HuRdling Senescence: HuR Breaks BRAF-Induced Senescence in Melanocytes and Supports Melanoma Growth

n addition to genetic changes, post-transcriptional events strongly contribute to the progression of malignant tumors. The RNA-binding protein HuR (ELAVL1) is able to bind and stabilize a large group of target mRNAs, which contain AU-rich elements (ARE) in their 3′-untranslated region. We found HuR to be upregulated in malignant melanoma in vitro and in vivo, significantly correlating with progression in vivo. Additionally, we could show that miR-194-5p can regulate HuR expression level. HuR knockdown in melanoma cells led to the suppression of proliferation and the induction of cellular senescence. Interestingly, HuR overexpression was sufficient to inhibit senescence in BRAFV600E-expressing melanocytes and to force their growth. Here, MITF (Microphthalmia-associated transcription factor), a key player in suppressing senescence and an ARE containing transcript, is positively regulated by HuR. Our results show for the first time that the overexpression of HuR is an important part of the regulatory pathway in the development of malignant melanoma and functions as a switch to overcome oncogene-induced senescence and to support melanoma formation. These newly defined alterations may provide possibilities for innovative therapeutic approaches

Properties of InGaAs/InP thermoelectric and surface bulk micromachined infrared sensors

We present a concept for the realization of InGaAs/InP micromachined thermoelectric sensors. The advantages of InGaAs lattice matched to InP combine perfectly for this application. The high selectivity of wet chemical etching of InP against InGaAs is ideally suited for surface bulk micromachining. Thermoelectric InGaAs sensors profit from the high thermal resistivity combined with high electrical conductivity and Seebeck effect. Thanks to the material parameters a responsivity of 257 V/W and relative detectivity of 6.4×108 cm Hz−1/2/W are expected for infrared sensors. © 1996 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70119/2/APPLAB-69-20-3039-1.pd

Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma

High malignancy and early metastasis are hallmarks of melanoma. Here, we report that the transcription factor Snail1 inhibits expression of the tumor suppressor CYLD in melanoma. As a direct consequence of CYLD repression, the protooncogene BCL-3 translocates into the nucleus and activates Cyclin D1 and N-cadherin promoters, resulting in proliferation and invasion of melanoma cells. Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo. Analysis of a tissue microarray with primary melanomas from patients revealed an inverse correlation of Snail1 induction and loss of CYLD expression. Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression. Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy

Complex Formation with Monomeric α-Tubulin and Importin 13 Fosters c-Jun Protein Stability and Is Required for c-Jun’s Nuclear Translocation and Activity

Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers. They are essential for a number of cellular processes, including intracellular trafficking and mitosis. Tubulin-binding chemotherapeutics are used to treat different types of tumors, including malignant melanoma. The transcription factor c-Jun is a central driver of melanoma development and progression. Here, we identify the microtubule network as a main regulator of c-Jun activity. Monomeric α-tubulin fosters c-Jun protein stability by protein–protein interaction. In addition, this complex formation is necessary for c-Jun’s nuclear localization sequence binding to importin 13, and consequent nuclear import and activity of c-Jun. A reduction in monomeric α-tubulin levels by treatment with the chemotherapeutic paclitaxel resulted in a decline in the nuclear accumulation of c-Jun in melanoma cells in an experimental murine model and in patients’ tissues. These findings add important knowledge to the mechanism of the action of microtubule-targeting drugs and indicate the newly discovered regulation of c-Jun by the microtubule cytoskeleton as a novel therapeutic target for melanoma and potentially also other types of cancer

Impedimetric array in polymer microfluidic cartridge for low cost point-of-care diagnostics

International audienc

Regulation of E-cadherin and Β-catenin by Ca 2+ in colon carcinoma is dependent on calcium-sensing receptor expression and function

An siRNA directed against the extracellular calcium-sensing receptor (CaSR) was used to down-regulate this protein in CBS colon carcinoma cells. In additional studies, we utilized a variant of the parental CBS line that demonstrates CaSR expression but does not upregulate this protein in response to extracellular Ca 2+ . In neither the siRNA-transfected cells nor the Ca 2+ -nonresponsive variant cells did inclusion of Ca 2+ in the culture medium inhibit proliferation or induce morphological alterations. Extracellular Ca 2+ also failed to induce E-cadherin production or a shift in Β-catenin from the cytoplasm to the cell membrane. In mock-transfected cells and in a Ca 2+ -responsive variant line derived from the same parental CBS cells, Ca 2+ treatment resulted in growth-reduction. This was accompanied by increased E-cadherin production and a shift in Β-catenin distribution from the cytoplasm to the cell membrane. Additionally, down-regulation of c-myc and cyclin D1 expression was observed in mock-transfected cells and in the Ca 2+ -responsive variant line (along with reduced T cell factor transcriptional activation). Neither c-myc nor cyclin D1 was significantly down-regulated in the siRNA-transfected cells or in the Ca 2+ -nonresponsive variant cells upon Ca 2+ stimulation. In histological sections of human colon carcinoma CaSR was significantly reduced as compared to the level in normal colonic crypt epithelial cells. Where CaSR expression was high, strong surface staining for E-cadherin and Β-catenin was observed. Where CaSR expression was reduced, Β-catenin surface expression was likewise reduced. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56113/1/22858_ftp.pd

Prescription of physical exercise in Crohn's disease

AbstractBackgroundPhysical exercise may be potentially beneficial for recovering physical condition and improving quality of life in populations suffering from chronic conditions, but little is known about its effects on patients suffering from Crohn's disease.AimsTo provide reasonable and conservative recommendations for exercise regimens that appear clinically safe and feasible in patients suffering from Crohn's disease.MethodsRelevant clinical studies about the effects of physical exercise on Crohn's disease, written in English language and carried out with human subjects were reviewed.ResultsFew relevant clinical studies have evaluated the effects of an exercise intervention on patients experiencing Crohn's disease. There seem to be two main types of physical interventions that should be recommended: aerobic activity and muscular resistance training.ConclusionsSome basic guidelines about how to prescribe physical exercise in Crohn's disease can be provided. However, more research is needed as few studies have been carried out so far

Cilengitide down-modulates invasiveness and vasculogenic mimicry of neuropilin-1 expressing melanoma cells through the inhibition of αvβ5 integrin.

During melanoma progression, tumour cells show increased adhesiveness to the vascular wall, invade the extracellular matrix (ECM) and frequently form functional channels similar to vascular vessels (vasculogenic mimicry). These properties are mainly mediated by the interaction of integrins with ECM components. Since we had previously identified neuropilin 1 (NRP-1), a coreceptor of vascular endothelial growth factor A (VEGF-A), as an important determinant of melanoma aggressiveness, aims of this study were to identify the specific integrins involved in the highly invasive phenotype of NRP-1 expressing cells and to investigate their role as targets to counteract melanoma progression. Melanoma aggressiveness was evaluated in vitro as cell ability to migrate through an ECM layer and to form tubule-like structures using transfected cells. Integrins relevant to these processes were identified using specific blocking antibodies. The αvβ5 integrin was found to be responsible for about 80% of the capability of NRP-1 expressing cells to adhere on vitronectin. In these cells αvβ5 expression level was twice higher than in low-invasive control cells and contributed to the ability of melanoma cells to form tubule-like structures on matrigel. Cilengitide, a potent inhibitor of αν integrins activation, reduced ECM invasion, vasculogenic mimicry and secretion of VEGF-A and metalloproteinase 9 by melanoma cells. In conclusion, we demonstrated that ανβ5 integrin is involved in the highly aggressive phenotype of melanoma cells expressing NRP-1. Moreover, we identified a novel mechanism that contributes to the antimelanoma activity of the αv integrin inhibitor cilengitide based on the inhibition of vasculogenic mimicry

Colorectal Cancer Metastases Settle in the Hepatic Microenvironment Through \u3b15\u3b21 Integrin

Colorectal cancer (CRC) metastasis dissemination to secondary sites represents the critical point for the patient0s survival. The microenvironment is crucial to cancer progression, influencing tumour cell behaviour by modulating the expression and activation of molecules such as integrins, the cell-extracellular matrix interacting proteins participating in different steps of the tumour metastatic process. In this work, we investigated the role of a5b1 integrin and how the microenvironment influences this adhesion molecule, in a model of colon cancer progression to the liver. The culture medium conditioned by the IHH hepatic cell line, and the extracellular matrix (ECM) proteins, modulate the activation of a5b1 integrin in the colon cancer cell line HCT-116, and drives FAK phosphorylation during the process of cell adhesion to fibronectin, one of the main components of liver ECM. In these conditions, a5b1 modulates the expression/activity of another integrin, a2b1, involved in the cell adhesion to collagen I. These results suggest that a5b1 integrin holds a leading role in HCT-116 colorectal cancer cells adhesion to the ECM through the modulation of the intracellular focal adhesion kinase FAK and the a2b1 integrin activity. The driving role of the tumour microenvironment on CRC dissemination, here detected, and described, strengthens and adds new value to the concept that a5b1 integrin can be an appropriate and relevant therapeutic target for the control of CRC metastases