Metformin reduces SATB2-mediated osteosarcoma stem cell-like phenotype and tumor growth via inhibition of N-cadherin/NF-kB signaling.

OBJECTIVE: To investigate the role of SATB2 in stem cell-like properties of osteosarcoma and identify new strategies to eliminate cancer stem cells of osteosarcoma. MATERIALS AND METHODS: Osteosarcoma cancer stem cells were derived by sarcosphere generation or chemo drug enrichment. SATB2 and pluripotency-associated gene expression in osteosarcoma CSCs were analyzed using qRT-PCR and Western blotting. The sphere formation assay, cell counting kit-8 assay and anti-chemotherapy proteins were used to measure the effects of altered SATB2, N-cadherin expression or metformin treatment in CSCs. Nude mice were injected with SATB2-deficient U2OS/MTX cells to assess the role of SATB2 in osteosarcoma growth and chemoresistance in vivo. Bioinformatics analyses were performed to identify SATB2 downstream target genes and immunochemistry to determine the correlation between SATB2 expression and patient outcome. Western blotting and luciferase reporter assays were used to examine the effects of N-cadherin and SATB2 inhibition on the NF-kB pathway. RESULTS: SATB2 was upregulated in osteosarcoma stem cells. Knockdown of SATB2 decreased sarcosphere formation, cell proliferation and stem cell-like gene expression in vitro, meanwhile reduced tumor growth and chemoresistance in vivo. High SATB2 expression in osteosarcoma patient samples was associated with poor clinical outcome. N-cadherin was one critical downstream target gene of SATB2 that mediated the stem cell-like phenotype. Reduction of SATB2 or N-cadherin resulted in NF-kB inactivation, which led to impaired osteosarcoma sphere formation and tumor cell proliferation. Metformin treatment of osteosarcoma cells enhanced the effects of chemotherapy via suppression of N-cadherin. CONCLUSIONS: SATB2 plays an important role in regulating osteosarcoma stem cell-like properties and tumor growth. The combination of conventional chemotherapy and metformin may be a promising therapeutic strategy for osteosarcoma patients.

Serum uric acid and non-alcoholic fatty liver disease in non-hypertensive Chinese adults: the Cardiometabolic Risk in Chinese (CRC) study.

OBJECTIVE: The causal relationship between serum uric acid (SUA) level and non-alcoholic fatty liver disease (NAFLD) has not yet been clarified. The objective of the study was to determine the association between SUA and NAFLD, as well as assess the interactions between SUA and other metabolic risk factors regarding NAFLD. PATIENTS AND METHODS: The study samples related to a community-based health examination survey conducted in Central China. Initially, a total of 24,878 patients with medical examination were included. After excluding the individuals with confounding factors, the remaining 21,798 subjects with biomarkers available were included in the present study. RESULTS: The data show that the risk of NAFLD significantly increased with the elevated SUA levels. Further adjustments for sex, age, and other confounding metabolic factors did not change the increasing trend of NAFLD risk. The odds ratios [ORs, 95% confidence interval (CI)] of NAFLD across the increasing quintiles of SUA were 1.00, 1,530 (1.174-1.995), 2.24 (1.714-2.886), 2.636 (2.019-3.441), and 3.714 (2.828-4.877) (p for trend < 0.0001). Also, significant interaction was found between SUA and prehypertension in relation to the NAFLD risk (p for interaction < 0.05). CONCLUSIONS: SUA was significantly associated with NAFLD risk, independent of other metabolic risk factors, and SUA also had significant interaction with prehypertension regarding the risk of NAFLD.

Metabolic signaling of insulin secretion by pancreatic ß-cell and its derangement in type 2 diabetes.

Pancreatic beta-cell is responsible for insulin secretion in response to the availability of nutrients. Type 2 diabetes mellitus (T2D) is the result of pancreatic b-cell failure to supply sufficient amount of insulin accompanied with decreased sensitivity of the body tissues to respond to insulin. The insulin secretion apparatus of beta-cell is uniquely equipped with multiple metabolic and signaling steps that are under rigorous control. The metabolic machinery of beta-cell is designed to sense the fluctuations in blood glucose level and supply insulin accordingly to the needs of body. Besides glucose, amino acids including glutamine and leucine and also fatty acids are known to either stimulate the beta-cell directly or potentiate the glucose stimulated insulin secretion (GSIS) response. Glucose metabolism dependent GSIS is linked with the production of ATP that is needed for K+ATP channel inhibition and influx of calcium, necessary for insulin granule exocytosis. Besides glucose metabolism, amino acid metabolism and lipid metabolism derived metabolites mediate the optimal glucose response of beta-cells to secrete insulin. Metabolites derived from nutrient secretagogues that directly or indirectly participate in the enhancement of GSIS are considered as metabolic coupling factors. In this review, we will discuss the regulation of insulin secretion by b-cell keeping the recent developments in metabolic signaling in focus. The relevant metabolic pathways in pancreatic beta-cell and their role in the control of fuel-stimulated insulin secretion will be reviewed to arrive at a consensus picture with respect to the metabolic signaling of insulin secretion.

Analysis of the efficacy and prognosis of limb-salvage surgery for osteosarcoma around the knee.

AIM: Limb-salvage surgery has become the standard of care for extremity osteosarcoma. In this study, we investigated the survival and functional outcomes of patients with osteosarcoma around the knee who were treated with limb-salvage surgery. METHODS: We retrospectively reviewed the clinical data for 120 patients with osteosarcoma around the knee who were treated with limb-salvage surgery between 1998 and 2008. The sample included 75 males and 45 females. The mean age of the patients was 18.9 years. Osteosarcoma was diagnosed in the distal femur in 78 patients and in the proximal tibia in 42 patients. Statistical analyses were conducted to process and record the patient data and analyse the surgery's efficacy, prognosis and survival rates. RESULTS: All patients were followed for 6-144 months (mean of 56.8 months). The overall 5-year survival rate was 61.8%. Lung metastasis developed in 31 patients. Local recurrence developed in 9 patients. The average Musculoskeletal Tumor Society Score (MSTS) was 25.5 points on a 30-point scale. Sixteen patients underwent prosthesis revision and twelve patients underwent amputation. The overall survivorship of the prosthesis based on Kaplan-Meier estimates was 77% at five years and 71% at ten years. There was a higher incidence of extensor lag for the patients with osteosarcoma in the proximal tibia than for those with osteosarcoma in the distal femur (P < 0.01). CONCLUSIONS: Treating osteosarcoma around the knee with limb-salvage surgery can preserve most of the knee's functionality. Attention must be paid to prevent the relatively high incidence of postoperative complications.