Les microARN sont de petits ARN non codant régulant post-transcriptionnellement l’expression de certains gènes. Du fait de leur fort potentiel régulateur, une modification de leur expression peut conduire à l’apparition de pathologies telles que le cancer ou l’inhibition des mécanismes de défense contre des pathogènes. Notre objectif est de caractériser le rôle de certains miARN dans la formation de cancer gastrique dû à Helicobacter pylori. En effet, cette bactérie peut conduire à l’apparition d’adénocarcinome gastrique et de lymphome du MALT. Sa virulence est essentiellement due à la protéine CagA, injectée dans les cellules de la muqueuse gastrique. Par séquençage à haut débit du contenu en miARN d’une lignée épithéliale gastrique humaine, co-cultivée ou non avec H. pylori, nous avons observé que les niveaux de miR-200b/c sont augmentés par l’infection. Ces miARN sont des inhibiteurs puissants de la transition épithélio-mésenchymateurse (TEM), modification morphologique promotrice d’invasion. Ils ciblent les facteurs de transcription ZEB1/2 avec lesquels ils sont impliqués dans une boucle de rétro-action mutuellement répressive. Le niveau basal élevé de miR-200b/c dans ces cellules réprime totalement ZEB1, tandis que l’infection par H. pylori, sous la dépendance de CagA, promeut une TEM en induisant ZEB1. Paradoxalement, les miR-200b/c sont aussi augmentés lors de l’infection transcriptionnellement. Nous avons pu démontrer que l’augmentation des miR-200b/c dans les cellules infectées a pour rôle de modérer l’induction de ZEB1 via l’activation de NF-kB, constituant ainsi un mécanisme de défense des cellules hôte contre la perte de leur identité épithéliale. / MicroRNA are small noncoding RNA that post-transcriptionally regulate gene expression. Due to their high regulator potential, a change in their expression may lead to the emergence of diseases such as cancer or inhibition of defense mechanisms against pathogens. Our aim is to characterize the role of miRNA in the response of gastric eptithelial cells to Helicobacter pylori (H. pylori). Indeed, H. pylori promote gastric adenocarcinoma and MALT lymphoma. Its virulence is essentially mediated by CagA, injected into cells of the gastric mucosa. Thanks to high throughput sequencing of miRNA content of a gastric epithelial cell line, infected or not with H. pylori: miR-200b and -200c appeared up-regulated upon infection. These miRNA are potent inhibitors of the “epithelial-to-mesenchymal transition” (EMT), a process that drastically alters cell morphology and promotes cell invasion. MiR-200b/c target the transcription factors ZEB1 and ZEB2, with which they are involved in a mutually repressive feedback loop. In basal conditions, the high levels miR-200b/c in gastric epithelial cells totally silence ZEB1 mRNA whereas H. pylori promotes EMT via ZEB1 expression, on the dependence of CagA translocation into host cells. But, paradoxically, miR-200b/c levels were also up-regulated upon infection. The increased miR-200b/c levels in infected cells moderate ZEB1 induction thanks to NF-kB activation and constitute a self-defense mechanism to thwart the loss of their epithelial phenotype upon infection.

Ovarian cancer results in more deaths per year than any other cancer of the female reproductive system. The low survival rate is partly due to the lack of early detection and the susceptibility to relapse. The AKT serine threonine kinase plays a pivotal role in hallmark cellular processes for the progression of ovarian cancer, including tumor cell growth and migration. Therapeutic targeting of pan-AKT has been problematic, in part due to feedback mechanisms and crosstalk with other pathways. The hypothesis for this study is that AKT 1, -2 and -3 isoforms may have different roles and regulate cell processes in uniquely varied ways. A transgenic mouse model that expresses the SV40 T-antigen viral oncogene and is known to have dramatically increased susceptibility to ovarian cancer was utilized, and it had genetic inactivation of either AKT1 or AKT2 through targeted deletion of the individual genes because these isoforms have been implicated in this cancer. Primary ovarian tumor cell cultures were established and found to exhibit different morphology, proliferation and migration that may indicate a different role for the AKT1 and AKT2 isoforms in these contexts. Ovarian tumor cells with absence of AKT1 predominantly exhibited reduced cell migration when compared to cells with retention of AKT1 and absence of AKT2. Since AKT is known to be important for epithelial-mesenchymal transition (EMT), a process potentially associated with tumor cell metastasis, the expression of transcription factors implicated in EMT was assessed by real-time array analysis in ovarian tumor cells knocked-out for either AKT1 or AKT2. Twist1, one of the major players in EMT, was not detectable in the cells missing the AKT1 isoform. Results indicate an association of Twist1 with AKT1 in EMT and migration of ovarian tumors cells. This finding is significant because AKT2 has been implicated as the major player of cell migration in human breast cancer iv cells. Collectively, these findings support a tissue specific role of the AKT isoforms, and may provide insights regarding the most useful cell context in order to target components of the AKT signaling pathway indirectly affecting EMT in order to prevent tumor progression in patients with ovarian and perhaps other types of cancers

The focus of this dissertation is analyzing and manipulating acoustic wave propagation in metamaterials, which can be used to assist the design of acoustic devices. Metamaterials are artificial materials, which are arranged in certain patterns at a scale smaller than the wavelength and can exhibit properties beyond those naturally occurring materials. With metamaterials, novel phenomena, such as focusing, super absorption, cloaking and localization of ultrasound, are theoretically proposed and experimentally verified. In recent years, a planar version of metamaterials, often called meta-surfaces, has attracted a great deal of attention. Meta-surfaces can control and manipulate the amplitude, phase, and directions of waves. In this dissertation, we conducted a systematic study by deriving the effective medium theories (EMTs), and developing the theoretical and numerical models for our proposed designed metamaterial. Very recently, acoustic meta-surfaces have been used in the design of acoustic lenses, which can achieve various functionalities such as focusing and collimation. In the designs of acoustic lenses, impedance is an important issue because it is usually difficult to make the impedance of the lens equal to that of the environment, and mismatched impedance is detrimental to the performance of the acoustic lens. We developed an EMT based on a coupled-mode theory and transfer matrix method to characterize the propagation behavior and, based on these models, we report two designs of acoustic lenses in water and air, respectively. They are rigid thin plates decorated with periodically distributed sub-wavelength slits. The building block of the acoustic lens in water is constructed from coiling-up spaces, and that of the acoustic lens in air is made of layered structures. We demonstrate that the impedances of the lenses are indeed matched to those of the background media. With these impedance-matched acoustic lenses, we demonstrate acoustic focusing and collimation, and redirection of transmitted acoustic energy by finite-element simulations. In the framework of the hidden source of the volume principle, an EMT for a coupled resonator structure is derived, which shows that coupled resonators are characterized by a negative value of the effective bulk modulus near the resonance frequency and induce flat bands that give rise to the confinement of the incoming wave inside the resonators. The leakage of sound waves in a resonance-based rainbow trapping device prevents the sound wave from being trapped at a specific location. Based on our EMT, we report a sound trapping device design based on coupled Helmholtz resonators, loaded to an air waveguide, to effectively tackle the wave leakage issue. We show that a coupled resonators structure can generate dips in the transmission spectrum by an analytical model derived from Newton’s second law and a numerical analysis based on the finite-element method. We compute the transmission spectra and band diagram from the effective medium theory, which are consistent with the simulation results. Trapping and the high absorption of sound wave energy are demonstrated with our designed device.

No description available.

No description available.

No description available.

No description available.

No description available.

No / Breast cancer is one of the most prevalent malignancies worldwide. It consists of a group of tumor cells that have the ability to grow uncontrollably, overcome replicative senescence (tumor progression) and metastasize within the body. Metastases are processes that consist of an array of complex gene dysregulation events. Although these processes are still not fully understood, the dysregulation of a number of key proteins must take place if the tumor cells are to disseminate and metastasize. It is now widely accepted that future effective and innovative treatments of cancer metastasis will have to encompass all the major components of malignant transformation. For this reason, much research is now being carried out into the mechanisms that govern the malignant transformation processes. Recent research has identified key genes involved in the development of metastases, as well as their mechanisms of action. A detailed understanding of the encoded proteins and their interrelationship generates the possibility of developing novel therapeutic approaches. This review will focus on a select group of proteins, often deregulated in breast cancer metastasis, which have shown therapeutic promise, notably, EMT, E-cadherin, Osteopontin, PEA3, Transforming Growth Factor Beta (TGF-β) and Ran.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25194号 / 医博第5080号 / 新制||医||1072(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 藤田 恭之, 教授 小濱 和貴, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM