NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
نویسندگان
چکیده
The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres ('acini'), the malignant T4-2 cells that form large tumor-like clusters, and the 'phenotypically reverted' T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture.
منابع مشابه
Vitamin D and Training Modulates Gene Expression of TLR4 and NFkB in Lung Tissue of Obese Rats in an Experimental Study
Objective: Physical exercise has different effects on oxidative stress. Oxidative stress influences TLR4 and NFkB gene expression. The purpose of this study was to investigate the effect of aerobic training and vitamin D on gene expression of TLR4 and NFkB in lung tissue of obese rats exposed to oxygenated water. Materials and Methods: In an experimental study, 30 obese male wistar rats were r...
متن کاملProper integration time of polarization signals of internetwork regions using Sunrise/IMaX data
Distribution of magnetic fields in the quiet-Sun internetwork areas has been affected by weak polarization (in particular Stokes Q and U) signals. To improve the signal-to-noise ratio (SNR) of the weak polarization signals, several approaches, including temporal integrations, have been proposed in the literature. In this study, we aim to investigate a proper temporal-integration time with which...
متن کاملTumor resistance
It is suggested that evolution has equipped humans and other species with powerful and, largely non-immunological resistance mechanisms that can nip pre-neoplastic cells, as well as cells disseminating from established tumors in the bud. These mechanisms must operate while maintaining tissue structure, polarity and a large variety of cell-to-cell interactions. Altogether, they are essential for...
متن کاملThe integration of local chromatic motion signals is sensitive to contrast polarity.
Global motion integration mechanisms can utilize signals defined by purely chromatic information. Is global motion integration sensitive to the polarity of such color signals? To answer this question, we employed isoluminant random dot kinematograms (RDKs) that contain a single chromatic contrast polarity or two different polarities. Single-polarity RDKs consisted of local motion signals with e...
متن کاملThe transforming Rho family GTPase Wrch-1 disrupts epithelial cell tight junctions and epithelial morphogenesis.
Wrch-1, an atypical and transforming Rho GTPase, regulates cellular activities including proliferation and actin organization, but its functions and effectors remain poorly characterized. We show here that Wrch-1 distributes along the apical and basolateral membranes in MDCK cells and binds the cell polarity protein Par6 in a GTP-dependent manner. Activated Wrch-1 negatively regulates the kinet...
متن کامل