Epigenetic silencing of miR-520c leads to induced S100A4 expression and its mediated colorectal cancer progression

The S100 calcium-binding protein A4 (S100A4) induces epithelial mesenchymal transition, migration, invasion, angiogenesis and metastasis. Its induced expression in several cancer types correlates with poor prognosis. Apart from the functional and transcriptional regulatory aspects of S100A4, its post-transcriptional regulation is not yet clearly elucidated. In this study, we show that microRNAs (miR) miR-505-5p and miR-520c-3p target the 3'-UTR of S100A4 and inhibits its expression and its mediated migration and invasion. 5-Aza treatment significantly increased miR-520c-3p expression and reduced the S100A4 protein amounts. The upstream promoter region of miR-520c is hypermethylated irrespective of the metastasis status of colorectal cancer (CRC) patient tissues and in all analyzed CRC cell lines. Moreover, in a cohort of CRC patient specimen (n = 59), miR-520c-3p was significantly downregulated. miR-520c-3p stably expressing HCT116 cells showed a reduced metastasis formation in livers after implanting in mice spleen. Taken together, our findings demonstrate that S100A4 is post-transcriptionally regulated by tumor suppressor miRs, miR-505c-5p and miR-520c-3p, and particularly miR-520c-3p expression is epigenetically silenced in CRC

MACC1 is post-transcriptionally regulated by miR-218 in colorectal cancer

Metastasis is a multistep molecular network process, which is lethal for more than 90% of the cancer patients. Understanding the regulatory functions of metastasis-inducing molecules is in high demand for improved therapeutic cancer approaches. Thus, we studied the post-transcriptional regulation of the crucial carcinogenic and metastasis-mediating molecule metastasis associated in colon cancer 1 (MACC1). In silico analysis revealed MACC1 as a potential target of miR-218, a tumor suppressor miRNA. Expression of these two molecules inversely correlated in colorectal cancer (CRC) cell lines. In a cohort of CRC patient tissues (n = 59), miR-218 is significantly downregulated and MACC1 is upregulated compared with normal mucosa. Luciferase reporter assays with a construct of the MACC1-3'-UTR harboring either the wild type or the mutated miR-218 seed sequence confirmed the specificity of the targeting. miR-218 inhibited significantly MACC1 protein expression, and consistently, MACC1-mediated migration, invasion and colony formation in CRC cells. Anti-miR-218 enhanced the MACC1-mediated migration, invasion and colony formation. Similar findings were observed in the gastric cancer cell line MKN-45. Further, we performed methylation-specific PCR of the SLIT2 and SLIT3 promoter, where miR-218 is encoded in intronic regions. The SLIT2 and SLIT3 promoters are hypermethylated in CRC cell lines. miR-218 and SLIT2 expressions correlated positively. Methyltransferase inhibitor 5-Azacytidine induced miR-218 expression and inhibited the expression of its target MACC1. We also determined that MACC1 has alternative polyadenylation (APA) sites, which results in different lengths of 3'-UTR variants in a CRC cell line. Taken together, miR-218 is post-transcriptionally inhibiting the MACC1 expression and its metastasis-inducing abilities

Higher Twist, ξw\xi_w Scaling, and Effective LOPDFsLO PDFs for Lepton Scattering in the Few GeV Region

We use a new scaling variable $\xi_w$, and add low $Q^2$ modifications to GRV98 leading order parton distribution functions such that they can be used to model electron, muon and neutrino inelastic scattering cross sections (and also photoproduction) at both very low and high energies.Comment: 6 pages, 3 figures. To be published in J. Phys. G (Conf. Proceedings) based on two talks by Arie Bodek at the NuFact$'02$ conference, Imperial College, London, England, July 200

Reflection Symmetric Ballistic Microstructures: Quantum Transport Properties

We show that reflection symmetry has a strong influence on quantum transport properties. Using a random S-matrix theory approach, we derive the weak-localization correction, the magnitude of the conductance fluctuations, and the distribution of the conductance for three classes of reflection symmetry relevant for experimental ballistic microstructures. The S-matrix ensembles used fall within the general classification scheme introduced by Dyson, but because the conductance couples blocks of the S-matrix of different parity, the resulting conductance properties are highly non-trivial.Comment: 4 pages, includes 3 postscript figs, uses revte

A C/EBPα-Wnt connection in gut homeostasis and carcinogenesis

We explored the connection between C/EBPα (CCAAT/enhancer-binding protein α) and Wnt signaling in gut homeostasis and carcinogenesis. C/EBPα was expressed in human and murine intestinal epithelia in the transit-amplifying region of the crypts and was absent in intestinal stem cells and Paneth cells with activated Wnt signaling. In human colorectal cancer and murine APC(Min/+) polyps, C/EBPα was absent in the nuclear β-catenin-positive tumor cells. In chemically induced intestinal carcinogenesis, C/EBPα KO in murine gut epithelia increased tumor volume. C/EBPα deletion extended the S-phase cell zone in intestinal organoids and activated typical proliferation gene expression signatures, including that of Wnt target genes. Genetic activation of β-catenin in organoids attenuated C/EBPα expression, and ectopic C/EBPα expression in HCT116 cells abrogated proliferation. C/EBPα expression accompanied differentiation of the colon cancer cell line Caco-2, whereas β-catenin stabilization suppressed C/EBPα. These data suggest homeostatic and oncogenic suppressor functions of C/EBPα in the gut by restricting Wnt signaling

Research review: young people leaving care

This paper reviews the international research on young people leaving care. Set in the context of a social exclusion framework, it explores young people's accelerated and compressed transitions to adulthood, and discusses the development and classification of leaving care services in responding to their needs. It then considers the evidence from outcome studies and argues that adopting a resilience framework suggests that young people leaving care may fall into three groups: young people 'moving on', 'survivors' and 'victims'. In concluding, it argues that these three pathways are associated with the quality of care young people receive, their transitions from care and the support they receive after care

Emergence of Quantum Ergodicity in Rough Billiards

By analytical mapping of the eigenvalue problem in rough billiards on to a band random matrix model a new regime of Wigner ergodicity is found. There the eigenstates are extended over the whole energy surface but have a strongly peaked structure. The results of numerical simulations and implications for level statistics are also discussed.Comment: revtex, 4 pages, 4 figure

Quantum localization and cantori in chaotic billiards

We study the quantum behaviour of the stadium billiard. We discuss how the interplay between quantum localization and the rich structure of the classical phase space influences the quantum dynamics. The analysis of this model leads to new insight in the understanding of quantum properties of classically chaotic systems.Comment: 4 pages in RevTex with 4 eps figures include