A multifactorial analysis of FAP to regulate gastrointestinal cancers progression

BackgroundFibroblast activation protein (FAP) is a cell-surface serine protease that has both dipeptidyl peptidase as well as endopeptidase activities and could cleave substrates at post-proline bond. Previous findings showed that FAP was hard to be detected in normal tissues but significantly up-regulated in remodeling sites like fibrosis, atherosclerosis, arthritis and embryonic tissues. Though increasing evidence has demonstrated the importance of FAP in cancer progression, no multifactorial analysis has been developed to investigate its function in gastrointestinal cancers until now.MethodsBy comprehensive use of datasets from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), scTIME Portal and Human Protein Atlas (HPA), we evaluated the carcinogenesis potential of FAP in gastrointestinal cancers, analyzing the correlation between FAP and poor outcomes, immunology in liver, colon, pancreas as well as stomach cancers. Then liver cancer was selected as example to experimentally validate the pro-tumor and immune regulative role of FAP in gastrointestinal cancers.ResultsFAP was abundantly expressed in gastrointestinal cancers, such as LIHC, COAD, PAAD and STAD. Functional analysis indicated that the highly-expressed FAP in these cancers could affect extracellular matrix organization process and interacted with genes like COL1A1, COL1A2, COL3A1 and POSTN. In addition, it was also observed that FAP was positively correlated to M2 macrophages infiltration across these cancers. To verify these findings in vitro, we used LIHC as example and over-expressed FAP in human hepatic stellate LX2 cells, a main cell type that produce FAP in tumor tissues, and then investigate its role on LIHC cells as well as macrophages. Results showed that the medium from FAP-over-expressed LX2 cells could significantly promote the motility of MHCC97H and SK-Hep1 LIHC cells, increase the invasion of THP-1 macrophages and induce them into pro-tumor M2 phenotype.ConclusionIn summary, we employed bioinformatic tools and experiments to perform a comprehensive analysis about FAP. Up-regulation of FAP in gastrointestinal cancers was primarily expressed in fibroblasts and contributes to tumor cells motility, macrophages infiltration and M2 polarization, revealing the multifactorial role of FAP in gastrointestinal cancers progression

MicroRNA-181a Functions as an Oncogene in Gastric Cancer by Targeting Caprin-1

MicroRNA-181a (miRNA-181a) is a multifaceted miRNA implicated in various cellular processes, particularly in cell fate determination and cellular invasion. It is frequently expressed aberrantly in human tumors and shows opposing functions in different types of cancers. In this study, we found that miRNA-181a is overexpressed in Gastric cancer (GC) tissues. Clinical and pathological analyses revealed that the expression of miRNA-181a is correlated with tumor size, lymph node metastasis, distant metastasis, and TNM stage. Kaplan-Meier analysis indicated that overexpression of miRNA-181a is associated with poor overall survival of patients with GC. Moreover, miRNA-181a is overexpressed in GC cells, and downregulation of miRNA-181a induced cell apoptosis and suppressed the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Target prediction and luciferase reporter assay showed that caprin-1 was a direct target of miRNA-181a. Downregulation of caprin-1 expression resulted in a converse change with miRNA-181a in GC. Spearman’s correlation test confirmed that the expression of miRNA-181a expression was inversely correlated with that of caprin-1 in GC cells. Furthermore, the expression of caprin-1 increased after downregulation of miRNA-181a in the GC cells. Caprin-1 siRNA can rescue the oncogenic effect of miRNA-181a on GC cell proliferation, apoptosis, migration, and invasion. These findings suggest that miRNA-181a directly inhibits caprin-1 and promotes GC development. miRNA-181a could be a target for anticancer drug development

Swinging open or slamming shut? The implications of China's open-door policy for women, educational choice and work.

This paper explores the link between international tertiary education and evolving attitudes about women and work in China. The paper reviews literature about gender and education in China, commenting on the late-twentieth-century post-reform environment. It goes on to present illustrative primary research material from two studies carried out between 1999 and 2004 with students studying for UK Business degrees in China and the UK. The research data is presented as extracts from oral histories, where participants discuss education and attitudes about work, gender and identity. The main conclusions are that women in post-reform China have been educationally and socially disadvantaged compared to men; traditional gender attitudes about women, work and education persist in contemporary China; women are seeking opportunities in international higher education to overcome domestic prejudices; and degree-educated professional women may be developing as a new social class in contemporary Chinese society

Collective total synthesis of stereoisomeric yohimbine alkaloids

Abstract Stereoisomeric polycyclic natural products are important for drug discovery-based screening campaigns, due to the close correlation of stereochemistry with diversified bioactivities. Nature generates the stereoisomeric yohimbine alkaloids using bioavailable monoterpene secolaganin as the ten-carbon building block. In this work, we reset the stage by the development of a bioinspired coupling, in which the rapid construction of the entire pentacyclic skeleton and the complete control of all five stereogenic centers are achieved through enantioselective kinetic resolution of an achiral, easily accessible synthetic surrogate. The stereochemical diversification from a common intermediate allows for the divergent and collective synthesis of all four stereoisomeric subfamilies of yohimbine alkaloids through orchestrated tackling of thermodynamic and kinetic preference

Minimal Active Space: NOSCF and NOSI in Multistate Density Functional Theory

In this Perspective, we introduce a minimal active space (MAS) for the lowest N eigenstates of a molecular system in the framework of a multistate density functional theory (MSDFT), consisting of no more than N2 nonorthgonal Slater determinants. In comparison with some methods in wave function theory in which one seeks to expand the ever increasing size of an active space to approximate the wave functions, it is possible to have an upper bound in MSDFT because the auxiliary states in a MAS are used to represent the exact N-dimensional matrix density D(r). In analogy to Kohn-Sham DFT, we partition the total Hamiltonian matrix functional H[D] into an orbital-dependent part, including multistate kinetic energy and Coulomb-exchange energy plus an external potential energy, and a correlation matrix density functional Ec[D]. The latter accounts for the part of correlation energy not explicitly included in the minimal active space. However, a major difference from Kohn-Sham DFT is that state interactions are necessary to represent the N-matrix density D(r) in MSDFT, rather than a non-interacting reference state for the scalar ground-state density. Two computational approaches are highlighted. We first derive a set of non-orthogonal multistate self-consistent-field (NOSCF) equations for the variational optimization of H[D]. We introduce the multistate correlation po tential, as the functional derivative of Ec[D], which includes both correlation effects within the MAS and that from the correlation matrix functional. Alternatively, we describe a non-orthogonal state interaction (NOSI) procedure, in which the determi nant functions are optimized separately. Both computational methods are useful for determining the exact eigenstate energies and for constructing variational diabatic states, provided that the universal correlation matrix functional is known. It is hoped that this discussion would stimulate developments of approximate multistate density functionals both for the ground and excited states

Exercise-Induced ADAR2 Protects against Nonalcoholic Fatty Liver Disease through miR-34a

Nonalcoholic fatty liver disease (NAFLD) is a growing health problem that is closely associated with insulin resistance and hereditary susceptibility. Exercise is a beneficial approach to NAFLD. However, the relief mechanism of exercise training is still unknown. In this study, mice on a normal diet or a high-fat diet (HFD), combined with Nω-nitro-L-arginine methyl ester, hydrochloride (L-NAME) mice, were either kept sedentary or were subjected to a 12-week exercise running scheme. We found that exercise reduced liver steatosis in mice with diet-induced NAFLD. The hepatic adenosine deaminases acting on RNA 2 (ADAR2) were downregulated in NAFLD and were upregulated in the liver after 12-week exercise. Next, overexpression of ADAR2 inhibited and suppression promoted lipogenesis in HepG2 cells treated with oleic acid (OA), respectively. We found that ADAR2 could down-regulate mature miR-34a in hepatocytes. Functional reverse experiments further proved that miR-34a mimicry eliminated the suppression of ADAR2 overexpression in lipogenesis in vitro. Moreover, miR-34a inhibition and mimicry could also affect lipogenesis in hepatocytes. In conclusion, exercise-induced ADAR2 protects against lipogenesis during NAFLD by editing miR-34a. RNA editing mediated by ADAR2 may be a promising therapeutic candidate for NAFLD