Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulatory components in cancer. Usually in advanced malignant stages, TGF-β signaling is elevated but global miRNA expression is suppressed. Such a gene expression signature is well illustrated in a fibrosis (or mesenchymal) subtype of ovarian cancer (OC) that is of poor prognosis. However, the interplay between the two pathways in the OC subtype has not yet been elucidated. nc886 is a recently identified non-coding RNA implicated in several malignancies. The high expression of nc886 is associated with poor prognosis in 285 OC patients. Herein, we find that in OC nc886 expression is induced by TGF-β and that nc886 binds to Dicer to inhibit miRNA maturation. By preventing the miRNA pathway, nc886 emulates TGF-β in gene expression patterns and potentiates cell adhesion, migration, invasion, and drug resistance. Here we report nc886 to be a molecular link between the TGF-β and miRNA pathways.

BackgroundStomach cancer is the third deadliest among all cancers worldwide. Although incidence of the intestinal-type gastric cancer has decreased, the incidence of diffuse-type is still increasing and its progression is notoriously aggressive. There is insufficient information on genome variations of diffuse-type gastric cancer because its cells are usually mixed with normal cells, and this low cellularity has made it difficult to analyze the genome.ResultsWe analyze whole genomes and corresponding exomes of diffuse-type gastric cancer, using matched tumor and normal samples from 14 diffuse-type and five intestinal-type gastric cancer patients. Somatic variations found in the diffuse-type gastric cancer are compared to those of the intestinal-type and to previously reported variants. We determine the average exonic somatic mutation rate of the two types. We find associated candidate driver genes, and identify seven novel somatic mutations in CDH1, which is a well-known gastric cancer-associated gene. Three-dimensional structure analysis of the mutated E-cadherin protein suggests that these new somatic mutations could cause significant functional perturbations of critical calcium-binding sites in the EC1-2 junction. Chromosomal instability analysis shows that the MDM2 gene is amplified. After thorough structural analysis, a novel fusion gene TSC2-RNF216 is identified, which may simultaneously disrupt tumor-suppressive pathways and activate tumorigenesis.ConclusionsWe report the genomic profile of diffuse-type gastric cancers including new somatic variations, a novel fusion gene, and amplification and deletion of certain chromosomal regions that contain oncogenes and tumor suppressors.

nc886 is a recently identified cellular non-coding RNA and its depletion leads to acute cell death via PKR (Protein Kinase RNA-activated) activation. nc886 expression is increased in some malignancies, but silenced in others. However, the precise role of nc886/PKR is controversial: is it a tumor suppressor or an oncogene? In this study, we have clarified the role of nc886 in thyroid cancer by sequentially generating PKR knockout (KO) and PKR/nc886 double KO cell lines from Nthy-ori 3-1, a partially transformed thyroid cell line. Compared to the wildtype, PKR KO alone does not exhibit any significant phenotypic changes. However, nc886 KO cells are less proliferative, migratory, and invasive than their parental PKR KO cells. Importantly, the requirement of nc886 in tumor phenotypes is totally independent of PKR. In our microarray data, nc886 KO suppresses some genes whose elevated expression is associated with poor survival confirmed by data from total of 505 thyroid cancer patients in the Caner Genome Atlas project. Also, the nc886 expression level tends to be elevated and in more aggressively metastatic tumor specimens from thyroid cancer patients. In summary, we have discovered nc886's tumor-promoting role in thyroid cancer which has been concealed by the PKR-mediated acute cell death.

BACKGROUND: Epidermal growth factor receptor (EGFR) T790M mutation drives acquired drug resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant lung cancer. However, it was reported that this mutation may exist before drug exposure. The objective of the current study was to evaluate whether the clinical outcomes are affected by the percentage of preexisting T790M mutations within a tumor. METHODS: Pretreatment tissues were collected from 124 patients with advanced non-small cell lung cancer with sensitizing EGFR mutations that were detected by direct sequencing. Genotyping for EGFR T790M mutation was further performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patients who were positive for the T790M mutation were divided to 2 subgroups according to T790M mutant signal frequency. RESULTS: The T790M mutation was found in 31 patients (25.0%). The T790M mutation frequency at which the risk of disease progression after therapy with EGFRTKIs begins to increase was estimated to be 3.2%. The patients with T790M-positive tumors had a shorter time to disease progression after treatment with EGFR-TKIs (median, 6.3 months vs 11.5 months; P <.001) and overall survival (median, 16.1 months vs 26.5 months; P 5.065) compared with those with T790M-negative tumors. Among the T790M-positive patients, the patients with high T790M frequency (9 patients) were found to have a shorter time to disease progression (median, 2.4 months vs 6.7 months; P 5.009) and overall survival (median, 9.1 months vs 18.7 months; P 5.018) compared with those with low T790M frequency (22 patients). CONCLUSIONS: A preexisting EGFR T790M mutation was noted in 25% of patients with EGFR-mutant lung cancer. Patients with a high T790M mutation frequency had worse clinical outcomes to EGFR-TKIs than patients with a low T790M mutation frequency.

There are two conflicting models regarding the role of the Neolithic millet cultivation in the appearance of the Bronze Age farming economy in South Korea. The “continuity model” suggests that the emergence of a farming economy was a consequence of increasing sedentism, and that millet cultivation practiced during the Neolithic played a significant role in the transition to the Bronze Age. On the contrary, the “discontinuity model” suggests that the appearance of the Bronze Age farming economy heavily dependent on rice had little to do with previous millet cultivation in the Neolithic and the degree of sedentism during the latest Neolithic was very low. We test these models by looking into a temporal variation of sedentism, by quantitatively analyzing the quantity of pit houses and settlements based on relative chronology and radiocarbon dates. Sedentary settlements with small-scale millet cultivation appeared in the central-western Korea during the early fourth millennium b.c . They increased sharply during the late fourth millennium b.c . and also appeared in central-eastern and southern Korea, but they almost disappeared in central and southern Korea from the late third millennium b.c ., suggesting a return to increased mobility and/or sharp decrease in population. Hence a continuity model for the emergence of a farming economy cannot be accepted. We suggest environmental deterioration as a prime mover for both the appearance of millet cultivation during the fourth millennium b.c . and the disappearance of sedentary settlement from the late third millennium b.c . in Korea.

ABSTRACT:Gastric cancer is the second leading cause of cancer death and remains a major clinical challenge due to poor prognosis and limited treatment options. Therefore, the basic mechanisms underlying gastric tumorigenesis deserve investigation. Although regulation of the galactoside-binding lectin galectin-7 in cancer has been studied, its role in tumor formation and progression remains controversial. In this study, we investigated galectin-7 expression and its role in gastric cancer. Immunohistochemical staining using a tissue microarray of gastric cancer patients revealed significantly low expression levels of galectin-7 in malignant tissues compared with matched normal tissues, and decreased expression of galectin-7 in malignant tissues was associated with advanced TMN stage disease (p=0.034). Importantly, low expression of galectin-7 in normal tissues was associated with a poor survival rate (p=0.0561). Over-expression of galectin-7 in AGS gastric adenocarcinoma cells suppressed cell proliferation, migration, and invasion, whereas ablation of galectin-7 in KATO III gastric carcinoma cells reversed these properties. AGS cells that overexpressed galectin-7 could not form gastric tumors in xenografted mice. More than 70% hypermethylation was observed in 7 of 9 gastric cancer cell lines tested and 5-azacytidine treatment lowered galectin-7 expression by reducing methylation in 24 cancer cell lines from five different organ origins. We analyzed CpG islands in the galectin-7 genomic region and detected hypermethylation at +1566bp of exon 2, the predicted p53 binding region. DNA hypermethylation of this region was also detected in gastric cancer tissues from 20 patients. Taken together, our data indicate that galectin-7 has a tumor suppressive function, and that the gene is epigenetically modified by DNA methylation and significantly down-regulated in gastric cancer. Further study of galectin-7 regulation may lead to improved gastric cancer diagnosis and therapy.

ObjectiveCytokines are believed to have a role in the pathophysiology of major depression. The alteration in levels of pro-inflammatory cytokines [interleukin 1β (IL-1β), IL-2, IL-6, IL-12, interferon γ, and tumor necrosis factor α] in major depression supports the cytokine hypothesis of this illness. IL-23 and IL-17 are also pro-inflammatory cytokines, but few studies have focused on their role in major depression. This study investigated the potential role of the IL-23 and IL-17 axis in major depression.MethodsPlasma IL-23 and IL-17 levels were measured in 26 major depressive disorder (MDD) patients before and after 6-week treatment with antidepressants; these levels were measured in 28 age- and sex-matched normal controls. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS). IL-23 and IL-17 plasma levels were estimated using quantitative enzyme-linked immunosorbent assay.ResultsPre-treatment plasma levels of IL-23 and IL-17 in MDD patients were not significantly different from those of normal controls. In MDD patients, IL-23 and IL-17 levels after 6 weeks of antidepressant treatment were not different from the baseline levels. There was no significant correlation between changes in the cytokine levels and changes in the HDRS scores representing the severity of depression.ConclusionThe present study does not support a potential involvement of IL-23 and IL-17 axis in major depression. Replication and extension using a larger sample are required.

Panic disorder (PD) is a complex and heterogeneous psychiatric condition. Dysfunction within the serotonergic system has been hypothesized to play an important role in PD. The novel brain-specific serotonin synthesizing enzyme, tryptophan hydroxylase 2 (TPH2), which represents the rate-limiting enzyme of serotonin production in the brain, may therefore be of particular importance in PD. We investigated the TPH2 703G/T SNP for association with PD. Patients with PD (n = 108), and control subjects (n = 247), were genotyped for rs4570625 (TPH2 703G/T). Male and female subjects were analyzed separately. The severity of their symptoms was measured using the Spielberger state-trait anxiety inventory (STAI), panic disorder severity scale (PDSS), anxiety sensitivity index (ASI), acute panic inventory (API), and Hamilton's rating scale for depression (HAMD). The genotype and allele frequencies of the PD patients and controls were analyzed using chi(2) statistics. There was a significant difference in the allele frequency in rs4570625 between the PD patients and normal controls. The T allele was significantly less frequent in the PD patients. We also found a significant association with rs4570625 in the female subgroup. There was no difference in symptom severity among the genotypes of this polymorphism. This result suggests that rs4570625 polymorphism may play a significant role in the pathogenesis of PD. Moreover, rs4570625 may have a gender-dependent effect on susceptibility to PD. Further studies are needed to replicate the association that we observed.