LAMC2 enhances the metastatic potential of lung adenocarcinoma.

Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin ß1- and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target.

Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising candidate for cancer therapy, however, emergence of drug resistance limits its potential use. Here, we report for the first time that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, sensitizes TRAIL-resistant LNCaP cells to TRAIL-mediated apoptosis through modulation of intrinsic and extrinsic apoptotic pathways. When combined with EGCG, Apo2L/TRAIL exhibited enhanced apoptotic activity in LNCaP cells characterized by three major molecular events. First, apoptosis induction was accompanied by the upregulation of poly(ADP-ribose) polymerase cleavage and modulation of pro- and antiapoptotic Bcl2 family of proteins. A synergistic inhibition of inhibitors of apoptosis with concomitant increase in caspase cleavage was observed. Second, pretreatment of cells with EGCG resulted in modulation of death-inducing signaling cascade complex involving DR4/TRAIL R1, Fas-associated death domain and FLICE-inhibitory protein proteins. Last, we observed a synergistic inhibition in the invasion and migration of LNCaP cells. This effect was observed to be mediated through inhibition in the protein expression of vascular endothelial growth factor, uPA and angiopoietin 1 and 2. Further, the activity and protein expression of MMP-2, -3 and -9 and upregulation of TIMP1 in cells treated with a combination of EGCG and TRAIL was observed. These data might have implications for developing new strategies aimed at eliminating prostate cancer cells resistant to TRAIL.

High-fat diet induced obesity and the effect of fructooligosaccharides on cardiac protein expression

Hypothesis: Obesity alters cardiac protein expression. Fructooligosaccharide modulates this effect. Design and Methodology: Rats fed AIN-93G chow were subsequently fed high-fat AIN-93G. The top 40% weight-gain category were allocated into control (CON), highfat (HF) and high-fat with fructooligosaccharide (HF-FOS) groups; n=10. Body weights were monitored. After 12 weeks, left ventricles were cryopreserved. Serum was stored for glucose and insulin estimations. Tissues were analysed by mass spectrometry using an Orbitrap with a nanospray source and EASY-nLC nano-LC system(ThermoFisher, San Jose, CA). Spectra were analysed with Sequest and fold changes with Scaffold Q+ (Proteome Software Inc., Portland, OR). T-Tests detected differentially expressed proteins (CON vs HF and HF vs HF-FOS) and mean (±SE) differences in body weights, glucose and insulin. The Database for Annotation, Visualization and Integrated Discovery and the Kyoto Encyclopedia of Genes and Genomes revealed pathways containing overrepresented proteins. Hematoxylin and eosin sections were graded for hypertrophy and chi-squared analyses sought differences. A p-value of <0.05 was considered significant with Benjamini­Hochberg corrections where applicable. Results: HF rats (549.4±17.1g) were significantly (p<0.05) heavier than CON (513.6±14.8g). Twenty-three proteins involved in mitochondrial function and lipid metabolism were differentially expressed (p<0.001) between the CON and HF. One hundred and thirty-two proteins involved in contractility, lipid/carbohydrate metabolism and signaling were differentially expressed (p<0.001) between HF and HF-FOS. HF cardiomyocytes were significantly (p<0.001) more hypertrophic than CON. Conclusion: High-fat feeding is associated with subclinical deviations in the cardiac proteome. Coupled to cellular hypertrophy this may influence myocardial compliance. Fructooligosaccharides modulates protein expression.