Gastric cardia cancer (GCC), which occurs at the gastricesophageal boundary, is one of the most malignant tumors. Despite its high mortality and morbidity, the molecular mechanism of initiation and progression of this disease is largely unknown. In this study, using proteomics and metabolomics approaches, we found that the level of several enzymes and their related metabolic intermediates involved in glucose metabolism were deregulated in GCC. Among these enzymes, two subunits controlling pyruvic acid efflux, lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase B (PDHB), were further analyzed in vitro. Either down-regulation of LDH subunit LDHA or overexpression of PDH subunit PDHB could force pyruvic acid into the Krebs cycle rather than the glycolysis process in AGS gastric cancer cells, which inhibited cell growth and cell migration. Our results reflect an important glucose metabolic signature, especially the dysregulation of pyruvic acid efflux in the development of GCC. Forced transition from glycolysis to the Krebs cycle had an inhibitory effect on GCC progression, providing potential therapeutic targets for this disease. Molecular & Cellular Proteomics 9: 2617-2628, 2010.

BackgroundNon-small-cell lung carcinomas (NSCLCs) exhibit poor prognosis and are usually resistant to conventional chemotherapy. Absence of p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor, has been linked to drug resistance in many in vitro cellular models. RNA activation (RNAa) is a transcriptional activation phenomena guided by double-strand RNA (dsRNA) targeting promoter region of target gene.MethodsIn this study, we explored the effect of up-regulation of p21 gene expression on drug-resistance in A549 non-small-cell lung carcinoma cells by transfecting the dsRNA targeting the promoter region of p21 into A549 cells.ResultsEnhanced p21 expression was observed in A549 cells after transfection of dsRNA, which was correlated with a significant growth inhibition and enhancement of chemosensitivity to cisplatin in A549 cells in vitro. Moreover, in vivo experiment showed that saRNA targeting the promoter region of p21 could significantly inhibit A549 xenograft tumor growth.ConclusionsThese results indicate that p21 plays a role in lung cancer drug-resistance process. In addition, this study also provides evidence for the usage of saRNA as a therapeutic option for up-regulating lower-expression genes in lung cancer.

Eph/Ephrin family, one of the largest receptor tyrosine kinase families, has been extensively studied in morphogenesis and neural development. Recently, growing attention has been paid to its role in the initiation and progression of various cancers. However, the role of Eph/Ephrins in hepatocellular carcinoma (HCC) has been rarely investigated. In this study, we found that the expression of EphrinA2 was significantly up-regulated in both established cell lines and clinical tissue samples of HCC, and the most significant increase was observed in the tumors invading the portal veins. Forced expression of EphrinA2 in HCC cells significantly promoted in vivo tumorigenicity, whereas knockdown of this gene inhibited this oncogenic effect. We further found that suppression of apoptosis, rather than accelerating proliferation, was responsible for EphrinA2-enhanced tumorigenicity. In addition, EphrinA2 endowed cancer cells with resistance to tumor necrosis factor alpha (TNF-␣)-induced apoptosis, thus facilitating their survival. Furthermore, we disclosed a novel EphrinA2/ras-related c3 botulinum toxin substrate 1 (Rac1)/V-akt murine thymoma viral oncogene homolog ( H epatocellular carcinoma (HCC) is a major health problem worldwide, ranking as the fifth most common cancer in the world and the third most common cause of cancer-related death. 1 HCC shows great geographical variation, with a very high incidence in Asia and sub-Saharan Africa, but it is now becoming more common in the West. During the past 20 years in the United States, HCC has risen by 114%. 2 This paralleled an increase in the incidence of chronic hepatitis, which serves as a main risk factor for HCC. 3 At the initiation of hepatic oncogenesis, transformed hepatocytes must elude various cellular defense activities and acquire abnormal capabilities to survive and proliferate. 4 Aberrant signaling through receptor tyrosine kinases plays a pivotal role in the development and progression of HCC. 5 Eph receptors constitute one of the largest receptor tyrosine kinase families and have been reported to be involved in a variety of cancers. For example, up-regulation of EphA2 has been observed in many malignant tumors [6][7][8] and is associated with accelerated cell prolifera-