RANKL/RANK promotes the migration of gastric cancer cells by interacting with EGFR

BACKGROUND: The incidence and mortality rates of gastric cancer (GC) rank in top five among all malignant tumors. Chemokines and their receptor-signaling pathways reportedly play key roles in the metastasis of malignant tumor cells. Receptor activator of nuclear factor κB ligand (RANKL) is a member of the tumor necrosis factor family, with strong chemokine-like effects. Some studies have pointed out that the RANKL/RANK pathway is vital for the metastasis of cancer cells, but the specific mechanisms in GC remain poorly understood. RESULTS: This study reports original findings in cell culture models and in patients with GC. Flow cytometry and western blotting analyses showed that RANK was expressed in BGC-823 and SGC-7901 cells in particular. Chemotaxis experiments and wound healing assay suggested that RANKL spurred the migration of GC cells. This effect was offset by osteoprotegerin (OPG), a decoy receptor for RANKL. RANKL contributed to the activation of human epidermal growth factor receptor (HER) family pathways. The lipid raft core protein, caveolin 1 (Cav-1), interacted with both RANK and human epidermal growth factor receptor-1(EGFR). Knockdown of Cav-1 blocked the activation of EGFR and cell migration induced by RANKL. Moreover, RANK-positive GC patients who displayed higher levels of EGFR expression had poor overall survival. CONCLUSIONS: In summary, we confirmed that with the promotion of RANKL, RANK and EGFR can form complexes with the lipid raft core protein Cav-1, which together promote GC cell migration. The formation of the RANK-Cav-1-EGFR complex provides a novel mechanism for the metastasis of GC. These observations warrant confirmation in independent studies, in vitro and in vivo. They also inform future drug target discovery research and innovation in the treatment of GC progression

Elevated limb-bud and heart development (LBH) expression indicates poor prognosis and promotes gastric cancer cell proliferation and invasion via upregulating Integrin/FAK/Akt pathway

The limb-bud and heart development (LBH) gene is a highly conserved, tissue-specific transcription cofactor in vertebrates that regulates multiple key genes in embryonic development. The role of LBH in various cancer types is still controversial, and its specific role and molecular mechanism in the oncogenesis of gastric cancer (GC) remains largely unexplored. In the present study, the prognostic significance and clinicopathological characteristics of LBH in GC was determined. The LBH mRNA expression was first investigated in four independent public datasets (TCGA-STAD, GSE15459, GSE29272, and GSE62254) and then validated with our samples at the protein level. LBH was overexpressed at both the mRNA and protein levels in cancer compared with normal tissues. High LBH expression was correlated with advanced T, N, and M stages. Kaplan–Meier analysis and log-rank test indicated that higher LBH expression was statistically correlated with shorter overall survival (OS) in the public datasets and our study samples. Univariate and multivariate Cox regression analysis showed that LBH was an independent prognostic biomarker for survival in TCGA-STAD, GSE15459, GSE62254 cohorts, and our GC patients. In vitro experiments showed that knockdown of LBH can significantly inhibit the proliferation and invasion of HGC-27 cells, while overexpression of LBH can significantly enhance the proliferation and invasion of BGC-823 cells. Gene Set Enrichment Analysis (GSEA), Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) indicated that high LBH expression is associated with the PI3K-Akt pathway, focal adhesion, and extracellular matrix (ECM)-receptor interaction. Western blot analysis showed that knockdown of LBH significantly inhibited the expression of integrin α5, integrin β1, p-FAK, and p-Akt. Therefore, results from the present study indicate that LBH is a potential independent prognostic biomarker and promotes proliferation and invasion of GC cells by activating the integrin/FAK/Akt pathway

β-Elemene-induced autophagy protects human gastric cancer cells from undergoing apoptosis

<p>Abstract</p> <p>Background</p> <p>β-Elemene, a compound found in an herb used in traditional Chinese medicine, has shown promising anti-cancer effects against a broad spectrum of tumors. The mechanism by which β-elemene kills cells remains unclear. The aim of the present study is to investigate the anti-tumor effect of β-elemene on human gastric cancer cells and the molecular mechanism involved.</p> <p>Results</p> <p>β-Elemene inhibited the viability of human gastric cancer MGC803 and SGC7901 cells in a dose-dependent manner. The suppression of cell viability was due to the induction of apoptosis. A robust autophagy was observed in the cells treated with β-elemene; it was characterized by the increase of punctate LC3 dots, the cellular morphology, and the increased levels of LC3-II protein. Further study showed that β-elemene treatment up-regulated Atg5-Atg12 conjugated protein but had little effect on other autophagy-related proteins. PI3K/Akt/mTOR/p70S6K1 activity was inhibited by β-elemene. Knockdown of Beclin 1 with small interfering RNA, or co-treatment with the autophagy inhibitor, 3-methyladenine or chlorochine enhanced significantly the antitumor effects of β-elemene.</p> <p>Conclusions</p> <p>Our data provides the first evidence that β-elemene induces protective autophagy and prevents human gastric cancer cells from undergoing apoptosis. A combination of β-elemene with autophagy inhibitor might thus be a useful therapeutic option for advanced gastric cancer.</p

Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR &lt; 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.</p

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity