No abstract

Abnormal metabolism of nonesterified fatty acids (NEFAs) and their derivatives has been reported to be the main cause of intracellular lipotoxic injury. Normally, NEFAs are stored in lipid droplets (LDs) in the form of triglyceride (TG), which could reduce the lipotoxicity of cytosolic NEFAs. Previous studies have implicated that Perilipin 5 (Plin5), an LD‐binding protein, regulates the storage and hydrolysis of TG in LD. However, its roles and underlying mechanisms in the liver remain unknown. Here we found that Plin5 expression was increased in steatotic livers. Using Plin5 knockout mice, we found that Plin5 deficiency resulted in reduced hepatic lipid content and smaller‐sized LDs, which was due to the elevated lipolysis rate and fatty acid utilization. Plin5‐deficient hepatocytes showed increased mitochondria proliferation, which could be explained by the increased expression and activity of PPARα stimulated by the increased NEFA levels. Meanwhile, Plin5‐deficient livers also exhibited enhanced mitochondrial oxidative capacity. We also found that Plin5 deficiency induces lipotoxic injury in hepatocytes, attributed to lipid peroxidation. Mechanistically, we found that Plin5 blocks adipose triglyceride lipase (ATGL)‐mediated lipolysis by competitively binding to comparative gene identification‐58 (CGI‐58) and disrupting the interaction between CGI‐58 and ATGL. Conclusion: Plin5 is an important protective factor against hepatic lipotoxicity induced by NEFAs generated from lipolysis. This provides an important new insight into the regulation of hepatic lipid storage and relation between lipid storage and lipotoxicity. (Hepatology 2015;61:870–882)

Purinergic signaling has emerged as an important player in cancer progression and is regulated by a series of nucleotidases. Among the enzyme cascade, CD73, which catelyzes AMP breakdown to adenosine, has been found to be overexpressed in many types of cancer. Various factors and mechanisms are employed to regulate expression of CD73. Accumulating studies have shown that CD73 is a key regulatory molecule of cancer cells proliferation, migration and invasion in vitro, tumor angiogenesis, and tumor immune escape in vivo. With such important roles in cancer, CD73 has become an appealing therapy target. Recent evidences in mice models demonstrated that targeted blockade of CD73 could be a favorable therapeutic approach for cancer patients in the future. In this review, we will summarize the multiple roles of CD73 in cancer development, including its clinical significance, its promotive effects on tumor growth, metastasis, and angiogenesis, and its suppressive effects on immune response, regulatory mechanisms of CD73 expression, and current situation of anti-CD73 cancer therapy.

No abstract

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Aberrant expression of Jab1/CSN5, a negative regulator of the cell cycle inhibitor p27, is correlated with reduced p27 expression and associated with advanced tumor stage and poor prognosis in several human cancers. In this study, we examined the functional relationship between Jab1 and p27 protein expression in NPC. Immunohistochemical analysis showed an inverse association between Jab1 and p27 in NPC tissue samples, and overexpression of Jab1 correlated with poor survival in NPC patients. Mechanistically, Jab1 and p27 were found to interact directly in NPC cells, with Jab1 mediating p27 degradation in a proteasome-dependent manner. Knockdown of Jab1 resulted in a remarkable increase in p27 levels and inhibition of cell proliferation, indicating that Jab1 targets p27 for degradation, thereby controlling its stability. Jab1 depletion also enhanced the antitumor effects of cisplatin in NPC cells. Together, our findings suggest that Jab1 overexpression plays an important role in the pathogenesis of NPC through Jab1-mediated p27 degradation. Jab1 therefore represents a novel diagnostic marker and therapeutic target in patients with NPC.

Astrocyte elevated gene 1 (AEG-1), a novel oncoprotein, has been implicated in oncogenesis and cancer progression in various types of human cancers. The clinical significance and biological role of AEG-1 in non-small cell lung cancer (NSCLC), however, remain unclear. In the present study, we found that the expression of AEG-1 was markedly up-regulated in NSCLC cell lines and NSCLC tissues at the level of both transcription and translation. Ectopically expressed AEG-1 enhanced the migratory and invasive abilities of NSCLC cells, whereas knockdown of endogenous AEG-1 by specific shRNAs significantly inhibited these abilities. The function of AEG-1 on metastasis modulation was associated with the activation of the PI3K-Akt and NF-kappaB signalling pathways. Furthermore, we showed high expression of AEG-1 in 99/200 (49.5%) paraffin-embedded archival NSCLC specimens. Moreover, statistical analysis displayed a significant correlation in AEG-1 expression with the clinical stage (p < 0.001), T classification (p = 0.001), N classification (p = 0.015), distant metastasis (p = 0.004) and differentiation (p = 0.027). Patients with higher AEG-1 expression had an overall shorter survival time, whereas patients with lower expression of AEG-1 had a better survival time. Multivariate analysis suggested that AEG-1 expression might be an independent prognostic indicator for the survival of NSCLC patients. Taken together, our results suggest that elevated expression of AEG-1 plays an important role in the aggressiveness of NSCLC, leading to a poor clinical outcome.

Deeper mechanistic understanding of lung adenocarcinoma (non-small cell lung carcinoma, or NSCLC), a leading cause of cancer-related deaths overall, may lead to more effective therapeutic strategies. In analyzing NSCLC clinical specimens and cell lines, we discovered a uniform decrease in miR-186 (MIR186) expression in comparison with normal lung tissue or epithelial cell lines. miR-186 expression correlated with patient survival, with median overall survival time of 63.0 or 21.5 months in cases exhibiting high or low levels of miR-186, respectively. Enforced overexpression of miR-186 in NSCLC cells inhibited proliferation by inducing G 1 -S checkpoint arrest. Conversely, RNA interference-mediated silencing miR-186 expression promoted cell-cycle progression and accelerated the proliferation of NSCLC cells. Cyclin D1 (CCND1), cyclin-dependent kinase (CDK)2, and CDK6 were each directly targeted for inhibition by miR-186 and restoring their expression reversed miR-186-mediated inhibition of cell-cycle progression. The inverse relationship between expression of miR-186 and its targets was confirmed in NSCLC tumor xenografts and clinical specimens. Taken together, our findings established a tumorsuppressive role for miR-186 in the progression of NSCLC. Cancer Res; 73(2); 756-66. Ó2012 AACR.

Our data suggests that the specific downregulation of Mcl-1 by RNAi is a promising approach to induce apoptosis and enhance the chemosensitivity for pancreatic carcinoma gene therapy.