Polycystic ovary syndrome (PCOS) is a globally prevalent gynecological disorder among women of childbearing age. The present study aimed to investigate the role of tenascin C (TNC) in PCOS and its potential mechanisms. Fasting blood glucose and serum insulin, the homeostasis model assessment of insulin resistance and the serum hormone levels were determined in PCOS rats. In addition, H&E staining was used for assessing pathology. In addition, the effects of TNC on oxidative stress and inflammation response in PCOS rat and cell models was assessed. Furthermore, the roles of TNC on KGN cell proliferation and apoptosis were determined employing EdU assay and flow cytometry. TLR4/NF‑κB pathway‑related proteins were measured using western blotting, immunofluorescence and immunohistochemistry. It was found that the mRNA and protein expression was upregulated in PCOS rats and in KGN cells induced by dihydrotestosterone (DHT). Knockdown of TNC relieved the pathological characteristics and the endocrine abnormalities of PCOS rats. Knockdown of TNC inhibited ovarian cell apoptosis, oxidative stress and inflammation in PCOS rats. Knockdown of TNC reversed the DHT‑induced reduction in cell proliferation and increase in apoptosis in KGN cells. Furthermore, knockdown of TNC alleviated oxidative stress and inflammatory responses induced by DHT in KGN cells. Additionally, knockdown of TNC inhibited the toll‑like receptor 4 (TLR4)/NF‑κB signaling pathway in PCOS rats and DHT‑treated KGN cells. In conclusion, knockdown of TNC could ameliorate PCOS in both rats and a cell model by inhibiting cell apoptosis, oxidative stress and inflammation via the suppression of the TLR4/NF‑κB signaling pathway.

Cartilage defects may lead to severe degenerative joint diseases. Tissue engineering based on type I collagen hydrogel that has chondrogenic potential is ideal for cartilage repair. However, the underlying mechanisms of chondrogenic differentiation driven by type I collagen hydrogel have not been fully clarified. Herein, we explored potential collagen receptors and chondrogenic signaling pathways through bioinformatical analysis to investigate the mechanism of collagen-induced chondrogenesis. Results showed that the super enhancer-related genes induced by collagen hydrogel were significantly enriched in the TGF-β signaling pathway, and integrin-β1 (ITGB1), a receptor of collagen, was highly expressed in bone marrow mesenchymal stem cells (BMSCs). Further analysis showed genes such as COL2A1 and Tenascin C (TNC) that interacted with ITGB1 were significantly enriched in extracellular matrix (ECM) structural constituents in the chondrogenic induction group. Knockdown of ITGB1 led to the downregulation of cartilage-specific genes (SOX9, ACAN, COL2A1), SMAD2 and TNC, as well as the downregulation of phosphorylation of SMAD2/3. Knockdown of TNC also resulted in the decrease of cartilage markers, ITGB1 and the SMAD2/3 phosphorylation but overexpression of TNC showed the opposite trend. Finally, in vitro and in vivo experiments confirmed the involvement of ITGB1 and TNC in collagen-mediated chondrogenic differentiation and cartilage regeneration. In summary, we demonstrated that ITGB1 was a crucial receptor for chondrogenic differentiation of BMSCs induced by collagen hydrogel. It can activate TGF-SMAD2/3 signaling, followed by impacting TNC expression, which in turn promotes the interaction of ITGB1 and TGF-SMAD2/3 signaling to enhance chondrogenesis. These may provide concernful support for cartilage tissue engineering and biomaterials development.

Prostaglandin E2 (PGE2) is an important metabolite of arachidonic acid which plays a crucial role in vascular physiology and pathophysiology via its four receptors (EP1-4). However, the role of vascular smooth muscle cell (VSMC) EP4 in neointimal hyperplasia is largely unknown. Here we showed that VSMC-specific deletion of EP4 (VSMC-EP4) ameliorated, while VSMC-specific overexpression of human EP4 promoted, neointimal hyperplasia in mice subjected to femoral artery wire injury or carotid artery ligation. In vitro studies revealed that pharmacological activation of EP4 promoted, whereas inhibition of EP4 suppressed, proliferation and migration of primary-cultured VSMCs. Mechanically, EP4 significantly increased the protein expression of tenascin C (TN-C), a pro-proliferative and pro-migratory extracellular matrix protein, at the translational level. Knockdown of TN-C markedly suppressed EP4 agonist-induced VSMC proliferation and migration. Further studies uncovered that EP4 upregulated TN-C protein expression via the PKA/mTORC1/Ribosomal protein S6 (rpS6) pathway. Together, our findings demonstrate that VSMC EP4 increases TN-C protein expression to promote neointimal hyperplasia via the PKA-mTORC1-rpS6 pathway. Therefore, VSMC EP4 may represent a potential therapeutic target for vascular restenosis.

Matricellular proteins are nonstructural extracellular matrix components that are expressed at low levels in normal adult tissues and are upregulated during development or under pathological conditions. Tenascin C (TNC), a matricellular protein, is a hexameric and multimodular glycoprotein with different molecular forms that is produced by alternative splicing and post-translational modifications. Malignant gliomas are the most common and aggressive primary brain cancer of the central nervous system. Despite continued advances in multimodal therapy, the prognosis of gliomas remains poor. The main reasons for such poor outcomes are the heterogeneity and adaptability caused by the tumor microenvironment and glioma stem cells. It has been shown that TNC is present in the glioma microenvironment and glioma stem cell niches, and that it promotes malignant properties, such as neovascularization, proliferation, invasiveness, and immunomodulation. TNC is abundantly expressed in neural stem cell niches and plays a role in neurogenesis. Notably, there is increasing evidence showing that neural stem cells in the subventricular zone may be the cells of origin of gliomas. Here, we review the evidence regarding the role of TNC in glioma progression, propose a potential association between TNC and gliomagenesis, and summarize its clinical applications. Collectively, TNC is an appealing focus for advancing our understanding of gliomas.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a major cause of stroke that causes high rates of disability and mortality in adults. Tenascin C (TNC) protein, one of the matricellular proteins associated with platelet-derived growth factor receptor (PDGFR) activation, has been reported to induce neuronal apoptosis. However, the role and underlying mechanisms of TNC in ICH-induced secondary brain injury (SBI) have not yet been fully explained. The main purpose of this study was to explore the role of TNC and its potential mechanisms in ICH.
METHODS: An ICH model was established by injecting autologous blood into the right basal ganglia in male Sprague Dawley (SD) rats, and imatinib, an inhibitor of PDGFR, was used to inhibit the release of TNC.
RESULTS: We found that TNC protein was significantly increased in the brain tissues after ICH and expressed in both neurons and microglia. We also found that the TNC level was elevated in the cerebrospinal fluid (CSF) after ICH. Additionally, we observed that the infiltration of activated microglia and the release of TNFα and IL-1β induced by ICH were decreased after inhibition of the protein levels of TNC and cleaved-TNC by a chemical inhibitor (imatinib). Furthermore, imatinib improved neuronal cell death and neurobehavioral abnormalities induced by ICH.
CONCLUSIONS: In summary, our study revealed that TNC protein plays an important role in ICH-induced SBI, and inhibition of TNC could alleviate ICH-induced neuroinflammation, neuronal cell death, and neurobehaviour. Therefore, TNC may be a potential therapeutic target for ICH-induced SBI.

Tenascin C is a potential biomarker of cancer-associated fibroblasts and has been significantly associated with poor prognosis in patients with prostate cancer. However, the effects of Tenascin C in prostate cancer cell glycolysis largely remain unclear. Thus, this study aimed to investigate the Tenascin C expression in prostate cancer and its correlation to glycolysis-related protein and gene expression, clinicopathological parameters, and survival of patients.
We performed immunohistochemical staining for Tenascin C in 141 cases of primary prostate cancer. Based on public data sets, we explored the association of Tenascin C with angiogenesis-related genes, M2 macrophage-related gene, androgen receptor levels, PI3K/AKT/NF-κB pathway genes, and glycolytic enzyme expression. The glucose uptake, lactate production, and glycolytic enzyme levels were detected by glycolysis assay and western blotting.
Our results showed that Tenascin C expression is upregulated in prostate cancer tissues compared with benign prostatic hyperplasia tissues. High Tenascin C expression in prostate cancer cells was positively associated with lymph node metastasis, advanced clinical stage, the expression of CD105, CD206, and androgen receptor levels. The Kaplan-Meier curves showed a significant association of Tenascin C expression with the patient\'s overall survival. Tenascin C expression was positively associated with PI3K p85, pAKT-ser308, and NF-κB p65 protein expression in prostate cancer samples. Moreover, siRNA-mediated knockdown of Tenascin C expression inhibited cell glucose uptake, lactate production, and glycolytic-enzyme expression in prostate cancer cells in vitro.
Together, our findings suggest that Tenascin C is a prognostic marker for patients with prostate cancer and that its effects might be mediated via regulation of the glycolysis process of prostate cancer cells.

Gliomas are the most malignant and common tumors of the human brain, and the prognosis of glioma patients is extremely poor. MicroRNAs (miRNAs or miRs) play critical roles in different types of cancer by performing post‑transcriptional regulation of gene expression. Although miR‑218 has been demonstrated to be decreased in gliomas, its role in gliomas remains largely unknown. miR‑218 expression was analyzed in gliomas and normal brain tissues (control subjects) using a dataset from The Cancer Genome Atlas. A series of in vitro and in vivo studies were performed to determine the biological roles of miR‑218 in glioma cells. Potential targets of miR‑218 were identified using a dual‑luciferase reporter system. Western blot and dual‑luciferase reporter system experiments were performed to evaluate the regulatory effect of miR‑218 on the tenascin C (TNC)/AKT/activator protein 1 (AP‑1)/transforming growth factor β1 (TGFβ1) pathway. It was demonstrated that miR‑218 was significantly downregulated in gliomas compared with control subjects, and played potent tumor suppressor roles in glioma cells by inhibiting cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice, as well as inducing cell cycle arrest and apoptosis. Mechanistically, miR‑218 inhibited malignant phenotypes of glioma cells by binding to the 3\'‑untranslated region of its target TNC and subsequently suppressing its expression. As a result, miR‑218 could reduce AKT phosphorylation and subsequently inhibit transcriptional activity of AP‑1 by reducing JNK phosphorylation, downregulating the expression of TGFβ1, while TGFβ1 was able to, in turn, activate the TNC/AKT/AP‑1 signaling axis. Our data revealed a previously unknown tumor suppressor role of miR‑218 by blocking the TNC/AKT/AP‑1/TGFβ1‑positive feedback loop in glioma.

UNASSIGNED: Tissue remodeling caused by increased MMPs is involved in the pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP). We previously found higher levels of periostin and tenascin C in CRSwNPs, but whether they are associated with the dysregulation of MMPs is unknown. Therefore, the present study aimed to investigate the regulatory roles of these two ECM proteins in the expression of MMPs in nasal polyps.
UNASSIGNED: The concentrations of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, TIMP-1, TIMP-2, TIMP-3, TIMP-4, periostin, and tenascin C in tissue homogenates of 51 patients with chronic rhinosinusitis with and without nasal polyps and 15 control subjects were measured and were analyzed by adjusted logistic regression and spearman correlation test. Primary human nasal polyp fibroblasts and epithelial cells were stimulated ex vivo with periostin and tenascin C and the gene expression of MMPs and TIMPs was determined by means of real-time PCR.
UNASSIGNED: The protein levels of MMP-3, MMP-7, MMP-8, MMP-9, TIMP-1, TIMP-2, periostin, and tenascin C were significantly higher in patients with CRSwNPs than in healthy control subjects. The adjusted logistic regression analyses showed that MMP-3, MMP-7, MMP-8, MMP-9, TIMP-2, periostin, and tenascin C were related to the occurrence of CRSwNP. Spearman correlation test showed periostin was positively correlated with MMP-3 and TIMP-2, and tenascin C was positively correlated with MMP-3, MMP-7, MMP-8, MMP-9, and TIMP-2. Periostin stimulated the gene expression of MMP-3, MMP-7, MMP-8, and MMP-9 in fibroblasts and MMP-9 in epithelial cells ex vivo. Tenascin C stimulated the expression of MMP-3, MMP-7, MMP-8, and MMP-9 in epithelial cells. The expression of TIMPs in fibroblasts and epithelial cells was affected by neither periostin nor tenascin C.
UNASSIGNED: Periostin and tenascin C might be involved in the remodeling of nasal polyps by regulating the expression of different MMPs in epithelial cells and fibroblasts. Our findings have the potential to identify key factors of tissue remodeling in CRSwNPs.

This study was conducted to investigate the role of Tenascin-C (TNC) in paraquat (PQ)-induced lung injury in vivo and in vitro and explore its related mechanism during this process. Six- to eight-week-old male C57BL/6 mice were injected with 30 mg/kg PQ by intraperitoneal injection and sacrificed on 2 days, 7 days, 14 days, and 28 days after PQ administration. In vivo, we detected the expression of TNC at all time points of lung tissues in mice by reverse transcription-quantitative-polymerase chain reaction, western blotting, and immunohistochemistry. Expression of TLR4, NF-κB p65, TGF-β1, and α-SMA in lung tissues have also been tested. In vitro, siRNA was used to knock down TNC expression in A549 cells and TLR4, NF-κB p65, and TGF-β1 expressions were examined after PQ exposure. TNC expression increased in both lung tissues of mice model and A549 cells after PQ administration. In vivo, TNC mostly located at the extracellular matrix of thickened alveolar septum, especially at sites of injury, together with the increasing of TLR4, NF-κB p65, TGF-β1, and α-SMA. In vitro, PQ exposure also increased the expressions of TLR4, NF-κB p65, and TGF-β1 in A549 cells, but knocking down TNC gene expression obviously down-regulated the expressions of TLR4, NF-κB p65, NF-κB Pp65, and TGF-β1. The results of this study demonstrate, for the first time, that TNC participates in the development of lung injury induced by PQ poisoning. The role of TNC in this process is closely related to TLR4 and TGF-β signaling pathways.

The present study aimed to detect the effect of tenascin C (TNC) on cell function and chemosensitivity to paclitaxel and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling in glioma cells.Human glioma cells U87, LN-229, T98G and U251 and normal human astrocytes were obtained, in which TNC expression was detected. The U87 cells and U251 cells were chosen and infected with lentivirus of control overexpression, TNC overexpression, control knockdown, and TNC knockdown for functional experiments. Rescue experiments were then performed to evaluate the effect of PI3K/AKT activator 740 Y-P on cell function and chemosensitivity to paclitaxel in TNC knockdown U251 cells. TNC mRNA and protein expression was elevated in glioma cells, including U87, LN-229, U251 and T98G cells, compared to normal human astrocytes. In U87 and U251 cells, TNC promoted proliferation while inhibiting apoptosis. In addition, TNC upregulated PI3K and p-AKT protein expression in U87 and U251 cells. As for chemosensitivity, TNC increased relative viability in U251 cells treated with 400 ng/mL and 800 ng/mL paclitaxel. In terms of stemness, TNC increased the sphere number per 1000 cells, CD44+CD133+ cell percentage and 1/stem cell frequency (assessed by extreme limiting dilution analysis) in U251 cells. In rescue experiments, 740 Y-P reduced the effect of TNC on proliferation, apoptosis, chemosensitivity to paclitaxel, and stemness in U251 cells. TNC acts as an oncogenic factor by promoting cancer cell proliferation and stemness while inhibiting apoptosis and chemosensitivity to paclitaxel in glioma via modulation of PI3K/AKT signaling.