H epatitis B, caused by hepatitis B virus (HBV) infection, is very common in Asia, Africa, and the Middle East. It is estimated that there are 280 million carriers worldwide, representing more than 5% of the global population. Chronic infection with HBV is a major risk factor for the development of hepatocellular carcinoma (HCC); however, the mechanism by which HBV induces events leading to HCC has not been clearly elucidated. The HBV genome consists of four overlapping open reading frames encoding DNA polymerase, surface antigen, core protein, and a regulatory X protein [hepatitis B virus X protein (HBx)].
The multifunctional cytokine p43 acts on endothelial and immune cells to control angiogenesis and inflammation. In this report, we describe an additional activity of p43 that specifically promotes fibroblast proliferation and wound repair. In skin wound regions from mice, tumor necrosis factor-␣ induced p43 expression and secretion from macrophages recruited to the site. p43 also promoted fibroblast proliferation through its 146-amino acid N-terminal domain as revealed by deletion mapping. This p43-induced fibroblast proliferation was mediated by extracellular signal-regulated kinase (Erk). Depletion of endogenous p43 in mice by gene disruption retarded wound repair, whereas exogenous supplementation of recombinant human p43 to the wound area stimulated dermal fibroblast proliferation, collagen production, and wound closure. Thus, we have identified a novel p43 activity involving the stimulation of fibroblast proliferation, which could be applied therapeutically to aid wound repair. (Am J Pathol 2005, 166:387-398)
Resistance to anticancer drugs is a major obstacle preventing effective treatment of disseminated cancers. Understanding the molecular basis to chemoresistance is likely to provide better treatment. Cell lines resistant to cisplatin or 5-fluorouracil (5-FU) were established from human gastric carcinoma cell lines SNU-638 and SNU-620. Comparative proteomics involving 2-dimensional gel electrophoresis (2-DE) and matrix-associated laser desorption ionization-mass spectroscopy (MALDI-MS) was performed on protein extracts from these parental and drug-resistant derivative lines to screen drug resistance-related proteins. Pyruvate kinase M2 (PK-M2) was identified as a protein showing lower expression in cisplatin-resistant cells compared to parental cells. Consistent with this finding, PK-M2 activity was also lower in cisplatin-resistant cells. Suppression of PK-M2 expression by antisense oligonucleotide resulted in acquired cisplatin resistance in SNU-638 cells. Furthermore, PK-M2 activity in 11 individual human gastric carcinoma cell lines positively correlated with cisplatin sensitivity. Taken together, PK-M2 protein and activity levels were lower in cisplatin-resistant human gastric carcinoma cell lines compared to their parental cell lines. Furthermore, suppression of PK-M2 expression using antisense oligonucleotides increased cisplatin resistance. These data clearly link PK-M2 and cisplatin resistance mechanisms. Key words: pyruvate kinase M2; chemoresistance; cisplatin; gastric cancerGastric cancer is one of the most common causes of cancerrelated mortality worldwide. 1 There are marked geographic variations in gastric cancer incidence, with the highest rates in Korea, Japan, China and South America, and much lower rates in Western countries. 2 Contemporary chemotherapies for advanced gastric cancer, usually containing 5-fluorouracil (5-FU) and/or cisplatin, demonstrate response rates in the 20 -40% range, with median survival between 6 and 12 months. 2 However, cancer cells can be insensitive to drug treatment at the outset of therapy (intrinsic resistance) or they may become insensitive after exposure to the antitumor agent (acquired resistance). 3 Drug resistance, especially acquired resistance, is a major obstacle preventing effective treatment of disseminated cancers. Despite extensive studies, the mechanisms underlying drug resistance have yet to be fully understood.Greater understanding of the molecular basis of gastric cancer chemoresistance is likely to provide more effective treatment for patients. In the present study, we created human gastric carcinoma cell lines that were resistant to cisplatin and 5-FU and performed comparative proteomics to identify proteins involved in drug resistance. We herein report that reduced pyruvate kinase M2 (PK-M2) activity is linked to cisplatin resistance. MATERIAL AND METHODS Drug-resistant human gastric carcinoma cell linesHuman gastric carcinoma cell lines SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-520, SNU-601, SNU-620, SNU-638, SNU-668 and SNU-719 4,5 were obta...
5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, resistance to this drug is a major obstacle in CRC chemotherapy. Accurate prediction of response to 5-FU would avoid unnecessary chemotherapy and allow the selection of other effective drugs. To identify a candidate predictor of 5-FU resistance, we isolated secreted proteins that were up- or downregulated in a 5-FU-resistant cancer cell line, compared with the parent cell line (SNU-C4), using a stable isotope-coded labeling protocol. For validating the clinical applicability of this method, levels of the identified proteins were determined in the sera of 46 patients treated with 5-FU. In total, 238 proteins with molecular weights ranging from 50 to 75 kDa were identified. Among these, 45 and 35 secreted proteins were up- and downregulated in the 5-FU-resistant cell line, respectively. We observed significant upregulation of glycolytic enzymes, including glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase M2 (PK-M2), transketolase, and NADP(+)-dependent malic enzyme 1. In particular, the level of PK-M2, a key enzyme in the glycolytic pathway, showed an increasing tendency in both sera and tissues from CRC patients displaying no response to 5-FU-based chemotherapy (progressive and stable disease cases), compared with that in complete or partial responders to 5-FU-based chemotherapy; however, it did not reach the statistical significance. In conclusion, increasing pattern of PK-M2 observed with 5-FU resistance induced in vitro and in sera and tissues from CRC patients displaying poor response to 5-FU-based chemotherapy suggest the relevance of dysregulated glycolysis and 5-FU-resistant CRC.
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