No abstract

Cbx4 is a polycomb group protein that is also a SUMO E3 ligase, but its potential roles in tumorigenesis remain to be explored. Here, we report that Cbx4, but not other members of the Cbx family, enhances hypoxia-induced vascular endothelial growth factor (VEGF) expression and angiogenesis in hepatocellular carcinoma (HCC) cells through enhancing HIF-1α sumoylations at K391 and K477 in its two SUMO-interacting motifs-dependent mechanisms and increasing transcriptional activity of HIF-1. The Cbx4 expression is significantly correlated with VEGF expression, angiogenesis, and the overall survival of HCC patients and also in subcutaneously and orthotopically transplanted mice HCC models. Collectively, our findings demonstrate that Cbx4 plays a critical role in tumor angiogenesis by governing HIF-1α protein.

This study is one of the very few investigating the dioxin body burden of a group of child-bearing-aged women at an electronic waste (e-waste) recycling site (Taizhou, Zhejiang Province) (24 ( 2.83 years of age, 40% were primiparae) and a reference site (Lin'an city, Zhejiang Province, about 245 km away from Taizhou) (24 ( 2.35 years of age, 100% were primiparae) in China. Five sets of samples (each set consisted of human milk, placenta, and hair) were collected from each site. Body burdens of people from the e-waste processing site (human milk, 21.02 ( 13.81 pg WHO-TEQ 1998 /g fat (World Health Organization toxic equivalency 1998); placenta, 31.15 ( 15.67 pg WHO-TEQ 1998 /g fat; hair, 33.82 ( 17.74 pg WHO-TEQ 1998 /g dry wt) showed significantly higher levels of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/ Fs) than those from the reference site (human milk, 9.35 ( 7.39 pg WHO-TEQ 1998 /g fat; placenta, 11.91 ( 7.05 pg WHO-TEQ 1998 /g fat; hair, 5.59 ( 4.36 pg WHO-TEQ 1998 /g dry wt) and were comparatively higher than other studies. The difference between the two sites was due to e-waste recycling operations, for example, open burning, which led to high background levels. Moreover, mothers from the e-waste recycling site consumed more foods of animal origin. The estimated daily intake of PCDD/Fs within 6 months by breastfed infants from the e-waste processing site was 2 times higher than that from the reference site. Both values exceeded the WHO tolerable daily intake for adults by at least 25 and 11 times, respectively. Our results implicated that e-waste recycling operations cause prominent PCDD/F levels in the environment and in humans. The elevated body burden may have health implications for the next generation.

The expression of galectin-1, one of the most important lectins participating in the malignant tumor development, has been shown to be regulated by hypoxia, but its exact mechanism remains elusive. Here, we find that ectopically expressed hypoxia-inducible factor (HIF) 1alpha protein, an oxygen-sensitive subunit of HIF-1 that is a master factor for cellular response to hypoxia, significantly increases galectin-1 expression in both messenger RNA and protein levels in all four colorectal cancer (CRC) cell lines tested. However, hypoxia-induced galectin-1 expression cannot be seen in sentrin/SUMO-specific protease 1 homozygous-null mouse embryonic fibroblasts that fail to accumulate HIF-1alpha protein. Furthermore, silence of HIF-1alpha or HIF-1beta expression by specific short hairpin RNAs (shRNAs) antagonizes hypoxia-induced galectin-1 expression. All these results propose that galectin-1 is a direct target of transcriptional factor HIF-1. Applying luciferase reporter assay and chromatin immunoprecipitation, we identify that two hypoxia-responsive elements located at -441 to -423 bp upstream to transcriptional start site of galectin-1 gene are essential for HIF-1-mediated galectin-1 expression. Finally, the knockdown of galectin-1 by its specific shRNA can significantly reduce hypoxia-induced invasion and migration of CRC cell line, and the ectopic expression of galectin-1 can remarkably restore invasion and migration abilities of HIF-1alpha-knocked SW620 cells, proposing that galectin-1 mediates the HIF-1-induced migration and invasion of CRC cells during hypoxia. Taken together, our results shed new light for understanding mechanism for hypoxia/HIF-1-mediated migration/invasion of CRC cells.

No abstract

To investigate the occupational exposure levels to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs), indoor dust (n = 3) in workshops and hair samples from male workers (n = 64) were collected at two electrical and electronic equipment waste (E-waste) dismantling factories located in the LQ area in east China in July 11−13, 2006. Pre- and postworkshift urines (64 of each) were also collected from the workers to study oxidative damage to DNA using 8-hydroxy-2′-deoxyguanosine (8-OHdG) as a biomarker. The concentrations of PCDD/Fs, PCDD/F-WHO-TEQs, PBDEs, PCBs and PCB-WHO-TEQs were (50.0 ± 8.1) × 103, 724.1 ± 249.6, (27.5 ± 5.8) × 106, (1.6 ± 0.4) × 109, (26.2 ± 3.0) × 103 pg/g dry weight (dw) in dust, and (2.6 ± 0.6) × 103 , 42.4 ± 9.3, (870.8 ± 205.4) × 103, (1.6 ± 0.2) × 106, 41.5 ± 5.5 pg/g dw in hair, respectively. The homologue and congener profiles in the samples demonstrated that high concentrations of PCDD/Fs, PBDEs, and PCBs were originated from open burning of E-waste. The 8-OHdG levels were detected at 6.40 ± 1.64 µmol/mol creatinine in preworkshift urines. However, the levels significantly increased to 24.55 ± 5.96 µmol/mol creatinine in postworkshift urines (p < 0.05). Then, it is concluded that there is a high cancer risk originated from oxidative stress indicated by the elevated 8-OHdG levels in the E-waste dismantling workers exposed to high concentrations of PCDD/Fs, PBDEs, and PCBs.

The ability to grow at moderate acidic conditions (pH 4.0-5.0) is important to Escherichia coli colonization of the host's intestine. Several regulatory systems are known to control acid resistance in E. coli, enabling the bacteria to survive under acidic conditions without growth. Here, we characterize an acid-tolerance response (ATR) system and its regulatory circuit, required for E. coli exponential growth at pH 4.2. A two-component system CpxRA directly senses acidification through protonation of CpxA periplasmic histidine residues, and upregulates the fabA and fabB genes, leading to increased production of unsaturated fatty acids. Changes in lipid composition decrease membrane fluidity, F 0 F 1 -ATPase activity, and improve intracellular pH homeostasis. The ATR system is important for E. coli survival in the mouse intestine and for production of higher level of 3-hydroxypropionate during fermentation. Furthermore, this ATR system appears to be conserved in other Gram-negative bacteria.

SENP1(SUMO-specific protease 1) has been shown to be essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1␣) under hypoxia conditions. However, it is unknown how SENP1 activation and hypoxia signaling are coordinated in the cellular response to hypoxia. Here, we report the essential role of SENP1 in endothelial cells as a positive regulator of hypoxia-driven VEGF production and angiogenesis. SENP1 expression is increased in endothelial cells following exposure to hypoxia. Silencing of HIF-1␣ blocks SENP1 expression in cell response to hypoxia. Mutation of the hypoxia response element (HRE) on the Senp1 promoter abolishes its transactivation in response to hypoxia. Moreover, silencing of SENP1 expression decreases VEGF production and abrogates the angiogenic functions of endothelial cell. We also find that the elongated endothelial cells in embryonic brain section and vascular endothelial cells in embryonic renal glomeruli in Senp1 ؊/؊ mice are markedly reduced than those in wild-type.Thus, these results show that hypoxia implies a positive feedback loop mediated by SENP1. This feedback loop is important in VEGF production, which is essential for angiogenesis in endothelial cells.SUMOylation has emerged as an important mechanism in the regulation of multiple cellular signaling pathways (1-3). SUMOylation is catalyzed by the activating (E1), conjugating (E2), and ligating (E3) enzymes. It also can be reversed by a family of sentrin/SUMO-specific 5 proteases (SENPs) (1, 2, 4). There are six human SENPs, each with different subcellular locations and substrate specificities (1, 4). These SENPs can be divided into three subfamilies based on their sequence homology, substrate specificity, and cellular localization. The first subfamily consists of SENP1 and SENP2, which are able to deconjugate either SUMO-1 or SUMO-2/3-modified proteins. The second subfamily members, SENP3 and SENP5, and third subfamily members, SENP6 and SENP7, prefer SUMO-2/3 as substrates (1, 2, 4). The embryonic lethality shown in many SENP knock-out mice indicates that the functions of SENPs are not redundant and have specific substrate specificity (5-7).SENP1 has been reported to play an important role in regulating cellular response to hypoxia (6). It is well known that the cellular response to hypoxia is mainly mediated by HIF-1␣ (8 -11). HIF-1␣ is a basic helix-loop-helix transcription factor and can regulate the expression of many hypoxia-responsive genes, which control multiple cellular processes in response to hypoxia (8,10,(12)(13)(14). At normoxia, HIF-1␣ is degraded but is stabilized and activated under hypoxic conditions (8,12,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Several laboratories showed that hypoxia could induce HIF-1␣ SUMOylation (6,(25)(26)(27)(28)(29). These studies suggest that SUMOylation plays an important role in the regulation of HIF-1␣ under hypoxia condition, although the impact of SUMOylation on HIF-1␣ activity is controversial (6,25,(27)(28). We have shown that hypoxia-induced stabilization of...