DHA inhibits invasion and metastasis in NSCLC cells by interfering with CCL18/STAT3 signaling pathway.

Omega-3 has been proposed as an antitumor substance that suppresses the growth and metastasis of multiple types of tumor cells, including lung cancer, but the specific mechanisms involved remain obscure. Our previous studies showed that the expression of chemokine ligand 18 was related to the migration and metastasis of non-small cell lung cancer. Here, we aim to explore whether omega-3 inhibits invasion and metastasis of NSCLC by regulating the expression of CCL18. The expression of CCL18, metastasis- and epithelial-mesenchymal transition (EMT)-related genes at mRNA and protein levels in NSCLC cell lines were detected by RT-qPCR and Western blot, respectively. The metastatic and invasive capability of NSCLC cells were evaluated by scratch wound healing and Transwell assays, respectively. Our results showed that the level of CCL18 is positively associated with metastatic ability of NSCLC cells. Docosahexaenoic acid, an important long-chain, polyunsaturated omega-3 (n-3) fatty acid, significantly inhibited invasion and metastasis of NSCLC cells, and concomitantly downregulated the expression of metastasis- and EMT-related genes and p-STAT3 signaling pathway. Additionally, we found that DHA inhibited CCL18 expression in lung cancer cells, while overexpression of CCL18 effectively reversed DHA-mediated downregulation in the expression of metastasis- and EMT-related genes and p-STAT3 signaling as well as DHA-mediated inhibitory effect on metastasis and invasion of NSCLC cells. DHA inhibits NSCLC cell invasion and metastasis possibly through targeted inhibition of CCL18/ STAT3 signaling pathway and EMT process.

Integrated analysis of microRNA and transcription factors in the bone marrow of patients with acute monocytic leukemia.

Acutemonocytic leukemia (AMoL) is a distinct subtype of acute myeloid leukemia (AML) with poor prognosis. However, the molecular mechanisms and key regulators involved in the global regulation of gene expression levels in AMoL are poorly understood. In order to elucidate the role of microRNAs (miRNAs/miRs) and transcription factors (TFs) in AMoL pathogenesis at the network level, miRNA and TF expression level profiles were systematically analyzed by miRNA sequencing and TF array, respectively; this identified 285 differentially expressed miRNAs and 139 differentially expressed TFs in AMoL samples compared with controls. By combining expression level profile data and bioinformatics tools available for predicting TF and miRNA targets, a comprehensive AMoL-specific miRNA-TF-mediated regulatory network was constructed. A total of 26 miRNAs and 23 TFs were identified as hub nodes in the network. Among these hubs, miR-29b-3p, MYC, TP53 and NFKB1 were determined to be potential AMoL regulators, and were subsequently extracted to construct sub-networks. A hypothetical pathway model was also proposed for miR-29b-3p to reveal the potential co-regulatory mechanisms of miR-29b-3p, MYC, TP53 and NFKB1 in AMoL. The present study provided an effective approach to discover critical regulators via a comprehensive regulatory network in AMoL, in addition to enhancing understanding of the pathogenesis of this disease at the molecular level.

Integrated analysis of microRNA and transcription factor reveals important regulators and regulatory motifs in adult B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B­ALL) is an aggressive hematological malignancy and a leading cause of cancer-related mortality in children and young adults. The molecular mechanisms involved in the regulation of its gene expression has yet to be fully elucidated. In the present study, we performed large scale expression profiling of microRNA (miRNA) and transcription factor (TF) by Illumina deep­sequencing and TF array technology, respectively, and identified 291 differentially expressed miRNAs and 201 differentially expressed TFs in adult B­ALL samples relative to their controls. After integrating expression profile data with computational prediction of miRNA and TF targets from different databases, we construct a comprehensive miRNA­TF regulatory network specifically for adult B­ALL. Network function analysis revealed 25 significantly enriched pathways, four pathways are well­known to be involved in B­ALL, such as PI3K­Akt signaling pathway, Jak­STAT signaling pathway, Ras signaling pathway and cell cycle pathway. By analyzing the network topology, we identified 28 hub miRNAs and 19 hub TFs in the network, and found nine potential B­ALL regulators among these hub nodes. We also constructed a Jak­STAT signaling sub­network for B­ALL. Based on the sub­network analysis and literature survey, we proposed a cellular model to discuss MYC/miR­15a­5p/FLT3 feed-forward loop (FFL) with Jak­STAT signaling pathway in B­ALL. These findings enhance our understanding of this disease at the molecular level, as well as provide putative therapeutic targets for B-ALL.

Galangin induces apoptosis of hepatocellular carcinoma cells via the mitochondrial pathway.

AIM: To investigate the mechanism by which galangin, a polyphenolic compound derived from medicinal herbs, induces apoptosis of hepatocellular carcinoma (HCC) cells. METHODS: The 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to measure cell viability. Apoptosis was evaluated by in situ uptake of propidium iodide and Hoechst 33258 and was then detected by fluorescence microscopy. Protein expressions were detected by Western blotting. To confirm the apoptotic pathway mediated by galangin, cells were transfected by bcl-2 gene to overexpress Bcl-2 or siRNA to down-regulate Bcl-2 expression. RESULTS: Galangin (46.25-370.0 micromol/L) exerted an anti-proliferative effect, induced apoptosis, and decreased mitochondrial membrane potential in a dose and time-dependent manner. Treatment with galangin induced apoptosis by translocating the pro-apoptotic protein Bax to the mitochondria, which released apoptosis-inducing factor and cytochrome c into the cytosol. Overexpression of Bcl-2 attenuated galangin-induced HepG2 cell apoptosis, while decreasing Bcl-2 expression enhanced galangin-induced cell apoptosis. CONCLUSION: Our data suggests that galangin mediates apoptosis through a mitochondrial pathway, and may be a potential chemotherapeutic drug for the treatment of HCC.