Metformin, an ancient drug commonly used for treating type II diabetes, has been associated to anti-cancer capacity in a variety of developing cancers, though the mechanism remains elusive. Here, we aimed to examine the inhibitory effect of metformin in osteosarcoma. Herein, we demonstrated that metformin treatment blocked proliferation progression by causing accumulation of G2/M phase in U2OS and 143B cells. Furthermore, metformin treatment triggered programmed cell death process in osteosarcoma cell lines. Further research indicated the induction of apoptosis and autophagy triggered by metformin could remarkably attenuate after the treatment of ROS scavenger NAC and JNK inhibitor SP600125. Additionally, our results showed that NAC-suppressed JNK/c-Jun signaling pathway could have been activated through metformin treatment. Lastly, metformin could inhibit osteosarcoma growth under safe dose in vivo. Thus, we propose that metformin could induce cell cycle arrest as well as programmed cell death, including apoptosis and autophagy, through ROS-dependent JNK/c-Jun cascade in human osteosarcoma. This metformin-induced pathway provides further insights into its antitumor potential molecular mechanism and illuminates potential cancer targets for osteosarcoma.
BackgroundThe aim of this study was to compare the microbiota community structure, assess differences in intestinal bacterial types, and identify metagenomic biomarkers for disparate stages of colorectal cancer formation.Material/MethodsA total of 160 individuals were recruited: 61 cases with non-tumor colon were regarded as the normal group, 47 cases with histology-substantiated colorectal adenomas were regarded as the adenoma group, and 52 cases with invasive adenocarcinomas were regarded as the cancer group. Biopsy on the mucosa was performed on each subject. USEARCH was used to process the sequences data and generate OTUs. Gut mucosal microbiota from healthy controls, adenoma patients, and carcinoma patients were analyzed.ResultsPrincipal coordinate analysis of unweighted and weighted UniFrac distance showed a separation in composition of microbiota in the 3 groups. Bacteria with potential tumorigenesis, like Bacteroides fragilis and Fusobacterium, were more common in the carcinoma group, while some SCFA (short chain fatty acids) – producing microbes were enriched in the normal group. The commensal Escherichia were more abundant in adenoma patients.ConclusionsOur study provides insights into possible function of gut microbiota in diagnosis and treatment of colorectal cancer. Some bacteria, such as Butyricicoccus, E. coli, and Fusobacterium, can be used as potential biomarkers for normal, adenoma, and cancer groups, respectively.
Expression of bacterial type II toxin-antitoxin (TA) systems is regulated at the transcriptional level through direct binding of the antitoxin to pseudo-palindromic sequences on operator DNA. In this context, the toxin functions as a co-repressor by stimulating DNA binding through direct interaction with the antitoxin. Here, we determine crystal structures of the complete 90 kDa heterooctameric VapBC1 complex from Caulobacter crescentus CB15 both in isolation and bound to its cognate DNA operator sequence at 1.6 and 2.7 Å resolution, respectively. DNA binding is associated with a dramatic architectural rearrangement of conserved TA interactions in which C-terminal extended structures of the antitoxin VapB1 swap positions to interlock the complex in the DNA-bound state. We further show that a pseudo-palindromic protein sequence in the antitoxin is responsible for this interaction and required for binding and inactivation of the VapC1 toxin dimer. Sequence analysis of 4127 orthologous VapB sequences reveals that such palindromic protein sequences are widespread and unique to bacterial and archaeal VapB antitoxins suggesting a general principle governing regulation of VapBC TA systems. Finally, a structure of C-terminally truncated VapB1 bound to VapC1 reveals discrete states of the TA interaction that suggest a structural basis for toxin activation in vivo.
Study Design. Retrospective survival analysis of 44 undifferentiated high grade pleomorphic sarcoma (UPS) of the spine. Objective. To identify factors related to overall survival (OS) and help decision making in the treatment of undifferentiated high grade pleomorphic sarcoma of the spine. Summary of Background Data. UPS is an aggressive malignant tumor rarely originating from the spine. Due to its scarcity, only a few studies had been reported to describe the clinical features, treatments, and outcomes of sporadic cases, devoid of evaluation on prognostic factors. Methods. Enrolled in this survival analysis were 44 patients who underwent surgery and adjuvant therapies from January 1999 to December 2015. Kaplan–Meier methods were applied to estimate the overall survival. A multivariate Cox algorithm was applied to recognize factors independently associated with overall survival. Results. Multivariate analysis suggested that age greater than or equal to 55 years (hazard ratio [HR], 3.923, P < 0.001), Eastern Cooperative Oncology Group (ECOG) score four (HR, 4.656, P < 0.001), and subtotal resection or piecemeal total resection (HR, 4.375, P < 0.001) were independently associated with poor overall survival. Conclusion. We identified independent prognostic factors of UPS of the spine. Subtotal resection or piecemeal total resection, age more than or equal to 55 years and ECOG score four are factors adversely affecting overall survival of patients with UPS of the spine. Level of Evidence: 4
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