Common transcriptional programs and the role of chemokine (C-C motif) ligand 20 (CCL20) in cell migration of cholangiocarcinoma

The incidence of cholangiocarcinoma (CCA) has risen in many countries, but there is still no appropriate screening and treatment available. The growing number of microarray data published todays can be a powerful resource for the discovery of biomarkers to tackle challenges in the management of CCA. This study analyzed multiple microarray datasets to identify the common transcriptional networks in CCA and select a possible biomarker for functional study in CCA cell lines. A systematic searching identified 4 microarray datasets from Gene Expression Omnibus (GEO) repository and PubMed articles. Differential expression analysis between tumor and normal tissues was performed in each dataset. In order to characterize the common expression pattern, differentially expressed genes (DEGs) from all datasets were combined and visualized by hierarchical clustering and heatmap. Gene enrichment analysis performed in each cluster revealed that over-expressed DEGs were enriched in cell cycle, cell migration and response to cytokines while under-expressed DEGs were enriched in metabolic processes such as oxidation-reduction, lipid, and drug. To explain tumor characteristics, genes enriched in cell migration and response to cytokines were further investigated. Among these genes, CCL20 was selected for functional study because its role has never been studied in CCA. Moreover, its signaling may be regulated by disrupting its only receptor, CCR6. Treatment with recombinant CCL20 induced higher cell migration and increased expression of N-cad. In contrast, knockdown of CCR6 by siRNA reduced cell migration ability and decreased N-cadherin level. Altogether, these results suggested the contribution of CCL20/CCR6 signaling in cell migration through epithelial-mesenchymal transition process. Thus, CCL20/CCR6 signaling might be a target for the management of CCA

First somatic mutation of E2F1 in a critical DNA binding residue discovered in well-differentiated papillary mesothelioma of the peritoneum

10.1186/gb-2011-12-9-r96Genome biology129R9

Therapeutic targeting of ARID1A and PI3K/AKT pathway alterations in cholangiocarcinoma

Background Genetic alterations in ARID1A were detected at a high frequency in cholangiocarcinoma (CCA). Growing evidence indicates that the loss of ARID1A expression leads to activation of the PI3K/AKT pathway and increasing sensitivity of ARID1A-deficient cells for treatment with the PI3K/AKT inhibitor. Therefore, we investigated the association between genetic alterations of ARID1A and the PI3K/AKT pathway and evaluated the effect of AKT inhibition on ARID1A-deficient CCA cells. Methods Alterations of ARID1A, PI3K/AKT pathway-related genes, clinicopathological data and overall survival of 795 CCA patients were retrieved from cBio Cancer Genomics Portal (cBioPortal) databases. The association between genetic alterations and clinical data were analyzed. The effect of the AKT inhibitor (MK-2206) on ARID1A-deficient CCA cell lines and stable ARID1A-knockdown cell lines was investigated. Cell viability, apoptosis, and expression of AKT signaling were analyzed using an MTT assay, flow cytometry, and Western blots, respectively. Results The analysis of a total of 795 CCA samples revealed that ARID1A alterations significantly co-occurred with mutations of EPHA2 (p < 0.001), PIK3CA (p = 0.047), and LAMA1 (p = 0.024). Among the EPHA2 mutant CCA tumors, 82% of EPHA2 mutant tumors co-occurred with ARID1A truncating mutations. CCA tumors with ARID1A and EPHA2 mutations correlated with better survival compared to tumors with ARID1A mutations alone. We detected that 30% of patients with PIK3CA driver missense mutations harbored ARID1A-truncated mutations and 60% of LAMA1-mutated CCA co-occurred with truncating mutations of ARID1A. Interestingly, ARID1A-deficient CCA cell lines and ARID1A-knockdown CCA cells led to increased sensitivity to treatment with MK-2206 compared to the control. Treatment with MK-2206 induced apoptosis in ARID1A-knockdown KKU-213A and HUCCT1 cell lines and decreased the expression of pAKTS473 and mTOR. Conclusion These findings suggest a dependency of ARID1A-deficient CCA tumors with the activation of the PI3K/AKT-pathway, and that they may be more vulnerable to selective AKT pathway inhibitors which can be used therapeutically

Exome sequencing of liver flukeg-associated cholangiocarcinoma

10.1038/ng.2273Nature Genetics446690-693NGEN

Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma

The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ~3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology

Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF

BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes