Trophodynamics and potential health risk assessment of heavy metals in the mangrove food web in Yanpu Bay, China.

Mangroves are the cradle of coastal water biodiversity and are susceptible to heavy metal pollution. However, the trophic transfer mechanism of heavy metals in the mangrove food web and the resulting human health risks are not fully understood. Heavy metal concentration (Cr, Ni, Cu, Zn, As, Cd, Pb, V, Co) and stable isotope ratios of carbon and nitrogen (δ13C and δ15N) were evaluated in sediments and particulate organic matter, litter, and aquatic organisms (plankton, arthropods, mollusks, omnivorous fish, and carnivorous fish) from the Yanpu Bay mangroves. The results revealed that heavy metals exhibited different trophic transfer patterns. As and Hg were efficiently biomagnified, with trophic magnification factors of 1.17 and 1.42, respectively; while Cr, Ni, Cu, Cd, Pb, V, and Co were efficiently biodiluted. Zn exhibited a trophic magnification factor > 1 and was not significantly correlated with δ15N (p > 0.05), suggesting no biomagnification or biodilution. The heavy metals in the important fishery species (omnivorous fish and carnivorous fish) were below the permissible limits, except for Zn in Ophichthus apicalis. The assessment of probabilistic health risks revealed that fish consumption in adults and children posed an acceptable risk (total target hazard quotient <1).

Unearthing new ccr genes and SCC elements in staphylococci through genome mining.

The SCCmec typing is crucial for investigating methicillin-resistant S. aureus, relying primarily on the combination of ccr and mec gene complexes. To date, 19 ccr genes and 10 ccr gene complexes have been identified, forming 15 SCCmec types. With the vast release of bacterial genome sequences, mining the database for novel ccr gene complexes and SCC/SCCmec elements could enhance MRSA epidemiological studies. In this study, we identified 12 novel ccr genes (6 ccrA, 3 ccrB and 3 ccrC) through mining of the NCBI database, which forming 12 novel ccr gene complexes and 10 novel SCC elements. Overexpression of five groups of novel Ccr recombinases (CcrA9B3, CcrA10B1, CcrC3, CcrC4, and CcrC5) in a mutant MRSA strain lacking the ccr gene and extrachromosomal circular intermediate (ciSCC) production significantly promoted ciSCC production, demonstrating their biological activity. This discovery provides an opportunity to advance MRSA epidemiological research and develop database-based bacterial typing methods.

Cytoplasmic localization of IRF5 induces Wnt5a/E-cadherin degradation and promotes gastric cancer cells metastasis.

IRF5, a nucleoplasm shuttling protein, is a pivotal transcription factor regulating immune system activity. It's well known that immunosuppression is involved in the development of gastric cancer. However, no data exist for the expression and function of IRF5 in gastric cancer. This study demonstrated that IRF5 was cytoplasm-enriched in gastric cancer cells. IRF5 promoted gastric cancer cell migration, which involved the inhibition of Wnt5a and E-cadherin proteins expression. IRF5 (LA) localized in nucleus had no significant effect on Wnt5a and E-cadherin expressions, while mutation of IRF5 (ΔNLS), which prevents IRF5 nuclear translocation, had more impact on these inhibitory effects. In addition, degradation rates of both Wnt5a and E-cadherin were enhanced by resiquimod, an IRF5 agonist. Further in vivo experiments indicated that IRF5 knockout of gastric cancer cells repressed their pulmonary metastasis in nude mice. Finally, the expression and clinical significance of IRF5 were analyzed using gastric cancer tissue microarrays, which suggested that the expression of IRF5 varied procedurally in different progressive stages of gastric cancer. Our data revealed that IRF5 cytoplasmic localization were associated with Wnt5a and E-cadherin degradation and gastric cancer cell metastasis. Inhibiting IRF5 expression and/or its cytoplasmic localization may provide a novel target for gastric cancer therapy.

Insights into melatonin-induced photosynthetic electron transport under low-temperature stress in cucumber.

In this study, the differences in chlorophyll fluorescence transient (OJIP) and modulated 820 nm reflection (MR820) of cucumber leaves were probed to demonstrate an insight into the precise influence of melatonin (MT) on cucumber photosystems under low temperature stress. We pre-treated cucumber seedlings with different levels of MT (0, 25, 50, 100, 200, and 400 µmol · L-1) before imposing low temperature stress (10 °C/6 °C). The results indicated that moderate concentrations of MT had a positive effect on the growth of low temperature-stressed cucumber seedlings. Under low temperature stress conditions, 100 µmol · L-1 (MT 100) improved the performance of the active photosystem II (PSII) reaction centers (PIabs), the oxygen evolving complex activity (OEC centers) and electron transport between PSII and PSI, mainly by decreasing the L-band, K-band, and G-band, but showed differences with different duration of low temperature stress. In addition, these indicators related to quantum yield and energy flux of PSII regulated by MT indicated that MT (MT 100) effectively protected the electron transport and energy distribution in the photosystem. According to the results of WO-I ≥ 1 and MR820 signals, MT also affected PSI activity. MT 100 decreased the minimal value of MR/MRO and the oxidation rate of plastocyanin (PC) and PSI reaction center (P700) (Vox ), while increased △MRslow/MRO and deoxidation rates of PC+ and P700 + (Vred ). The loss of the slow phase of MT 200 and MT 400-treated plants in the MR820 kinetics was due to the complete prevention of electron movement from PSII to re-reduce the PC+ and P700 +. These results suggest that appropriate MT concentration (100 µmol · L-1) can improve the photosynthetic performance of PS II and electron transport from primary quinone electron acceptor (QA) to secondary quinone electron acceptor (QB), promote the balance of energy distribution, strengthen the connectivity of PSI and PSII, improve the electron flow of PSII via QA to PC+ and P700 + from reaching PSI by regulating multiple sites of electron transport chain in photosynthesis, and increase the pool size and reduction rates of PSI in low temperature-stressed cucumber plants, All these modifications by MT 100 treatment promoted the photosynthetic electron transfer smoothly, and further restored the cucumber plant growth under low temperature stress. Therefore, we conclude that spraying MT at an appropriate concentration is beneficial for protecting the photosynthetic electron transport chain, while spraying high concentrations of MT has a negative effect on regulating the low temperature tolerance in cucumber.

An Investigation of a Confirmed Imported Case of COVID-19 Infected Abroad - Qingpu District, Shanghai Municipality, China, November 15, 2020.

SUMMARY: What is already known about this topic? A passenger who was from the United States was taken to the hotel for the required isolation on November 13, 2020. During the quarantine she was diagnosed as the COVID-19 patient on November 15, 2020. Controlling the importation of COVID-19 remains a major challenge.What is added by this report? In this study, an epidemiological investigation was conducted for a confirmed case of COVID-19, including the treatment records in the hospital and 14-day travel trajectory before the onset of disease.What are the implications for public health practice? This study described an epidemiological investigation and management process on an imported case of COVID-19 and analyzed the test results, aiming to provide useful warnings to strengthen the capacity of public health system in response to the importation.

Anaerobic digestion: An alternative resource treatment option for food waste in China.

With the implementation of zero-waste city and waste classification in China, a large amount of food waste (FW) began to appear in concentration, and there was an urgent requirement for appropriate and efficient treatment technology. Traditional FW disposal methods (landfill and incineration) could cause several environmental problems, so resource recycling has become the main development trend of FW in China. In recent years, anaerobic digestion (AD) technology for FW resource treatment has attracted much attention due to its advantages such as the ability to obtain clean energy, low carbon emissions, and suitability for large-scale treatment compared with other recycling technologies (composting, feed, and breeding insects). Chinese policy is conducive to the development of AD for FW, which has the potential to produce methane and achieve economic and environmental benefits. This paper presents an overview of the researches, application situations, and perspectives for the AD of FW resource treatment in China. The bibliometric analysis shows that China has the most interest in the AD of FW compared to other countries, and the amount and characteristics analysis of FW indicates that FW is suitable for treatment by AD. At the same time, this review analyzes the influence factors, methods to promote AD, working mechanism, secondary pollution of AD. Besides, the article introduces and analyzes the current policies, application status, economic and environmental benefits, and problems of AD for FW resource treatment in China. AD is considered as an alternative resource treatment technology for FW, although there are still several problems such as odors, digestate, etc. In the future, China should focus on the reform of management policy, the implementation of the AD circular economy model, and the research of the biorefinery model based on AD technology.

FLCN Regulates HIF2α Nuclear Import and Proliferation of Clear Cell Renal Cell Carcinoma.

Aims and Hypothesis: This study aims to explore the specific molecular mechanism of folliculin (FLCN)-induced proliferation, migration, and invasion in clear cell renal cell carcinoma (ccRCC) and to investigate the relationship of FLCN and HIF2α. Folliculin was identified as a tumor suppressor gene. Its deletions and mutations are associated with a potential risk of renal cancer. At present, the specific molecular mechanism of FLCN-induced proliferation, invasion, and migration in ccRCC remains elusive. Methods: Cell proliferation was measured by flow cytometry analysis, while cell migration and invasion were measured by wound healing assay and Matrigel invasion assay. The expression of FLCN, HIF2α, MMP9, and p-AKT was examined by Western blotting. The cells were transfected with plasmids or siRNA to upregulate or downregulate the expression of FLCN. Immunofluorescence microscopy was carried out to display the HIF2α location. We also determined the correlation of FLCN and HIF2α in human renal cancer samples. Results: FLCN was combined with HIF2α in renal tubular epithelial and cancer cells, and it effectively alleviates the deterioration of renal cancer cells by degrading HIF2α. The silencing of FLCN showed a promotion of HIF2α protein expression via PI3K/mTORC2 pathway, which in turn led to an increase in downstream target genes Cyclin D1 and MMP9. Moreover, interfering with siFLCN advanced the time of HIF2α entry into the nucleus. Conclusions: Our study illustrated that FLCN could be a new therapeutic target in ccRCC. FLCN combined with HIF2α and identified a novel PI3K/mTORC2/HIF2α signaling in ccRCC cells.

WNT7A Promotes EGF-Induced Migration of Oral Squamous Cell Carcinoma Cells by Activating ß-Catenin/MMP9-Mediated Signaling.

AIMS AND HYPOTHESIS: Epidermal growth factor (EGF) has been shown to induce the migration of various cancer cells. However, the underlying signaling mechanisms for EGF-induced migration of oral squamous cell carcinoma (OSCC) remain to be elucidated. WNT7A, a member of the family of 19 Wnt secreted glycoproteins, is commonly associated with tumor development. It is mostly unknown whether and, if so, how EGF modulates WNT7A in OSCC cells. The role of WNT7A in OSCC was thus investigated to explore the underlying signaling mechanisms for EGF-induced migration of OSCC. METHODS: Cell migration was measured by Wound healing assay and Transwell assay. Western blotting was carried out to detect the expression of WNT7A, MMP9, ß-catenin, p-AKT, and p-ERK. The cells were transfected with plasmids or siRNA to upregulate or downregulate the expression of WNT7A. The location of ß-catenin was displayed by immunofluorescence microscopy. Immunohistochemistry was carried out to confirm the relation between WNT7A expression and OSCC progression. RESULTS: The present study showed that the levels of WNT7A mRNA and protein were increased by EGF stimulation in OSCC cells. Besides, it was proved that p-AKT, but not p-ERK, mediated the expression of WNT7A protein induced by EGF. Furthermore, the inhibition of AKT activation prevented the EGF-induced increase of WNT7A and matrix metallopeptidase 9 (MMP9) expression and translocation of ß-catenin from the cytoplasm to the nucleus. Moreover, histological analysis of OSCC specimens revealed an association between WNT7A expression and poor clinical prognosis of the disease. CONCLUSIONS: The data in this paper indicated that WNT7A could be a potential oncogene in OSCC and identified a novel PI3K/AKT/WNT7A/ß-catenin/MMP9 signaling for EGF-induced migration of OSCC cells.

MICAL-L2 Is Essential for c-Myc Deubiquitination and Stability in Non-small Cell Lung Cancer Cells.

Objectives: MICAL-L2, a member of the molecules interacting with the CasL (MICAL) family, was reported to be highly expressed in several types of cancers, however, the roles of MICAL-L2 in NSCLC pathogenesis remain to be explored. This study is designed to clarify the mechanisms by which MICAL-L2 participates in NSCLC cell proliferation. Materials and Methods: The expression levels of MICAL-L2 in human lung cancer samples were assessed by immunohistochemical staining. Cells were transfected with siRNA or plasmids to regulate MICAL-L2 expression. Cell proliferation was measured by EdU staining and CCK-8 assays. MICAL-L2 and phosphorylated/total c-Myc expression were examined by Western blotting analysis. Interaction between MICAL-L2 and c-Myc was assessed by immunofluorescence staining, Western blotting and co-immunoprecipitation assays. Western blotting, polyubiquitylation detection and protein stability assays were used to assess whether MICAL-L2 exerts its oncogenic effect via c-Myc. Results: We found that MICAL-L2 was highly expressed in human NSCLC. While overexpressing MICAL-L2 increased NSCLC cell proliferation, MICAL-L2 depletion decreased the proliferation of NSCLC cells, an effect that was linked to cell cycle arrest. MICAL-L2 physically interacted with the c-Myc protein and functioned to maintain nuclear c-Myc levels and prolonged its half-life. Knockdown of MICAL-L2 expression led to decreased c-Myc protein stability through accelerating polyubiquitylation of c-Myc and gave rise to c-Myc degradation. We further found that MICAL-L2 deubiquitinated c-Myc and blocked its degradation, presumably by inhibiting c-Myc phosphorylation at threonine residue 58. Conclusions: These results indicate that MICAL-L2 is a key regulator of c-Myc deubiquitination and stability in the nucleus, and this activity may be involved in promoting NSCLC cell proliferation.

Non-canonical Notch Signaling Regulates Actin Remodeling in Cell Migration by Activating PI3K/AKT/Cdc42 Pathway.

Tumor cell migration is a critical step in cancer metastasis. Over-activated Notch pathway can promote the migration of cancer cells, especially in the breast cancer. However, the underlying mechanism of non-canonical Notch signaling in modulating the migration has not yet been clearly characterized. Here we demonstrated that DAPT, a gamma secretase inhibitor, inhibited protrusion formation and cell motility, and then reduced the migration of triple-negative breast cancer cells, through increasing the activity of Cdc42 by non-canonical Notch pathway. Phosphorylation of AKT on S473 was surprisingly increased when Notch signaling was inhibited by DAPT. Inhibition of PI3K and AKT by LY294002 and MK2206, respectively, or knockdown of AKT expression by siRNA blocked DAPT-induced activation of Cdc42. Moreover, immunofluorescence staining further showed that DAPT treatment reduced the formation of lamellipodia and induced actin cytoskeleton remodeling. Taken together, these results indicated that DAPT inhibited Notch signaling and consequently activated PI3K/AKT/Cdc42 signaling by non-canonical pathway, facilitated the formation of filopodia and inhibited the assembly of lamellipodia, and finally resulted in the decrease of migration activity of breast cancer cells.

MICAL-L2 potentiates Cdc42-dependent EGFR stability and promotes gastric cancer cell migration.

Enhanced migration potential is a common characteristic of cancer cells induced by mechanisms that are incompletely defined. The present study was designed to investigate relationship of a new discovered cytoskeleton regulator MICAL-L2 and the endogenous epidermal growth factor receptor (EGFR) signalling pathways in gastric cancer cell migration. Increased expression of MICAL-L2 in gastric cancer cells up-regulated EGFR protein level, accompanied by the increase of cell migration, whereas silencing MICAL-L2 down-regulated EGFR and inhibited cell migration. Expression of MICAL-L2 was also shown positively correlated with the activation of HSP27/cytoskeleton and HSP27/ß-catenin signalling pathways that provide key mechanisms controlling cell migration. The up-regulating effect of MICAL-L2 on EGFR is mediated through a transcription-independent mechanism that involves inhibiting EGFR protein degradation in lysosome. Further analysis indicated that Cdc42 activation contributed in maintaining the effect of MICAL-L2 on EGFR stability. Furthermore analysis of clinic specimens revealed increased expression of MICAL-L2 in carcinoma tissues and a positive correlation between MICAL-L2 and EGFR expression levels. The above results indicate that MICAL-L2 potentiates gastric cell migration via inhibiting EGFR degradation in lysosome via a Cdc42-dependent manner that leads to the activation of EGFR/HSP27 signalling pathways.

NEDD9 Facilitates Hypoxia-Induced Gastric Cancer Cell Migration via MICAL1 Related Rac1 Activation.

Aims and Hypothesis: NEDD9 is highly expressed in gastric cancer and has a significant involvement in its pathogenesis. However, the mechanism behind hypoxia-promoted cancer cell migration and its regulation because of NEDD9 is still unknown. The aim of this study is to investigate the involvement of NEDD9 in gastric cancer cell migration under hypoxia and explore the underlying potential molecular mechanisms. METHODS: Cell motility was measured by wound healing and transwell assay. NEDD9 and MICAL1 expressions were examined by western blot analysis. Interaction between NEDD9 and MICAL1 was assessed by immunohistochemistry and co-immunoprecipitation assay, respectively. Cells were transfected with plasmids or siRNA to upregulate or downregulate the expression of NEDD9 and MICAL1. Rac1, Cdc42, and RhoA activation was assessed by pulldown assay. RESULTS: The mRNA and protein level of NEDD9 increased as a result of hypoxia in gastric cancer cell lines BGC-823 and SGC-7901 while decreased levels of NEDD9 caused reduced cell migratory potential in response to hypoxia. Hypoxia also caused the enhancement of MICAL1 expression. Furthermore, it was revealed that there is a positive correlation between NEDD9 and MICAL1 protein while hypoxia played role in increasing their interaction. Under hypoxic conditions, silencing of NEDD9 caused reduction in the stability of MICAL1 protein, while depletion of MICAL1 also inhibited the migration of NEDD9-overexpressing gastric cancer cells. In addition, silencing of NEDD9 or MICAL1 expression reversed the increased GTP forms of Rac1 and Cdc42 in hypoxic cells. However, only the upregulation of Rac1-GTP level was observed in gastric cancer cells that were already overexpressed by MICAL1. CONCLUSION: In all, it is concluded that MICAL1 is regulated by NEDD9 that facilitates hypoxia-induced gastric cancer cell migration via Rac1-dependent manner.

Effect of melatonin on EGF- and VEGF-induced monolayer permeability of HUVECs.

Melatonin is a natural hormone involved in the regulation of circadian rhythm, immunity, and cardiovascular function. In the present study, we focused on the mechanism of melatonin in the regulation of vascular permeability. We found that melatonin could inhibit both VEGF- and EGF-induced monolayer permeability of human umbilical vein endothelial cells (HUVECs) and change the tyrosine phosphorylation of vascular-endothelial (VE-)cadherin, which was related to endothelial barrier function. In addition, phospho-AKT (Ser473) and phospho-ERK(1/2) played significant roles in the regulation of VE-cadherin phosphorylation. Both the phosphatidylinositol 3-kinase/AKT inhibitor LY49002 and MEK/ERK inhibitor U0126 could inhibit the permeability of HUVECs, but with different effects on tyrosine phosphorylation of VE-cadherin. Melatonin can influence the two growth factor-induced phosphorylation of AKT (Ser473) but not ERK(1/2). Our results show that melatonin can inhibit growth factor-induced monolayer permeability of HUVECs by influencing the phosphorylation of AKT and VE-cadherin. Melatonin can be a potential treatment for diseases associated with abnormal vascular permeability. NEW & NOTEWORTHY We found that melatonin could inhibit both EGF- and VEGF-induced monolayer permeability of human umbilical vein endothelial cells, which is related to phosphorylation of vascular-endothelial cadherin. Blockade of phosphatidylinositol 3-kinase/AKT and MEK/ERK pathways could inhibit the permeability of human umbilical vein endothelial cells, and phosphorylation of AKT (Ser473) might be a critical event in the changing of monolayer permeability and likely has cross-talk with the MEK/ERK pathway.

Cucurbitacin E induces apoptosis of human prostate cancer cells via cofilin-1 and mTORC1.

Cucurbitacin E is an important member of the cucurbitacin family and exhibits inhibitory effects in various types of cancer. Cucurbitacin is a potential antineoplastic drug; however, its anticancer effect in human prostate cancer (PC) remains unknown. The aim of the present study was to determine whether the effect of cucurbitacin E on the cell viability and apoptosis of the human PC cell line, LNCaP, was mediated by cofilin-1- and mammalian target of rapamycin (mTOR). The results of the present study demonstrated that cucurbitacin E significantly exhibited cytotoxicity, suppressed cell viability (P<0.0001) and induced apoptosis (P=0.0082) in LNCaP cells. In addition, it was demonstrated that treatment with cucurbitacin E significantly induced cofilin-1 (P=0.0031), p-mTOR (P=0.0022), AMP-activated protein kinase (AMPK; P=0.0048), cellular tumor antigen p53 (p53; P=0.0018) and caspase-9 (P=0.0026) protein expression in LNCaP cells, suggesting that cucurbitacin E exerts its effects on LNCaP cells through cofilin-1, mTOR, AMPK, p53 and caspase-9 signaling. These results suggested that cucurbitacin E maybe used as a therapeutic agent in the treatment of human PC.

Elevated levels of autophagy-related marker ULK1 and mitochondrion-associated autophagy inhibitor LRPPRC are associated with biochemical progression and overall survival after androgen deprivation therapy in patients with metastatic prostate cancer.

AIM: To evaluate the expression levels and prognostic significance of autophagy-related markers, UNC-51-like kinase1 (ULK1), Beclin1, microtubule-associated protein light chain 3 (LC3), autophagy-related gene 5 (ATG5) and mitochondrion-associated autophagy inhibitor, LRPPRC, in patients with metastatic prostate cancer (PCa) after androgen deprivation therapy (ADT). METHODS: Expressions of ULK1, Beclin1, LC3, ATG5 and LRPPRC were assessed by immunohistochemical examination in 198 patients with metastatic PCa who were receiving ADT (goserelin and bicalutamide). RESULTS: High expression levels of LRPPRC and ULK1were significantly associated with Gleason score, serum prostate-specific antigen (PSA) levels, PSA levels after ADT and number of metastatic sites. High expression of ULK1 in patients with concomitant high expression of LRPPRC was significantly associated with multiple metastases, shorter biochemical progression (BCP)-free survival and shorter overall survival (OS). ULK1 expression, LRPPRC expression, Gleason score, PSA levels after ADT and number of metastatic sites were independently associated with shorter BCP-free survival and OS on multivariate analysis. Furthermore, two-year BCP rate of patients with ≥3 risk factors was found to be significantly higher as compared with that of patients with ≤1 and 2 risk factors. Three-year OS rate in patients with ≥3 risk factors was significantly lower than that of those with ≤1 and 2 risk factors. CONCLUSIONS: High expression of ULK1 concomitant with high expression of LRPPRC may serve as useful markers for shorter BCP-free survival and OS in patients with metastatic PCa after ADT.

miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2.

MicroRNAs play critical roles in the development and progression of human cancers. Although it has been reported that miR-106a* is downregulated in follicular lymphoma, its role in renal cell carcinoma (RCC) remains unknown. This study investigated the expression and role of miR-106a* in human RCC. Our results showed that the miR-106a* expression decreased dramatically in clinical RCC tissues and cell lines. In vitro, overexpression of miR-106a* suppressed RCC cell proliferation and S/G2 transition, whereas inhibition of miR-106a* promoted cell proliferation and S/G2 transition. It was also found that miR-106a* expression was inversely correlated with the expression of insulin receptor substrate 2 (IRS-2). IRS-2 was determined to be a direct target of miR-106a* by a luciferase reporter assay. Importantly, silencing IRS-2 resulted in the same biologic effects as those of miR-106a* overexpression in RCC cells, including inhibition of RCC cell proliferation and triggering of S/G2 cell cycle arrest with inhibition of the PI3K/Akt signaling pathway. These results indicate that miR-106a* affects RCC progression by targeting IRS-2 with suppression of the PI3K/Akt signaling pathway in RCC cells. The findings suggest miR-106a* as a novel strategy for RCC treatment.

HIF-1alpha links beta-adrenoceptor agonists and pancreatic cancer cells under normoxic condition.

AIM: To examine whether beta-adrenoceptor (beta-AR) agonists can induce hypoxia-inducible factor (HIF)-1alpha accumulation which then up-regulate the expression of its target genes in pancreatic cancer cells at normoxia, and to further elucidate the mechanism involved. METHODS: Pulse-chase assay, RT-PCR, and Western blot were employed to detect the effects of beta-AR agonists and antagonists, siRNA as well as several inhibitors of signal transduction pathways on MIA PaCa2 and BxPC-3 pancreatic cancer cells. RESULTS: Treatment of pancreatic cancer cell lines with beta-AR agonists led to accumulation of HIF-1alpha and then up-regulated expression of its target genes independently of oxygen levels. The induction was partly or completely inhibited not only by beta-AR antagonists but also by inhibitors of PKA transduction pathways and by siHIF-1alpha. Both beta1-AR and beta2-AR agonists produced the above-mentioned effects, but beta2-AR agonist was more potent. CONCLUSION: Activation of beta-AR receptor transactivates epidermal growth factor receptor (EGFR) and then elicits Akt and ERK1/2 in a PKA-dependent manner, which together up-regulate levels of HIF-1alpha and downstream target genes independently of oxygen level. Our data suggest a novel mechanism in pancreatic cancer cells that links beta-AR and HIF-1alpha signaling under normoxic conditions, with implications for the control of glucose transport, angiogenesis and metastasis.