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.
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