Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Many patients suffer from bone metastasis. Sclerostin, a key regulator of normal bone remodeling, is critically involved in osteolytic bone diseases. However, its role in breast cancer bone metastasis remains unknown. Here, we found that sclerostin was overexpressed in breast cancer tumor tissues and cell lines. Inhibition of sclerostin by antibody (Scl-Ab) significantly reduced migration and invasion of MDA-MB-231 and MCF-7 cells in a time-and dose-dependent manner. In xenograft model, sclerostin inhibition improved survival of nude mice and prevented osteolytic lesions resulting from tumor metastasis. Taken together, sclerostin promotes breast cancer cell migration, invasion and bone osteolysis. Inhibition of sclerostin may serve as an efficient strategy for interventions against breast cancer bone metastasis or osteolytic bone diseases.Breast cancer is the second leading cause of cancer-related deaths among women worldwide. 75-80% of patients with advanced disease develop bone metastasis 1, 2 . As an end-stage complication of breast cancer, bone metastasis frequently leads to detrimental skeletal-related events associated with significant morbidity 3-5 . Since current treatment for bone metastasis has limited efficacy, development of an effective therapeutic strategy is urgently needed. To improve the prognosis of breast cancer bone metastasis (BCBM), molecular mechanisms involved in breast cancer proliferation, invasion, metastasis and osteolytic lesions should be further explored.Sclerostin, a key regulator of normal bone remodeling, inhibits bone formation through inhibition of Wnt signaling 6,7 . Recent studies have revealed a vital role of sclerostin in multiple myeloma with osteolytic bone lesions [8][9][10][11][12] . BCBM patients exhibit a high level of circulating sclerostin, which correlates with disease stage and fractures, however, the origin and impact of sclerostin on BCBM remains to be defined. Thus, the purpose of our study was to evaluate the expression level of sclerostin in tumor tissue derived from BCBM patients and explore its association with clinical outcome and tumor characteristics, including the presence of lytic bone disease.Activation of Wnt signaling pathway has been indicated to participate in both initiation and progression of cancer metastasis 13,14 . During multiple-steps of metastasis to bone, breast cancer cells successfully induce a sequence of changes, for instance, secreting cytokines to inhibit differentiation and maturation of osteoblasts whereas to enhance the activity of osteoclasts. As such, we hypothesized that decreased sclerostin would suppress osteolytic bone lesions and reduce tumor burden, which may represent a target for inhibiting cancer-induced bone diseases and facilitating restoration of normal bone homeostasis. ResultsSclerostin is up-regulated in tumor tissues derived from patients with BCBM. To assess the expression of sclerostin in BCBM, paraffin sections of tissu...

Lung cancer is the leading cause of cancer-related deaths worldwide, with 50-70% of patients suffering from bone metastasis. Accumulating evidence has demonstrated that miRNAs are involved in cell proliferation, migration, and invasion in malignancy, such as lung cancer bone metastasis. In the present study, we demonstrated that reduced miR-192-5p and increased TRIM44 levels were associated with the proliferation, migration and invasion of lung cancer. Furthermore, the potential functions of miR-192-5p were explored in A549 and NCI-H1299 cells. We found that miR-192-5p upregulation suppressed tumour behaviours in lung cancer cells. To further investigate whether miR-192-5p is associated with TRIM44, we used TargetScan software to predict the binding site between miR-192-5p and TRIM44. Luciferase activity assays were performed to verify this prediction. In addition, the significant role of miR-192-5p in negatively regulating TRIM44 expression was manifested by our research group. our results suggest that miR-192-5p inhibited the proliferation, migration and invasion of lung cancer through TRIM44.

BackgroundThe outcomes for open tibial fractures with severe soft tissue injury are still a great challenge for all the trauma surgeons in the treatment. However, most of the existing open tibial fracture models can only provide minimal soft tissue injury which cannot meet the requirement of severe trauma research. Our goal is to investigate a novel tibial fracture model providing different fractures combined with soft tissue injury for better application in trauma research.MethodsA total of 144 Sprague-Dawley rats were randomly divided into 4 groups. With group 1 as control, the other groups sustained different right tibial fractures by the apparatus with buffer disc settings either 3 mm, 10 mm, or 15 mm. X-ray and computed tomography angiography (CTA) were performed at 6 h to evaluate the fracture patterns and vascular injuries. Peripheral blood and tibialis anterior muscle were harvested at 6 h, 1 day, 3 days, 7 days, 14 days, and 28 days for ELISA and histological analysis.ResultsX-ray and μCT results indicated that different fractures combined with soft tissue injuries could be successfully provided in this model. According to OTA and Gustilo classification, the fractures and soft tissue injuries were evaluated and defined: 36 type I in group 2, 34 type II in group 3, and 36 type III in group 4. The CTA confirmed no arterial injuries in groups 1 and 2, 2 arterial injuries in group 3, and 35 in group 4. ELISA indicated that the levels of pro-inflammatory cytokines TNF-α and IL-1β were significantly higher in group 4 than in other groups, and the levels of anti-inflammatory cytokines TGF-β and IL-10 were significantly higher in surgery groups than in group 1 in later stage or throughout the entire process. HE, Masson, and caspase-3 stains confirmed the most severe inflammatory cell infiltration and apoptosis in group 4 which lasted longer than that in groups 2 and 3.ConclusionsThe novel apparatus was valuable in performing different fractures combined with soft tissue injuries in a rat tibial fracture model with high reproducibility and providing a new selection for trauma research in the future.

Skeletal muscle is capable of repairing itself after injury to maintain the stability of its own tissue, but this ability declines with aging. Circular RNAs (circRNAs) are involved in cell aging. However, there is little research into their role and underlying mechanisms, especially in skeletal muscle stem cells (SkMSCs). In this study, we assessed circRNA FUT10 expression in aged and adult SkMSCs. We observed that circRNA FUT10 was upregulated in aged SkMSCs compared with that in adult SkMSCs. Furthermore, we identified putative miR-365-3p binding sites on circRNA FUT10, suggesting that this circRNA sponges miR-365a-3p. We also found that HOXA9 is a downstream target of miR-365a-3p and confirmed that miR-365a-3p can bind to circRNA FUT10 and the 3′-untranslated region of HOXA9 mRNA. This finding indicated that miR-365a-3p might serve as a “bridge” between circRNA FUT10 and HOXA9. Finally, we found that the circRNA FUT10/miR365a-3p/HOXA9 axis is involved in SkMSC aging. Collectively, our results show that the circRNA FUT10/miR365a-3p/HOXA9 axis is a promising therapeutic target and are expected to facilitate the development of therapeutic strategies to improve the prognosis of degenerative muscle disease.

has been implicated in cell proliferation; however, its role in skeletal muscle stem cells (SkMScs) remains unknown. The present study aimed to explore the roles of mir-217-5p in the biological characteristics of SkMSCs. SkMSCs were identified by cell surface markers using flow cytometry. The present study observed that mir-217-5p mimics accelerated the proliferation and suppressed the differentiation in SkMScs. in addition, the results of the present study revealed that fibroblast growth factor receptor 2 (FGFr2) was a target of mir-217-5p, as mir-217-5p bound directly to the 3'-untranslated region of FGFr2 mrna, resulting in increased FGFr2 mrna and protein levels. in addition, the present study suppressed the expression of FGFr2 in SkMScs using a selective FGFr inhibitor AZD4547 and detected the efficiency of inhibition by reverse transcription-quantitative Pcr and western blotting. mir-217-5p levels were positively associated with FGFr2 expression, which was upregulated and accelerated the proliferation of SkMScs compared with that of the mir-nc group. collectively, these results demonstrated that mir-217-5p may act as a myogenesis promoter in SkMScs by directly targeting FGFr2 and may regulate the myogenesis of these cells.

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Background: The purpose of this study was to illustrate the characteristics of skeletal muscle ECM hydrogels and assess the function and underlying mechanisms of hydrogels combined with TGFβ1 for the myogenesis of skeletal muscle stem cells (SkMSCs). Methods: Six methods were used to obtain extracellular matrix (ECM) from rat skeletal muscle. Hydrogel components and cytocompatibility were assessed by Masson’s trichrome staining, scanning electron microscopy, the sulfated glycosaminoglycan (s-GAG) and bFGF contents and a cell viability assay. Satellite cells were sorted, identified and seeded into skeletal muscle ECM hydrogels with TGFβ1. To determine the function of decellularized aligned skeletal muscle ECM hydrogels with TGFβ1 for the proliferation and differentiation of SkMSCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-2′-deoxyuridine (EdU) analysis and immunofluorescence staining were conducted. RNA stability assay and Gene set enrichment analysis (GSEA) were used to further investigated the mechanism underlying the function. Results: Our study established a highly efficient method for the decellularization of skeletal muscle and fabricated an ECM hydrogel without cell components that preserves the rich ECM composition. This hydrogel formed a three-dimensional microstructure and showed good biocompatibility. We found that the decellularized aligned ECM scaffold with TGFβ1 promoted SkMSC proliferation and suppressed SkMSC differentiation through extracellular signal-regulated kinase (ERK) signaling. Our study suggested that TGFβ1 increases the m6A methylation of the integrin mRNA 3’UTR, thereby inducing the phosphorylation of ERK and promoting SkMSCs proliferation and differentiation.Conclusions: Our study explored a highly efficient method for the decellularization of skeletal muscle and fabricated an ECM hydrogel with a three-dimensional microstructure and good biocompatibility. Furthermore, we demonstrated that decellularized aligned ECM scaffolds with TGFβ1 promoted SkMSC proliferation and differentiation through enhancing the m6A methylation of the integrin mRNA 3’UTR, which may serve as a potential therapeutic strategy for the acute and chronic muscle injuries

BackgroundCircular RNAs (circRNAs) are involved in the occurrence and development of breast cancer bone metastasis. This study aims to identify whether the circRNA DENND4C/ miR145-5p/HOXA9 axis is involved in the regulation of cell invasion and migration and breast cancer progression.MethodscircRNA DENND4C, miR-145-5p and HOXA9 expression was measured in serum samples from healthy volunteers, breast cancer patients without bone metastasis and breast cancer patients with bone metastasis. Moreover, we analyzed the levels of circRNA DENND4C, miR‑145-5p and HOXA9 according to different conditions of differentiation, tumor volume and lymph node metastasis. The online software starBases and the dual-luciferase reporter gene assay were used to predict the relationship miR-145-5p, circRNA DENND4C and HOXA9 mRNA. MTT assays were performed to assess the effect of circRNA DENND4C on proliferation. To assess the proliferation of breast cancer cells among different groups. Statistical significance was determined byStudent's t‑test which was used for comparisons between two groups and one‑way analysis of variance followed by Tukey's post hoc test for comparisons between more than two groups.ResultsThe expression patterns of circRNA DENND4C, miR145-5p and HOXA9 were altered in patients with breast cancer bone metastasis. Notably, the stimulatory effects of circRNA DENND4C overexpression on HOXA9 were eliminated by miR-145-5p upregulation. circRNA DENND4C overexpression promotes proliferation, migration and invasiveness by regulating the miR-145-5p/HOXA9 axis. circRNA DENND4C downregulation suppresses proliferation, cell viability and invasiveness by regulating the miR-145-5p/HOXA9 axis. ConclusionOur study suggest that circRNA DENND4C/miR-145-5p/HOXA9 pathway was involved in tumor growth and bone metastasis in breast cancer. This findings may facilitate the development of potential therapeutic agents to improve the prognosis of patients with breast cancer bone metastasis.