Oncogenic role of EAPII in lung cancer development and its activation of the MAPK–ERK pathway

Cancer progression involves multiple complex and interdependent steps, including progressive proliferation, angiogenesis and metastases. The complexity of these processes requires a comprehensive elucidation of the integrated signaling networks for better understanding. EAPII interacts with multiple cancer-related proteins, but its biological significance in cancer development remains unknown. In this report we identified the elevated level of EAPII protein in non-small-cell lung carcinoma (NSCLC) patients and NSCLC cell lines in culture. The oncogenic role of EAPII in lung cancer development was demonstrated using NSCLC cells with genetic manipulations that influence EAPII expression: EAPII overexpression increases proliferation of NSCLC cells with an accelerated transition of cell cycle and facilitates xenograft tumor growth in vivo; EAPII knockdown results in apoptosis of NSCLC cells and reduces xenograft tumor formation. To further explore the mechanism of EAPII's oncogenic role in lung cancer development and to elucidate the potential signaling pathway(s) that EAPII may impact, we employed antibody array to investigate the alternation of the major signaling pathways in NSCLC cells with altered EAPII level. We found that EAPII overexpression significantly activated Raf1 and ERK1/2, but not c-Jun N-terminal kinase and p38 pathways. Consistently, the protein and mRNA levels of MYC and cyclin D1, which are targets of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK–ERK) pathway, are significantly increased by EAPII overexpression. Taken together, we demonstrated that EAPII is an oncogenic factor and the activation of MAPK–ERK signaling pathway by EAPII may contribute to lung cancer development

Use of wearable inertial sensor in the assessment of Timed-Up-and-Go Test: Influence of device placement on temporal variable estimation

The \u201cTimed Up and Go\u201d (TUG) test is widely used in various disorders to evaluate subject\u2019s mobility, usually evaluating only time execution. TUG test specificity could be improved by using instrumented assessment based on inertial sensors. Position of the sensor is critical. This study aimed to assess the reliability and validity of an inertial sensor placed in three different positions to correctly segment the different phases in the TUG test. Finding demonstrated good reliability of the proposed methodology compared to the gold standard motion analysis approach based on surface markers and an optoelectronic system. Placing the sensor just beneath the lumbar-sacral joint reported the lower values of deviation with respect to the gold standard. Optimized position can extend the proposed methodology from the clinical context towards ubiquitous solutions in an ecological approach

A rapid and sensitive bioassay for the simultaneous measurement of multiple bone morphogenetic proteins.:Identification and quantification of BMP4, BMP6 and BMP9 in bovine and human serum

<p>Abstract</p> <p>Background</p> <p>Bone morphogenetic proteins (BMPs) are pleiotropic members of the TGF-beta superfamily which regulate many biological processes during development and adult tissue homeostasis and are implicated in the pathogenesis of a number of human diseases. Their involvement in both normal and aberrant physiology creates a need for rapid, sensitive and methodologically simple assays to evaluate their activity from a variety of biological samples. Previously alkaline phosphatase based assays, ELISA and luciferase based bioassays have been developed to evaluate either individual or total BMP activity. In this paper, we describe a highly sensitive, rapid and specific cell based assay for the simultaneous quantification of total and isoform specific BMP activity from biological samples.</p> <p>Results</p> <p>A C2C12 cell line stably transfected with a reporter plasmid consisting of the BMP response element (BRE) from the Id1 promoter fused to a luciferase reporter gene was generated. Exposure of this cell line to human recombinant BMP2, BMP4, BMP6, BMP7, BMP9 and BMP10 induced the expression of luciferase which was quantified using a luminometer. This assay was specific for BMP activity as the other TGF-β superfamily members TGF-β 1, Nodal and Mullerian Inhibiting Substance (MIS) did not induce the reporter. Pretreatment of samples with isoform specific BMP blocking antibodies coupled with isoform specific titration analysis allowed the simultaneous identification and quantification of BMP4, BMP6 and BMP9 in serum samples.</p> <p>Conclusion</p> <p>The assay is rapid (<48 hours) and can be used to simultaneously measure isoform specific and total BMP activity in complex solutions.</p

Bone morphogenetic protein modulator BMPER is highly expressed in malignant tumors and controls invasive cell behavior

Bone morphogenetic proteins (BMPs) are growth factors that exert important functions in cell proliferation, migration and differentiation. Till date, multiple human tumors have been reported to display a dysregulation of several members of the BMP pathway that is associated with enhanced malignant tumor growth and metastasis. BMPER (BMP endothelial cell precursor-derived regulator) is a direct BMP modulator that is necessary for BMPs to exert their full-range signaling activity. Moreover, BMPER is expressed by endothelial cells and their progenitors, and has pro-angiogenic features in these cells. Here, we describe the expression of BMPER in human specimens of lung, colon and cervix carcinomas and cell lines derived from such carcinomas. In contrast to healthy tissues, BMPER is highly expressed upon malignant deterioration. Functionally, loss of BMPER in the lung tumor cell line A549 impairs proliferation, migration, invasion as well as tumor cell-induced endothelial cell sprout formation. In contrast, stimulation of A549 cells with exogenous BMPER had no further effect. We found that the BMPER effect may be transduced by regulation of the BMP target transcription factor inhibitor of DNA binding 1 (Id1) and matrix metalloproteinases (MMPs) 9 and 2. These facilitators of cell migration are down-regulated when BMPER is absent. To prove the relevance of our in vitro results in vivo, we generated Lewis lung carcinoma cells with impaired BMPER expression and implanted them into the lungs of C57BL/6 mice. In this model, the absence of BMPER resulted in severely reduced tumor growth and tumor angiogenesis. Taken together, these data unequivocally demonstrate that the BMP modulator BMPER is highly expressed in malignant tumors and tumor growth is dependent on the presence of BMPER