MALT1 paracaspase is overexpressed in hepatocellular carcinoma and promotes cancer cell survival and growth.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, therapeutic management of HCC remains a challenge, emphasizing the importance of exploring novel targets. MALT1 paracaspase is a druggable signaling molecule whose dysregulation has been linked to hematological and solid tumors. However, the role of MALT1 in HCC remains poorly understood, leaving its molecular functions and oncogenic implications unclear. Here we provide evidence that MALT1 expression is elevated in human HCC tumors and cell lines, and that correlates with tumor grade and differentiation state, respectively. Our results indicate that ectopic expression of MALT1 confers increased cell proliferation, 2D clonogenic growth, and 3D spheroid formation in well differentiated HCC cell lines with relatively low MALT1 levels. In contrast, stable silencing of endogenous MALT1 through RNA interference attenuates these aggressive cancer cell phenotypes, as well as migration, invasion, and tumor-forming ability, in poorly differentiated HCC cell lines with higher paracaspase expression. Consistently, we find that pharmacological inhibition of MALT1 proteolytic activity with MI-2 recapitulates MALT1 depletion phenotypes. Finally, we show that MALT1 expression is positively correlated with NF-kB activation in human HCC tissues and cell lines, suggesting that its tumor promoting functions may involve functional interaction with the NF-kB signaling pathway. This work unveils new insights into the molecular implications of MALT1 in hepatocarcinogenesis and places this paracaspase as a potential marker and druggable liability in HCC.

Diclofenac induced apoptosis via altering PI3K/Akt/MAPK signaling axis in HCT 116 more efficiently compared to SW480 colon cancer cells.

Diclofenac is a preferential cyclooxygenase 2 inhibitor (COX-2) and member of non-steroidal anti-inflammatory drugs (NSAIDs). Inflammation is one of the main reason of poor prognosis of colon cancer cases; thereby NSAIDs are potential therapeutic agents in colon cancer therapy. In this study, our aim to understand the potential molecular targets of diclofenac, which may propose new therapeutic targets in HCT 116 (wt p53) and SW480 (mutant p53R273H) colon cancer cells. For this purpose, we identified different response against diclofenac treatment through expression profiles of PI3K/Akt/MAPK signaling axis. Our hypothesis was diclofenac-mediated apoptosis is associated with inhibition of PI3K/Akt/MAPK signaling axis. We found that sub-cytotoxic concentration of diclofenac (400 µM) promoted further apoptosis in HCT 116 cells compared to SW480 colon cancer cells. Diclofenac triggered dephosphorylation of PTEN, PDK, Akt, which led to inhibition of PI3K/Akt survival axis in HCT 116 colon cancer cells. However, diclofenac showed lesser effect in SW480 colon cancer cells. In addition, diclofenac further activated p44/42, p38 and SAPK/JNK in HCT 116 cells compared to SW480 cells.

Epibrassinolide alters PI3K/MAPK signaling axis via activating Foxo3a-induced mitochondria-mediated apoptosis in colon cancer cells.

Epibrassinolide (EBR), a steroid-derived plant growth regulator, has been recently suggested as an apoptotic inducer in different cancer cells. In this experimental study, we investigated the potential apoptotic effect of EBR on stress-related and survival signaling molecules in colon carcinoma cells. EBR decreased cell viability and colony formation in HCT 116 and HT-29 colon carcinoma cells. The inactivation of PI3K/AKT by EBR treatment led to upregulation of Foxo3a, which in turn induced apoptosis in HCT 116 and HT-29 cells. In addition, the upstream non-receptor protein tyrosine kinase Src was found elevated allowing to the upregulation of p38, stress-activated protein kinase/Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2 and their target genes c-jun, c-fos and c-myc in a time-dependent manner in HCT 116 cells within 48h. The alterations in PA metabolism caused intracellular PA pool decrease. The upregulation of pro-apoptotic Bak, Bax, Puma and Bim were accompanied with the decrease in Mcl-1 in HCT 116 and Bcl-xL expression profiles in HT-29 following 48h EBR treatment. We suggest that the upregulation of Bim expression levels might be related with one of the PI3K/AKT target transcription factor Foxo3a, which was dephosphorylated by EBR treatment in HCT 116 and HT-29 cells.

Fetuin-A 742 (C/T) and 766 (C/G) polymorphic sites are associated with increased risk of myocardial infarction in older patients (≥ 40 years of age).

Inflammation and genetics have key roles in the pathogenesis of atherosclerosis, and the etiology of myocardial infarction (MI). Recent studies have indicated that lower serum levels of fetuin-A may accelerate the vascular mineralization process, which leads to pathophysiological conditions, such as coronary heart disease and chronic renal failure. The aim of the present study was to evaluate the association between specific fetuin-A polymorphisms (742 and 766) that are associated with circulating serum levels, and MI cases. The study consisted of 292 participants; 146 healthy control subjects and 146 patients with MI. The patient group was divided into two subgroups: 56 MI ≤ 40 years and 90 MI ≥ 40 years. The genotype distribution of fetuin 742 (C/T) and fetuin 766 (C/G) were determined by restriction enzyme digestion of polymerase chain reaction products. A significant difference was determined between the patients with MI and the control subjects with regards to fetuin-A 742 C/T gene polymorphism (P=0.028), regardless of age. Genotype distributions of fetuin-A 742 (C/G, P=0.004) and 766 (C/T, P=0.017) were statistically different in the older patients with MI (MI ≥ 40 years old), as compared with the healthy controls; however, there were no significant differences between the younger patients with MI and the controls, with regards to fetuin-A 742 C/T (P=0.519) and 766 C/G (P=0.653) gene polymorphisms. In addition, an association was observed between the presence of fetuin-A 742 T and 766 G alleles, and MI cases. The present study demonstrates that fetuin-A 742 (C/T) and 766 (C/G) genotypes may be risk factors for MI in patients older than 40 years of age.