IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway.

Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer.In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF-I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 upregulation required the activation of the PI3K/AKT pathway while the ERK1/2, the p70/mTOR and the PKC pathways were not involved. Moreover, we observed that DDR1 protein upregulation was induced by translational mechanisms involving miR-199a-5p suppression through PI3K/AKT activation. This effect was confirmed by both IGF-II produced by cancer-associated fibroblasts from human breast cancer and by stable transfection of breast cancer cells with a human IGF-II expression construct. Transfection with a constitutively active form of AKT was sufficient to decrease miR-199a-5p and upregulate DDR1. Accordingly, IGF-I-induced DDR1 upregulation was inhibited by transfection with pre-miR-199a-5p, which also impaired AKT activation and cell migration and proliferation in response to IGF-I.These results demonstrate that, in breast cancer cells, a novel pathway involving AKT/miR-199a-5p/DDR1 plays a role in modulating IGFs biological responses. Therefore, this signaling pathway may represent an important target for breast cancers with over-activation of the IGF-IR axis

Identification of Gene Networks and Pathways Associated with Guillain-Barré Syndrome

BACKGROUND: The underlying change of gene network expression of Guillain-Barré syndrome (GBS) remains elusive. We sought to identify GBS-associated gene networks and signaling pathways by analyzing the transcriptional profile of leukocytes in the patients with GBS. METHODS AND FINDINGS: Quantitative global gene expression microarray analysis of peripheral blood leukocytes was performed on 7 patients with GBS and 7 healthy controls. Gene expression profiles were compared between patients and controls after standardization. The set of genes that significantly correlated with GBS was further analyzed by Ingenuity Pathways Analyses. 256 genes and 18 gene networks were significantly associated with GBS (fold change ≥2, P<0.05). FOS, PTGS2, HMGB2 and MMP9 are the top four of 246 significantly up-regulated genes. The most significant disease and altered biological function genes associated with GBS were those involved in inflammatory response, infectious disease, and respiratory disease. Cell death, cellular development and cellular movement were the top significant molecular and cellular functions involved in GBS. Hematological system development and function, immune cell trafficking and organismal survival were the most significant GBS-associated function in physiological development and system category. Several hub genes, such as MMP9, PTGS2 and CREB1 were identified in the associated gene networks. Canonical pathway analysis showed that GnRH, corticotrophin-releasing hormone and ERK/MAPK signaling were the most significant pathways in the up-regulated gene set in GBS. CONCLUSIONS: This study reveals the gene networks and canonical pathways associated with GBS. These data provide not only networks between the genes for understanding the pathogenic properties of GBS but also map significant pathways for the future development of novel therapeutic strategies

Acute Symptomatic Sinus Bradycardia in High-Dose Methylprednisolone Therapy in a Woman With Inflammatory Myelitis: A Case Report and Review of the Literature

High dose corticosteroid therapy is widely used as attack therapy of inflammatory central nervous system disorders and can induce several adverse reactions. Bradycardia is an infrequent event after corticosteroids administration and is often asymptomatic. We report a case of a woman admitted to the neurological department of our hospital for paraesthesias of the lower limbs. She received adiagnosis of inflammatory myelitis and high dose corticosteroid therapy was prescribed. During the therapy she complained of chest tightness, dyspnoea, weakness and malaise. An electrocardiogram revealed sinus bradycardia. A significant increase in body weight, probably due to plasma volume expansion, was detected. Bradycardia and high blood pressure spontaneously resolved in few days. We provide a collection and a statistical analysis of literature data about steroid induced bradycardia. We found that higher total doses are associated with lower pulse rate and symptomatic bradycardia. Bradycardia is more frequent in older patients and those with underlying cardiac disease or with autonomic disturbance. However clinicians must be aware about the occurrence of symptomatic bradycardia in all patients who undergo high dose corticosteroid therapy, not only in those at risk, to early detect and treat this potentially dangerous condition