas the overexpression of SOX21 restored the impaired cell viability and promoted the proliferation of NSCs, the findings suggest that the radiation-induced interaction of miR-181b-2-3p with SOX21 may play dual roles in microglia and NSCs, respectively, leading to the impairment of brain neurogenesis.

Circular RNA_0000326 accelerates breast cancer development via modulation of the miR-9-3p/YAP1 axis.

Circular RNA (circ)_0000326 has been reported in bladder cancer and cervical cancer and is concerned to be involved with the development of cancerous cells. Whereas, there have been no reports concentrating on the influences of circ_0000326 in breast cancer (BC). Therefore, the latent modulatory mechanisms of circ_0000326 in BC are researched. circ_0000326 expression in BC tissues and correlative cells was evaluated via RT-qPCR, and the relevance between circ_0000326 expression and overall survival and the clinicopathological feature was also investigated. After a series of transfection, the effects of circ_0000326, microRNA-9-3p (miR-9-3p), and Yes-associated protein 1 (YAP1) in BC cell growth, invasion, and stemness were studied by CCK-8, flow cytometry, Transwell, and sphere-forming assays. The binding sites and correlation of circ_0000326, miR-9-3p, and YAP1 were certified via starBase website, luciferase reporter assay, and Pearson's χ2 test. The in vivo experiment was evaluated by establishing a subcutaneous tumorigenesis model. High-expressed circ_0000326 in BC tissues and cells was discovered, which was connected with an undesirable prognosis. Silencing of circ_0000326 visibly inhibited MCF-7 and BT549 cell growth, invasion, stemness, meanwhile declining the protein levels of SRY-related high-mobility group box gene 2 (SOX2) and octamer binding transcription factor 4 (OCT4). miR-9-3p was a sponger of circ_0000326, which was negatively regulated by circ_0000326. Moreover, YAP1 was confirmed as a target gene of miR-9-3p. circ_0000326 affected BC cell behaviors via mediating miR-9-3p and YAP1. Furthermore, circ_0000326 silencing prohibited tumor growth of BC in vivo. The research uncovered that circ_0000326 facilitated BC development via mediating the miR-9-3p/YAP1 axis.

SMOC2 promotes aggressive behavior of fibroblast-like synoviocytes in rheumatoid arthritis through transcriptional and post-transcriptional regulating MYO1C

Fibroblast-like synoviocytes (FLSs), play a key role in perpetuating synovial inflammation and bone erosion in rheumatoid arthritis (RA), however, the underlying mechanism(s) of RA FLSs activation and aggression remain unclear. Identifying endogenous proteins that selectively target FLSs is urgently needed. Here, we systematically identified that secreted modular calcium-binding protein 2 (SMOC2), was significantly increased in RA FLSs and synovial tissues. SMOC2 knockdown specifically regulated cytoskeleton remodeling and decreased the migration and invasion of RA FLSs. Mechanistically, cytoskeleton-related genes were significantly downregulated in RA FLSs with reduced SMOC2 expression, especially the motor protein myosin1c (MYO1C). SMOC2 controlled MYO1C expression by SRY-related high-mobility group box 4 (SOX4) and AlkB homolog 5 (ALKHB5) mediated-m6A modification through transcriptional and post-transcriptional regulation. Furthermore, intra-articular Ad-shRNA-SMOC2 treatment attenuated synovial inflammation as well as bone and cartilage erosion in rats with collagen-induced arthritis (CIA). Our findings suggest that increased SMOC2 expression in FLSs may contribute to synovial aggression and joint destruction in RA. SMOC2 may serve as a potential target against RA.SMOC2-mediated regulation of the synovial migration and invasion in RA FLSs. In RA FLSs, SMOC2 is significantly increased, leading to the increased level of MYO1C via SOX4-mediated transcriptional regulation and ALKBH5-mediated m6A modification, thereby causing cytoskeleton remodeling and promoting RA FLSs migration and invasion. The Figure was drawn by Figdraw.

Impact of SOX2 function and regulation on therapy resistance in bladder cancer.

Bladder cancer (BC) is a malignant disease with high rates of recurrence and mortality. It is mainly classified as non-muscle-invasive BC and muscle-invasive BC (MIBC). Often, MIBC is chemoresistant, which, according to cancer stem cells (CSCs) theory, is linked to the presence of bladder cancer stem cells (BCSCs). Sex-determining region Y- (SRY) Box transcription factor 2 (SOX2), which is a molecular marker of BCSCs, is aberrantly over-expressed in chemoresistant BC cell lines. It is one of the standalone prognostic factors for BC, and it has an inherently significant function in the emergence and progression of the disease. This review first summarizes the role of SRY-related high-mobility group protein Box (SOX) family genes in BC, focusing on the SOX2 and its significance in BC. Second, it discusses the mechanisms relevant to the regulation of SOX2. Finally, it summarizes the signaling pathways related to SOX2 in BC, suggests current issues to be addressed, and proposes potential directions for future research to provide new insights for the treatment of BC.

Regulatory effects of differential dietary energy levels on spermatogenesis and sperm motility of yellow-feathered breeder cocks.

The semen quality of breeder cocks profoundly impacted the numbers of matched layer hens and the economic benefits of the poultry industry. Adequacy and balance of poultry nutrition, especially the energy provision, critically modulated the reproductive potential of breeder cocks, however, the underlying mechanism was still unclear. For the purpose of this study, a total of 90 yellow-feathered 13-week-old roosters with the same age in days and similar body weight (1,437 ± 44.3 g) were selected and randomly divided into the low energy diet (LE), the moderate energy diet (ME), and the high energy diet (HE) treatments. The phenotypic parameters related to reproduction include semen quality, fertility, and hatchability, and the testis morphological parameters, including seminiferous epithelium length (SEL), seminiferous tubule perimeter (STP), seminiferous tubule area (STA), and Johnsen score, were measured to investigate the regulatory effects of different energy diets on reproductive performances. Furthermore, spermatogenesis and sperm motility-related genes, which included the sry-related high mobility group box (SOX) gene family and sperm-associated antigen (SPAG) gene family, and mitochondria apoptosis-related genes, such as Cyt-C, Bcl-2, and Bax, were measured to determine the underlying mechanism of energy on the reproductive performances. The The results showed that the gonadosomatic index and sperm motility in the ME treatment significantly increased compared with the LE treatment. Chickens in the ME treatment showed a preferable performance of testis development, especially a significant increment of SEL and Johnsen Score, compared with the LE and HE treatments. Finally, spermatogenesis-related genes, which included SPAG6, SPAG16, SOX5, SOX6, and SOX13, and apoptosis-related genes of mitochondria, such as the Cyt-C and Bcl-2, were significantly upregulated in the ME treatment. This study concluded that proper energy provision stimulated regular energy metabolism for spermatogenesis and sperm capacitation, which finally increased semen quality and reproductive performances of breeder cocks.

Effects of microRNA-101-3p on predicting pediatric acute respiratory distress syndrome and its role in human alveolar epithelial cell

ABSTRACT Pediatric acute respiratory distress syndrome (PARDS) is a severe form of respiratory failure associated with high mortality among children. The objective of this study is reported to explore the clinical function and molecular roles of microRNA-101-3p (miR-101-3p) in PARDS. The levels of miR-101-3p and mRNA levels of SRY-related high-mobility group box 9 (Sox9) were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Additionally, the diagnostic role of miR-101-3p was identified by using the Receiver operating characteristic (ROC) curve. The cell proliferation and apoptosis were examined through Cell Counting Kit-8 (CCK-8) assay and flow cytometry. To detect inflammation in cells, enzyme-linked immunosorbent assays (ELISA) were performed. The target gene of miR-101-3p was confirmed through data obtained from the luciferase activity. In patients with PARDS, miR-101-3p expression was decreased. Moderate and severe PARDS patients had lower levels of miR-101-3p than mild PARDS patients. The inflammatory progression was related to the aberrant expression of miR-101-3p in all PARDS children. MiR-101-3p was highly predictive for the detection of children with PARDS. In addition, miR-101-3p might protect A549 cells from abnormal proliferation, apoptosis, and inflammation caused by lipopolysaccharide (LPS). Sox9 might be a target gene of miR-101-3p and increased mRNA expression of Sox9 in LPS-treated A549 cells was inhibited by overexpression of miR-101-3p. Ultimately, this study suggested that reduced expression of miR-101-3p plays a role in PARDS, providing a novel angle to study the disease.

SRY-related high-mobility group box 9 (SOX9) alleviates cigarette smoke extract (CSE)-induced inflammatory injury in human bronchial epithelial cells by suppressing stromal interaction molecule 1 (STIM1) expression.

Chronic obstructive pulmonary disease (COPD) is a chronic airway disease with airflow limitation and abnormal inflammatory response. It has been verified that SOX9 plays a key role in lung function of various lung diseases and SOX9 is closely associated with COPD. Additionally, literature has reported that STIM1 is involved in lung injury and is highly expressed in neutrophils from COPD patients. This study aimed to characterize the biological roles of SOX9 and STIM1 in the pathogenesis of COPD and to elucidate the regulatory mechanism. Human bronchial epithelial cells (BEAS-2B) were treated with CSE to construct in vitro COPD model. The levels of SOX9 and STIM1 in CSE-treated BEAS-2B cells were detected by western blot and RT-qPCR assay. Then, JASPAR datasets were utilized to analyze SOX9 binding sites in the promoter region of STIM1. Besides, luciferase reporter assay and ChIP assay were employed to validate the binding sites in STIM1 promoter region to SOX9. In addition, viability and apoptosis of BEAS-2B cells were assessed by utilizing MTT assay and TUNEL staining. ELISA kits and corresponding commercial kits were applied to measure the levels of TNF-α, IL-6, IL-1β, SOD, GSH-Px and MDA. CSE treatment dose- and time-dependently reduced SOX9 expression in BEAS-2B cells. SOX9 overexpression enhanced the viability and suppressed the apoptosis of CSE-treated BEAS-2B cells as well as attenuated CSE-induced inflammation and oxidative stress. Then, it was validated that SOX9 bound to the promoter region of STIM1. Moreover, SOX9 overexpression-mediated impacts on cell viability, cell apoptosis, inflammation and oxidative stress in CSE-treated BEAS-2B cells were partially abolished by upregulation of STIM1. To sum up, results here suggested that overexpression of SOX9 could mitigate inflammatory injury in CSE-treated bronchial epithelial cells by suppressing STIM1.

Circular RNA hsa_circ_0000277 promotes tumor progression and DDP resistance in esophageal squamous cell carcinoma

BackgroundCircular RNAs (circRNAs) are well-known regulators of cancer progression and chemoresistance in various types of cancers. This study was performed to investigate the function of hsa_circ_0000277 in esophageal squamous cell carcinoma (ESCC).MethodsRNA levels were analyzed via the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8) assay was applied to determine cell proliferation and half maximal inhibitory concentration (IC50) of cisplatin (DDP). Colony formation ability was evaluated by colony formation assay. Cell cycle and apoptosis were measured using flow cytometry. RNA immunoprecipitation (RIP), pull-down assay and dual-luciferase reporter assays were performed for target interaction analysis. The protein levels were determined through western blot. Xenograft models were established for researching hsa_circ_0000277 function in vivo.ResultsHsa_circ_0000277 expression was increased in ESCC cells and tissues, and it had important clinical significance. Downregulation of hsa_circ_0000277 repressed ESCC cell proliferation, colony formation, cell cycle, and DDP resistance. Hsa_circ_0000277 acted as a microRNA-873-5p (miR-873-5p) sponge and Sry-related high-mobility group box 4 (SOX4) was validated as a target of miR-873-5p. Moreover, hsa_circ_0000277/miR-873-5p axis and miR-873-5p/SOX4 axis regulated ESCC cell progression and DDP resistance. Hsa_circ_0000277/miR-873-5p axis activated SOX4/Wnt/β-catenin signaling pathway. Hsa_circ_0000277 facilitated tumorigenesis and DDP resistance by miR-873-5p/SOX4 axis in vivo.ConclusionThese findings unraveled that hsa_circ_0000277 promoted ESCC progression and DDP resistance via miR-873-5p/SOX4/Wnt/β-catenin axis, showing a specific molecular mechanism of carcinogenesis and chemoresistance in ESCC.

SOX9 negatively regulates the RLR antiviral signaling by targeting MAVS.

Mitochondrial virus-induced signal adaptor (MAVS), also known as VISA, IPS-1, and Cardif, is a crucial adaptor protein in the RIG-I-like receptor (RLR) signaling pathway. Upon viral infection, RIG-I recognizes viral dsRNA and further transfers it to mitochondria, where it binds to MAVS through its CARD domain, generating a series of signal cascades. Transduction through this signaling cascade leads to phosphorylation and nuclear translocation of interferon regulatory factor 3/7 (IRF3/IRF7) and activation of NF-κB, which ultimately produces type I interferon (IFN) and proinflammatory cytokines. Here, our experiments demonstrated that overexpression of SRY-related high-mobility group protein 9 (SOX9) significantly inhibited Sendai virus (SeV)-induced and MAVS-mediated activation of the IFN-β promoter and ISRE. However, knocking out the expression of SOX9 in cells promoted SeV-induced IFN-β promoter and ISRE activation. Further studies have shown that SOX9 interacts with MAVS and targets MAVS to inhibit the association of MAVS-TRAF2, thereby inhibiting MAVS-mediated TRAF2 ubiquitination. Taken together, these results indicate that SOX9 downregulates IFN-β expression and antiviral signal transduction by targeting MAVS.

LINC00520 up-regulates SOX5 to promote cell proliferation and invasion by miR-4516 in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common human cancers. Long non-coding RNA (lncRNA) has been demonstrated to play an important role in regulating tumor development. The current study aims to explore the specific role of LINC00520 during HCC progression. The present study identified that LINC00520 was upregulated in HCC tissues and indicated poor patient survival. Overexpression of LINC00520 promoted HCC cell proliferation, migration and invasion, while LINC00520 downregulation led to the opposite effects. Besides, LINC00520 knockdown was found to inhibit tumor growth in vivo. Furthermore, LINC00520 acted as a sponge of miR-4516 to regulate SRY-related high mobility group box 5 (SOX5). In addition, the inhibition of miR-4516 partly reversed the inhibitory effect of LINC00520 silencing on HCC cell proliferation, migration and invasion. In conclusion, the inhibition of LINC00520 suppressed HCC cell proliferation, migration and invasion through mediating miR-4516/SOX5 axis. Therefore, our study provides a basis for the development of treatment strategies for HCC.

Linagliptin ameliorated interleukin-29-induced reduction of extracellular matrix genes through the nuclear factor erythroid 2-related factor 2 (Nrf2)/sry-type high-mobility-group box (SOX)-9 axis in an in vitro study on C-28/I2 chondrocytes

ABSTRACT Osteoarthritis (OA) is a severe orthopedic disease commonly observed in the elderly population and is closely related to the degradation of extracellular matrix (ECM) in cartilage tissues. Interleukin-29 (IL-29) is a cytokine that has been recently linked with the progression of OA. However, the physiological roles of IL-29 in ECM genes and function are unknown. Linagliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor recently reported to exert significant anti-inflammatory properties. In this study, we used IL-29 to stimulate C-28/I2 chondrocytes to build an inflammatory injury model. We aimed to investigate the protective effect of Linagliptin on IL-29-induced degradation of ECM. We found that IL-29 stimulation reduced the expressions of Col2a1 and Acan in C-28/I2 chondrocytes, and this effect was mediated by SRY-related high-mobility group box gene-9 (SOX-9), as we showed that overexpression of SOX-9 could rescue the reduction of Col2a1 and Acan. Interestingly, we found that IL-29 stimulation pronouncedly promoted the expression of DPP-4. Treatment with 100 nM of the DPP-4 inhibitor Linagliptin ameliorated IL-29-induced expressions of SOX-9, Col2a1, and Acan. Lastly, the nuclear level of nuclear factor erythroid 2-related factor 2 (Nrf2) was dramatically declined in IL-29-challenged chondrocytes and the protective effects of Linagliptin on the expressions of SOX-9, Col2a1, and Acan were abolished by the knockdown of Nrf2. Taken together, our data reveal that Linagliptin ameliorated IL-29-induced reduction of ECM genes partially through the Nrf2/SOX-9 axis in C-28/I2 chondrocytes. Further in vivo and clinical studies will be done to clarify the protective benefits of Linagliptin in OA.

Utility of SOX11 for the diagnosis of solid pseudopapillary neoplasm of the pancreas on cytological preparations.

The diagnosis of solid pseudopapillary neoplasm (SPN) on fine needle aspiration specimens can be challenging because of morphological overlap with other pancreatic neoplasms, including pancreatic neuroendocrine tumour (PanNET). SRY-related high-mobility group box 11 (SOX11) is a recently described sensitive and specific marker for SPN diagnosis. However, SOX11 immunocytochemistry on cytological smears has not been reported. We evaluated the utility of SOX11 for diagnosis of SPN on cytological preparations. SOX11 immunocytochemistry was performed on Papanicolaou-stained smears and/or corresponding cell blocks from aspirates of 7 SPN and 10 PanNET cases identified between 2005 and 2020. Findings were compared with those for beta-catenin, a frequently used diagnostic marker for SPN. Six smears and 6 cell blocks from SPN cases and 8smears and 10 cell blocks from PanNET cases were available for immunostaining. For SPN, nuclear staining for SOX11 was seen in 6 of 6 (100%) smears and 5 of 6 (83%) cell blocks, with equivocal staining in 1 cell block. In contrast, 7 of 8 (88%) smears and 9 of 10 (90%) cell blocks were negative for SOX11 for PanNet, with equivocal staining seen in 1 case. Beta-catenin immunocytochemistry showed nuclear staining in 6 of 7 (86%) SPN cases and no staining in all 10 (100%) PanNET cases. SOX11 detected by immunocytochemistry can serve as a useful diagnostic marker for SPN, in addition to beta catenin, and can be performed on cytological smears in cases without a cell block preparation.

Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor.

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

Efficacy of Yishen Huoxue Tongluo() medicated serum on apoptosis of nucleus pulposus cells of human intervertebral disc under overload static pressure

To explore the efficacy of Yishen Huoxue Tongluo() decoction containing serum on the apoptosis of human disc nucleus pulposus cells under the overload static pressure stress and its related mechanism. Human nucleus pulposus cells were divided into three groups. The blank group had no intervention. The model group and traditional Chinese medicine serum intervention group were treated with 3 MPa compressive stress in vitro for 2, 4 and 6 hours. The changes and differences of morphology, growth status and ultrastructure of intervertebral disc nucleus pulposus cells were observed. The apoptosis rate of nucleus pulposus cells and nuclear factor kappa-B p65 (NF-κB p65), SRY-related high mobility group box 9 (SOX9), C/EBP-homologous protein (CHOP), matrix metalloprotein-13 (MMP-13) and corresponding gene expression were detected. At the same time, compared with the blank group, the nucleus pulposus cells in the model group were smaller in volume, less in cytoplasm and worse in growth; the nucleus pulposus cells in the traditional Chinese medicine serum intervention group were slightly larger in volume, more complete in morphology, richer in cytoplasm and better in growth. Under the same action time, the ultrastructure of nucleus pulposus cells in blank group was complete, and the structures of primary and secondary processes were not broken;and the ultrastructure of model group and traditional Chinese medicine serum intervention group were damaged, the main and secondary processes were broken to varying degrees, and there was no significant difference between the two groups. At the same time, the apoptosis rate of nucleus pulposus cells in model group was higher than that in blank group, while the apoptosis rate of nucleus pulposus cells in the traditional Chinese medicine serum intervention group was lower than that inmodel group, the difference was statistically significant (P<0.05); with the increase of action time, there was no significant difference in the apoptosis rate of nucleus pulposus cells between blank group and traditional Chinese medicine serum intervention group, and the apoptosis rate of nucleus pulposus cells in model group was increased. Compared with model group, the expression of NF-κB p65, CHOP, MMP-13 were decreased and SOX9 was increased in traditional Chinese medicine serum intervention group at the same time (P<0.05);with the increase of action time, the expression of NF-κB p65, CHOP and MMP-13 were increased, and the expression of SOX9 was decreased in blank group and model group(P<0.05), and the expression level of model group was higher than that of blank group(P<0.05). Overall observation by gene expression, under the same action time, the relative quantifications of NF-κB p65, CHOP and MMP-13 in traditional Chinese medicine serum intervention group were lower than that in model group, while SOX9 was increased (P<0.05);compared with model group, the relative quantifications of NF-κB p65, CHOP and MMP-13 in blank group were decreased(P<0.05), and the relative quantification of SOX9 was increased(P<0.05);with the increase of action time, the relative quantifications of NF-κB p65, CHOP and MMP-13 of nucleus pulposus cells in blank group and model group were increased and SOX9 was decreased(P<0.05). Yishen Huoxue Tongluo() decoction can reduce the apoptosis of nucleus pulposus cells under overload and static pressure, and has the effect of delaying the degeneration of nucleus pulposus cells. Its mechanism may be related to the decrease of CHOP, MMP-13 expression and the increase of SOX9 expression by inhibiting NF-κB p65 signal pathway of nucleus pulposus cells.

SOX9 is associated with advanced T-stages of clinical stage II colon cancer in young Mexican patients.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and includes colon cancer (CC) and rectal cancer (RC). Regarding CC, the development of novel molecular biomarkers for the accurate diagnosis and prognosis, as well as the identification of novel targets for therapeutic intervention, are urgently needed. SRY-related high-mobility group box 9 (SOX9), a transcription factor, is involved in development, and has been associated with the progression of human cancer. However, its underlying clinical and functional effects in CRC have not been fully understood. Therefore, the present study aimed to evaluate the clinical and functional relevance of SOX9 expression in CC. The expression of SOX9 in tumor tissues was evaluated in 97 biopsies from Mexican patients with CC with early-stage I and II disease by immunohistochemistry (IHC). In addition, SOX9 silencing in the HCT116 cell line was performed using specific small interfering RNAs, while downregulation efficiency was verified by reverse transcription-quantitative PCR and immunofluorescence. Spheroid-formation assay was carried out using ultra-low attachment plates. The IHC results showed that SOX9 was upregulated in patients with stage II (91%) and advanced T3 stage (67%) CC. Interestingly, higher SOX9 expression was associated with clinical stage, tumor size and tumor location. Furthermore, increased SOX9 expression was found in relapsed cases with local tumors; however, it was not associated with increased survival probability. Additionally, functional analysis indicated that SOX9 silencing significantly attenuated the sphere-formation capability of HCT116 cells. The present study was the first to evaluate the expression levels of SOX9 in Mexican patients diagnosed with early-stage CC. The aforementioned findings indicated that high SOX9 expression could play an important role in tumorigenesis and be associated with advanced T-stages of clinical-stage II patients, but not with relapse-free survival.