Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide because of metastasis. Epithelial‐mesenchymal transition (EMT) is widely considered to be crucial to the invasion‐metastasis cascade during cancer progression. Actin‐like 6A (ACTL6A) is initially verified important for cell proliferation, differentiation, and migration. In this study, we find that ACTL6A plays an essential role in metastasis and EMT of HCC. ACTL6A expression is up‐regulated in HCC cells and tissues. A high level of ACTL6A in HCCs is correlated with aggressive clinicopathological features and is an independent poor prognostic factor for overall and disease‐free survival of HCC patients. Ectopic expression of ACTL6A markedly promotes HCC cells migration, invasion, as well as EMT in vitro and promotes tumor growth and metastasis in the mouse xenograft model. Opposite results are observed when ACTL6A is knocked down. Mechanistically, ACTL6A promotes metastasis and EMT through activating Notch signaling. ACTL6A knockdown has the equal blockage effect as the Notch signaling inhibitor, N‐[N‐(3,5‐difluorophenacetyl)‐L‐alanyl]‐S‐phenylglycine t‐butylester, in HCC cells. Further studies indicate that ACTL6A might manipulate SRY (sex determining region Y)‐box 2 (SOX2) expression and then activate Notch1 signaling. Conclusions: ACTL6A promotes metastasis and EMT by SOX2/Notch1 signaling, indicating a prognostic biomarker candidate and a potential therapeutic target for HCC. (Hepatology 2016;63:1256–1271)
BackgroundThe DEK protein is related to chromatin reconstruction and gene transcription, and plays an important role in cell apoptosis. High expression levels of the human DEK gene have been correlated with numerous human malignancies. This study explores the roles of DEK in tumor progression and as a prognostic determinant of colorectal cancer.MethodsColorectal cancer specimens from 109 patients with strict follow-up, and colorectal adenomas from 52 patients were selected for analysis of DEK protein by immunohistochemistry. The correlations between DEK over expression and the clinicopathological features of colorectal cancers were evaluated by Chi-square test and Fisher’s exact tests. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models.ResultsDEK protein showed a nuclear immunohistochemical staining pattern in colorectal cancers. The strongly positive rate of DEK protein was 48.62% (53/109) in colorectal cancers, which was significantly higher than that in either adjacent normal colon mucosa (9.17%, 10/109) or colorectal adenomas (13.46%, 7/52). DEK over expression in colorectal cancers was positively correlated with tumor size, grade, lymph node metastasis, serosal invasion, late stage, and disease-free survival- and 5-year survival rates. Further analysis showed that patients with late stage colorectal cancer and high DEK expression had worse survival rates than those with low DEK expression. Moreover, multivariate analysis showed high DEK expression, serosal invasion, and late stage are significant independent risk factors for mortality in colorectal cancer.ConclusionsDEK plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor of colorectal cancers.
Three new quinazoline-containing diketopiperazines, polonimides A–C (1–3), along with four analogues (4–7), were obtained from the marine-derived fungus Penicillium polonicum. Among them, 2 and 4, 3 and 5 were epimers, respectively, resulting the difficulty in the determination of their configurations. The configurations of 1–3 were determined by 1D nuclear overhauser effect (NOE), Marfey and electron circular dichroism (ECD) methods. Nuclear magnetic resonance (NMR) calculation with the combination of DP4plus probability method was used to distinguish the absolute configurations of C-3 in 3 and 5. All of 1–7 were tested for their chitinase inhibitory activity against OfHex1 and OfChi-h and cytotoxicity against A549, HGC-27 and UMUC-3 cell lines. Compounds 1–7 exhibited weak activity towards OfHex1 and strong activity towards OfChi-h at a concentration of 10.0 μM, with the inhibition rates of 0.7%–10.3% and 79.1%–95.4%, respectively. Interestingly, 1–7 showed low cytotoxicity against A549, HGC-27 and UMUC-3 cell lines, suggesting that good prospect of this cluster of metabolites for drug discovery.
Muscle atrophy is a severe clinical problem involving the loss of muscle mass and strength that frequently accompanies the development of numerous types of cancer, including pancreatic, lung and gastric cancers. cancer cachexia is a multifactorial syndrome characterized by a continuous decline in skeletal muscle mass that cannot be reversed by conventional nutritional therapy. The pathophysiological characteristic of cancer cachexia is a negative protein and energy balance caused by a combination of factors, including reduced food intake and metabolic abnormalities. numerous necessary cellular processes are disrupted by the presence of abnormal metabolites, which mediate several intracellular signaling pathways and result in the net loss of cytoplasm and organelles in atrophic skeletal muscle during various states of cancer cachexia. currently, the clinical morbidity and mortality rates of patients with cancer cachexia are high. once a patient enters the cachexia phase, the consequences are difficult to reverse and the treatment methods for cancer cachexia are very limited. The present review aimed to summarize the recent discoveries regarding the pathogenesis of cancer cachexia-induced muscle atrophy and provided novel ideas for the comprehensive treatment to improve the prognosis of affected patients. Contents 1. introduction 2. activation of the uPS 3. Induction of proinflammatory factors 4. regulation of signaling pathways, transcription factors and micrornas (mirnas/mirs) 5. cell autophagy/lysosomal and ca 2+-dependent protein degradation pathways 6. endoplasmic reticulum stress and mitochondrial dysfunction 7. other receptors and substances that affect metabolism 8. Treatment of muscle atrophy caused by cancer cachexia 9. conclusion
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