[Influence of Land Use Structure and Spatial Pattern on Water Quality of Small and Medium-sized Rivers in Poyang Lake Basin].

To reveal the influence mechanism of land use structure and spatial pattern on water quality of small and medium-sized rivers, water samples were collected from 25 sampling points in three small and medium-sized rivers of the Poyang Lake Basin in January 2022 and July 2022. Bioenv analysis, the Mantel test, and variance partitioning analysis were used to quantify the effects of land use structure and spatial patterns on water quality at different spatial scales; generalized additive models were used to fit the relationship between water quality and different land use structures and spatial patterns; and a generalized linear model was used to construct segmented regression models and calculate the thresholds based on the stepwise recursive method. The results showed that:① the average interpretation rate of land use structure and spatial pattern on river water quality was 59.72% during the wet period and 48.95% during the dry period. The sub-basin and riparian 100 m scales were the key scales of land use structure and spatial pattern affecting water quality in small and medium-sized rivers, with an average explanation rate of 54.70% and 64.88%, respectively. The joint explanation of land use structure and spatial pattern was an important factor driving the change in river water quality, accounting for 66.90% of the total explanation. ② The impact of land use structure on the water quality of small and medium-sized rivers had a significant threshold effect. When the proportion of construction land was less than 2%, farmland was less than 8%, or forest land was more than 82% at the sub-basin scale and the proportion of construction land was less than 12%, farmland was less than 41%, or forest land was more than 49% at the riparian buffer scale, all could significantly improve water quality. ③ The effect of spatial pattern on water quality in small and medium-sized rivers also had a threshold effect but was weaker than that of land use structure. A patch shape value more than 28.77 or patch diversity more than 0.69 at the sub-basin scale and a patch shape value more than 2.99 or patch diversity more than 1.02 at the riparian buffer scale could improve water quality. The above results showed that strengthening the management of land use at the sub-basin and riparian 100 m scales and setting a reasonable threshold of land use structure and spatial pattern can effectively prevent water quality from deteriorating.

[Community Composition, Symbiotic Patterns, and Influencing Factors of Planktonic Fungi in Urban Lakes of Nanchang].

To investigate the characteristics of planktonic fungal communities in Nanchang lakes and the mechanism of environmental stress on planktonic fungal communities, surface water samples were collected from seven major urban lakes evenly distributed in different county-level districts of Nanchang in the dry (February and December), normal (April and October), and wet (June and August) seasons, respectively. The environmental stressors such as WT, DO, NH4+-N, and NO3--N were measured; the characteristics of planktonic fungal communities were studied using high-throughput sequencing; the symbiotic patterns of planktonic fungal communities were elucidated using network analysis and other methods; and the environmental stressors affecting the structure and symbiotic patterns of planktonic fungal communities were revealed. The results showed that ① the planktonic fungal community composition in lakes of Nanchang varied significantly among seasons but not significantly among the lakes. WT, DO, pH, and NH4+-N were the significant environmental stressors affecting the planktonic fungal community composition. ② The dominant phyla of the planktonic fungal community were Chytridiomycota (9.55%-33.14%), Basidiomycota (0.48%-4.25%), and Ascomycota (1.29%-3.19%), and the sizes of the dominant phyla were in the following order:wet season>normal season>dry season. The relative abundance of Chytridiomycota was significantly higher in the wet season than that in the normal season and the dry season, the relative abundance of Basidiomycota was significantly lower in the dry season than that in the normal and wet seasons, and the difference in Ascomycota among seasons was not significant. ③ The stability size of the planktonic fungal community symbiosis network in lakes of Nanchang was in the following order:wet season>normal season>dry season. WT was the best environmental stressor affecting the planktonic fungal community symbiosis pattern. The study can provide theoretical basis for the comprehensive evaluation and management study of the lake and provide guidance for protecting the lake ecosystem in the middle and lower reaches of the Yangtze River.

Glucocorticoids promote lung metastasis of pancreatic cancer cells through enhancing cell adhesion, migration and invasion.

Glucocorticoids (GCs) are the important stress hormones and widely prescribed as drugs. Although stress has been suggested as a promoter of tumor progression, the direct influence of GCs on metastasis of tumor is not fully understood. Metastasis is a major cause of death in pancreatic cancer patients. In the present study, we investigated the effect of GCs on progression of pancreatic cancer and elucidated the underlying mechanism. It was found that GCs significantly promote cell adhesion, migration, and invasion of pancreatic cancer cells in vitro and their lung metastasis in vivo. Further mechanistic studies showed that GCs notably up-regulate the expression of a trans-membrane glycoprotein, mucin 1 (MUC1) and increase the activation of AKT. Inhibiting MUC1 expression not only attenuates the activation of AKT, but also significantly reduces the promoting effects of GCs on cell adhesion, migration, invasion, and lung metastasis of pancreatic cancer cells. Moreover, GCs not only significantly up-regulate expression of Rho-associated kinase 1/2 (ROCK1/2) and matrix metalloproteinase 3 and 7 (MMP3/7), but also activate ROCK2, which are also involved in the pro-migratory and pro-invasive effects of GCs in pancreatic cancer cells. Taken together, our findings reveal that GCs promote metastasis of pancreatic cancer cells through complex mechanism. MUC1-PI3K/AKT pathway, ROCK1/2 and MMP3/7 are involved in the promoting effect of GCs on cell migration, invasion and metastasis in pancreatic cancer cells. These results suggest the importance of reducing stress and GCs administration in patients with pancreatic cancer to avoid an increased risk of cancer metastasis.

Novel characteristics for immunophenotype, FISH pattern and molecular cytogenetics in synovial sarcoma.

As a rare and highly aggressive soft tissue sarcoma, the new immunophenotype, atypical FISH pattern and relevant molecular cytogenetics of synovial sarcoma (SS) remain less known, although it is characteristically represented by a pathognomonic chromosomal translocation t (X; 18) (p11.2; q11.2). Methodologically, the morphology was retrospectively analysed by using H&E staining, and immunohistochemical features were investigated by using markers that have been recently applied in other soft tissue tumors. Moreover, FISH signals for SS18 and EWSR-1 break-apart probes were examined. Finally, cytogenetic characteristics were analysed via RT-PCR and Sanger sequencing. Consequently, nine out of thirteen cases that were histologically highly suspected as SS were finally identified as SS via molecular analysis. Histologically, nine SS cases were divided into monophasic fibrous SS (4/9), biphasic SS (4/9) and poorly differentiated SS (1/9). Immunohistochemically, SOX-2 immunostaining was positive in eight cases (8/9) and PAX-7 immunostaining was diffusely positive in the epithelial component of biphasic SS (4/4). Nine cases showed negative immunostaining for NKX3.1 and reduced or absent immunostaining for INI-1. Eight cases showed typically positive FISH signalling for the SS18 break-apart probe, whereas one case exhibited an atypical FISH pattern (complete loss of green signalling, case 2). Furthermore, the SS18-SSX1 and SS18-SSX2 fusion genes were identified in seven cases and two cases, respectively. The fusion site in 8 out of 9 cases was common in the literature, whereas the fusion site in case 2 was involved in exon 10 codon 404 in SS18 and exon 7 codon 119 in SSX1 (which has not been previously reported), which notably corresponded to the complete loss of green signalling in the FISH pattern. Additionally, FISH analysis of the EWSR-1 gene in nine SS cases demonstrated aberrant signalling in three cases that were recognized as a monoallelic loss of EWSR-1 (1/9), an amplification of EWSR-1 (1/9) and a translocation of EWSR-1 (1/9). In conclusion, SS18-SSX fusion gene sequencing is obligatory for a precise diagnosis of SS when dealing with a confusing immunophenotype and atypical or aberrant FISH signalling for SS18 and EWSR-1 detection.

[Bacterioplankton Communities and Assembly Mechanisms in Wet Season of Lakes, Nanchang].

Bacterioplankton communities play an important role in nutrient cycling and organic matter decomposition in urban lakes. Based on high-throughput sequencing, we analyzed the temporal (April, June, and August) and urban-suburban difference and assembly of bacterioplankton communities in lakes of Nanchang City. Our results showed that:① the dominant bacterioplankton communities in the lakes were Actinobacteria (41.60%), Proteobacteria (22.29%), Cyanobacteria (16.21%), and Bacteroidota (10.17%). ② There were significant differences in bacterial communities between April, June, and August but not between urban lakes and suburban lakes. The abundance of 10 bacteria, mainly Proteobacteria (April>June>August) and Cyanobacteria (June>August>April), was significantly different among the three months. There was a significant distance decay pattern in June, which was not seen in April and August. ③ The proportion of non-freshwater bacteria was significantly higher in June than that in April and August, but there were no significant differences between urban lakes and suburban lakes. ④ Deterministic processes dominated the assembly of bacterioplankton communities, whereas stochastic processes had a lower contribution. Water temperature (WT) was the environmental factor that best explained the changes in bacterioplankton communities in the lakes.

[Enrichments, Migrations, and Conversions of Heavy Metal in the Soil/Sediment-Plant System Towards the Lake in Typical Poyang Lake Wetland].

A large area of periodic water-level-fluctuating zone (WLFZ) in the Poyang Lake, regulated by a special hydrologic rhythm, was deposited with significant amounts of nutrients and pollutants. In this study, the WLFZ located in a typical estuarine wetland was chosen and sampling transects were arranged according to different vegetation types towards the lake. Soil/sediment and dominant plant (different tissues) samples were collected, and contents and enrichment levels of heavy metals (Cr, Ni, Cu, Zn, As, Cd, Sb, and Pb) in these samples were analyzed. The migrations and conversions of heavy metal in the soil/sediment-plant system were evaluated, and driving environmental factors were explored. The results indicated that the contents of heavy metal in the soil/sediment presented an obvious single-peak distribution towards the lake, that is, the seasonally flooded zone was identified as the main deposited zone of heavy metals. There was a high enrichment level of Cu, Pb, and Sb in the soil/sediment from the WLFZ, and significant Cu and Sb pollution was identified (EF>5). The results from the potential ecological risk evaluation (RI) indicated that the ecological risk of the seasonally flooded zone was significantly higher than that in the flooded and unflooded zones, being at a low ecological risk (70 ≤ RI<140). There was no obvious spatial distribution of heavy metal contents in the dominant plant towards the lake, whereas significant seasonal differences were detected. The levels of heavy metals in plants at the growth phase (April) were higher compared to those at the other sampling times. The tissue distributions of heavy metal content basically followed the sequence of soil/sediment>root ≥ above-ground part, except for in Cd and Sb. The Cd content in the roots was significantly higher than that in the sediment/soil, and the Sb concentration was not significantly different among the three tissues. The bio-enrichment coefficient (BAF) and transfer factor (TF) of heavy metal in the dominant plant towards the lake did not show an obvious spatial pattern, and BAF and TF of heavy metals in the Artemisia capillaris Thunb. was higher than those in other dominant plants. The RDA revealed that pH, organic matter, plant height, and Fe-Mn oxides were the key environmental factors driving the migrations of heavy metals in the soil/sediment-plant system. These results will provide scientific basis and theoretical support for the biodiversity conservation and heavy metal pollution prevention and management in wetlands of the Poyang Lake.

[Effects of Landscape Structures on Bacterioplankton Communities at Multi-spatial Scales in the Yuanhe River].

The aim of this study was to examine the relationships between land use and bacterioplankton communities at different spatial scales and the mechanisms underlying the effects of land use on bacterioplankton communities. Here, surface water samples were collected in 14 tributaries of the Yuanhe River in August 2019 (wet season) and January 2020 (dry season), and high-throughput sequencing technology was used to determine the characteristics of the bacterioplankton communities. Statistical methods such as Bioenv and variance partitioning analysis (VPA) were used to explore the relationships among landscape structure (i.e., landscape compositions and landscape configurations), water chemistry, and bacterioplankton communities. Furthermore, metacommunity theory was employed to explain the mechanisms by which land use and water chemistry affect bacterial communities. The results showed that:① in general, the effects of landscape configuration on bacterial communities were weak, whereas the effects of landscape composition on bacterial communities were significant and greater at the buffer scale than that at the sub-basin scale. ② There was no distinct distance-decay pattern for the effects of landscape composition on bacterial communities from the near-distance (100 m) to the long-distance (1000 m) buffer zones, with the maximal effects occurring in the 500 m circular buffer (wet season) and 300 m riparian buffer (dry season), respectively. ③ Land use influenced the bacterioplankton communities both directly through exogenous inputs (i.e., "mass effect" process) and indirectly by affecting water chemistry (i.e., "species sorting" process). VPA showed that the total explanation of bacterial community variations by water chemistry and the intersection of water chemistry and land use (13.5% in the wet season and 11.7% in the dry season) was higher than that of land use alone (2.7% in the wet season and 6.9% in the dry season). These results suggest that mass effects and species sorting jointly shaped bacterial community assembly but that the effects of species sorting outweighed those of mass effects. This study revealed the variability of landscape structure at different spatial scales on bacterial communities, and its results will help to determine the optimal spatial scale affecting bacterial communities and provide a reference basis for watershed land-use management.

Up-regulation of heat shock protein 27 inhibits apoptosis in lumbosacral nerve root avulsion-induced neurons.

Lumbosacral nerve root avulsion leads to widespread death of neurons in the anterior horn area of the injured spinal cord, which results in dysfunction in the lower extremities. Heat shock protein 27 (Hsp27) has been found to play cytoprotective roles under adverse conditions. However, the role of Hsp27 in neurons after lumbosacral nerve root avulsion is unknown. The aim of the present study was to investigate the effects and mechanism of action of Hsp27 on neurons after lumbosacral nerve root avulsion. It was found that Hsp27 expression was elevated in the anterior horn area of the injured spinal cord and the up-regulation of Hsp27 protected neurons against apoptosis after lumbosacral nerve root avulsion. In addition, Hsp27 plays an anti-apoptotic role by suppressing oxidative stress reactions. These findings indicated that Hsp27 may play a key role in resistance to lumbosacral nerve root avulsion-induced neuron apoptosis and may prove to be a potential strategy for improving prognosis after lumbosacral nerve root avulsion.

Primary malignant gastrointestinal neuroectodermal tumor occurring in the ileum with intra-abdominal granulomatous nodules: A case report and review of the literature.

Malignant gastrointestinal neuroectodermal tumors (GNETs) are rare aggressive malignant neoplasms that exclusively occur within the wall of the gastrointestinal tract. The GNET was first described as an 'osteoclast-rich tumor of the gastrointestinal tract with features resembling clear cell sarcoma (CCS) of soft parts' in 2003. Although the GNET shares certain histological features with CCS, it is characterized by a lack of melanocytic differentiation and the presence of non-tumoral osteoclast-like giant cells (OLGCs). The present study reports a case of a GNET of the ileum with intra-abdominal granulomatous nodules, an uncommon accompanying finding, and summarizes the current literature. A 30-year-old woman presented with the symptoms of intestinal obstruction, and a mass was found within the ileum wall. Multiple grey-white nodules were found adhering to the omentum and serosa of the ileum. Histologically, the tumor was located in the muscularis propria and infiltrated the mucosa and the serosa. Tumor cells presented with oval or polygonal nuclei and prominent nucleoli, and were predominantly arranged in nested and pseudopapillary patterns, with the presence of cluster of differentiation (CD)68-positive, scattered OLGC. Immunohistochemically, it was determined that the tumor cells expressed Vimentin, CD56, S-100 and transcription factor SOX-10, while being negative for pan-cytokeratin, cytokeratin (CK)7, CK20, synaptophysin, chromogranin-A, CD117, anoctamin-1, CD34, human melanoma black-45, Melan-A, smooth muscle actin, CD3 and CD20 expression. Ewing sarcoma breakpoint region 1 gene rearrangement was identified by fluorescence in situ hybridization analysis. Ultrastructurally, no typical melanosomes were identified. In addition, the intra-abdominal grey-white nodules were microscopically identified as chronic granulomatous inflammation. The patient received four cycles of adjuvant chemotherapy following routine tumor resection. Due to its rarity and histological similarity with other neoplasms, unfamiliarity with the features of GNETs by surgical pathologists can easily lead to a misdiagnosis. Therefore, comprehensive assessments, including morphology and ancillary studies, are required for an accurate diagnosis of GNET.

circRNA.33186 Contributes to the Pathogenesis of Osteoarthritis by Sponging miR-127-5p.

Osteoarthritis (OA), the most prevalent age-related joint disorder, is characterized by chronic inflammation, progressive articular cartilage destruction, and subchondral bone sclerosis. Accumulating evidences indicate that circular RNAs (circRNAs) play a critical role in various diseases, but the function of circRNAs in OA remains largely unknown. Here we showed that circRNA.33186 was significantly upregulated in IL-1ß)-treated chondrocytes and in cartilage tissues of a destabilized medial meniscus (DMM)-induced OA mouse model. Knockdown of circRNA.33186 increased anabolic factor (type II collagen) expression and decreased catabolic factor (MMP-13) expression. Knockdown of circRNA.33186 also promoted proliferation and inhibited apoptosis in IL-1ß-treated chondrocytes. Silencing of circRNA.33186 in vivo markedly alleviated DMM-induced OA. Mechanistic study showed that circRNA.33186 directly binds to and inhibits miR-127-5p, thereby increasing MMP-13 expression, and contributes to OA pathogenesis. Taken together, our findings demonstrated a fundamental role of circRNA.33186 in OA progression and provide a potential drug target in OA therapy.

Silencing of circRNA.2837 Plays a Protective Role in Sciatic Nerve Injury by Sponging the miR-34 Family via Regulating Neuronal Autophagy.

Circular RNAs (circRNAs) represent a class of non-coding RNAs that are involved in transcriptional and posttranscriptional gene expression regulation and associated with different kinds of human diseases. However, the characterization and function of circular RNAs in peripheral nerve injuries remain elusive. Here, we established a rat sciatic nerve injury model and identified at least 4,942 distinct circular RNA candidates and a series of circular RNAs that were differentially expressed in injured nerve tissues compared with matched normal tissues. We characterized one frequently downregulated circular RNA, circRNA.2837, and further investigated its function in sciatic nerve injury. We found that circRNA.2837 regulated autophagy in neurons in vitro and in vivo, and downregulation of circRNA.2837 alleviated sciatic nerve injury via inducing autophagy in vivo. Mechanistically, knockdown of circRNA.2837 may protect neurons against neurological injury by acting as a sponge for members of miR-34 family. Our findings suggested that differentially expressed circular RNAs were involved in the pathogenesis of sciatic nerve injury, and circular RNAs exerted regulatory functions in sciatic nerve injury and might be used as potential targets in sciatic nerve injury therapy.

Circular RNA Atp9b, a competing endogenous RNA, regulates the progression of osteoarthritis by targeting miR-138-5p.

Osteoarthritis (OA) is the most common joint disease and is mainly characterized by degradation of the articular cartilage. Recently, circular RNAs (circRNAs), novel noncoding RNAs with different biological functions and pathological implications, have been reported to be closely associated with various diseases. Growing evidence indicates that circRNAs act as competing endogenous RNAs (ceRNAs) that bind with microRNAs (miRNAs) and regulate their downstream functions. Here, we identified a new circRNA, circRNA_Atp9b, and further investigated its function in OA using a well-established mouse chondrocyte model. We demonstrated that circRNA_Atp9b expression was significantly up-regulated in mouse chondrocytes after stimulation with interleukin-1 beta (IL-1ß), and that knockdown of circRNA_Atp9b promoted the expression of type II collagen while inhibiting the generation of MMP13, COX-2 and IL-6. Moreover, there was a negative correlation between the expression levels of circRNA_Atp9b and microRNA (miR)-138-5p, indicating that miR-138-5p also played a role in IL-1ß-induced chondrocytes. Bioinformatics analysis predicted circRNA_Atp9b directly target miR-138-5p, which was validated by dual-luciferase assay. Further functional experiments revealed that down-regulation of miR-138-5p partly reversed the effects of circRNA_Atp9b on extracellular matrix (ECM) catabolism and inflammation. Taken together, these results suggest that circRNA_Atp9b regulates OA progression by modulating ECM catabolism and inflammation in chondrocytes via sponging miR-138-5p. Our findings provide novel insight into the regulatory mechanism of circRNA_Atp9b in OA and may contribute to establishing potential therapeutic strategies.

Involvement of upregulation of fibronectin in the pro­adhesive and pro­survival effects of glucocorticoid on melanoma cells.

Glucocorticoids (GCs) are important stress hormones, which are used as a concomitant medication during malignant tumor chemotherapy. Clinical and preclinical studies have linked GCs to melanoma growth and progression. However, the effects and mechanism of action of GCs on the adhesion and survival of melanoma cells are still unknown. In the present study the effect of dexamethasone (Dex), a synthetic GC, on fibronectin (FN) expression and its roles in regulating the adhesion and survival of melanoma cells were investigated. It was revealed that Dex significantly increased the levels of intracellular and secreted FN in melanoma cell lines by increasing glucocorticoid receptor­mediated FN protein stability. Additionally, it was demonstrated that Dex (100 nM) significantly promoted the adhesion and survival of melanoma cells. Silencing FN expression abrogated the pro­adhesive and pro­survival effects of Dex in melanoma cells. Extracellular FN significantly enhanced melanoma cell adhesion and survival in the presence of cisplatin, whereas partially blocking extracellular FN signaling with a CD44 antibody significantly reduced FN­enhanced adhesion and survival. This indicated that the upregulation of FN contributed to the pro­survival effect of Dex by enhancing cell adhesion. It was also observed that activation of the PI3K/AKT signaling pathway by extracellular FN was involved in the FN­mediated increase in melanoma cell survival. These findings increase understanding of the possible mechanisms by which GCs regulate melanoma cell adhesion and survival.

Up-regulation of Rho-associated kinase 1/2 by glucocorticoids promotes migration, invasion and metastasis of melanoma.

Although glucocorticoids (GCs) regulate proliferation, differentiation and apoptosis of tumor cells, their influence on metastasis of tumor cells is poorly understood. Melanoma is a type of skin cancers with high metastasis. We investigated the effect of GCs on metastasis of melanoma cells and its mechanism. We found that GCs significantly promoted the adhesion, migration, invasion of melanoma cells in vitro and lung metastasis in experimental melanoma metastasis mice. Dexamethasone (Dex), a synthetic GC, did not change the RhoA, RhoB and RhoC signalings, but significantly increased the expression and activity of Rho-associated kinase 1/2 (ROCK1/2). The effect of Dex was to increase ROCK1/2 stability mediated by glucocorticoid receptor. Inhibiting ROCK1/2 activity with Y-27632, a ROCK1/2 inhibitor abrogated the pro-migration and pro-metastasis effects of GCs in vitro and in vivo, indicating that ROCK1/2 mediated the pro-metastasis effects of GCs. Activation of PI3K/AKT also contributed to the pro-migration and pro-invasion effects of Dex partially through up-regulating ROCK1/2 expression. Additionally, Dex also down-regulated the expression of tissue inhibitors of matrix metalloproteinase-2. Taken together, our findings provide new data to understand the possible promoting roles and mechanisms of GCs in melanoma metastasis.

The mechanisms and significance of up-regulation of RhoB expression by hypoxia and glucocorticoid in rat lung and A549 cells.

Small guanosine triphosphate (GTP)-binding protein RhoB is an important stress sensor and contributes to the regulation of cytoskeletal organization, cell proliferation and survival. However, whether RhoB is involved in the hypoxic response and action of glucocorticoid (GC) is largely unknown. In this study, we investigated the effects of hypoxia or/and GC on the expression and activition of RhoB in the lung of rats and human A549 lung carcinoma cells, and further studied its mechanism and significance. We found that hypoxia and dexamethasone (Dex), a synethic GC, not only significantly increased the expression and activation of RhoB independently but also coregulated the expresion of RhoB in vitro and in vivo. Up-regulation of RhoB by hypoxia was in part through stabilizing the RhoB mRNA and protein. Inhibiting hypoxia-activated hypoxia-inducible transcription factor-1α (HIF-1α), c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) with their specific inhibitors significantly decreased hypoxia-induced RhoB expression, indicating that HIF-1α, JNK and ERK are involved in the up-regulation of RhoB in hypoxia. Furthermore, we found that knockdown of RhoB expression by RhoB siRNA not only significantly reduced hypoxia-enhanced cell migration and cell survival in hypoxia but also increased the sensitivity of cell to paclitaxel (PTX), a chemotherapeutic agent, and reduced Dex-enhanced resistance to PTX-chemotherapy in A549 cells. Taken together, the novel data revealed that hypoxia and Dex increased the expression and activation of RhoB, which is important for hypoxic adaptation and hypoxia-accelerated progression of lung cancer cells. RhoB also enhanced the resistance of cell to PTX-chemotherapy and mediated the pro-survival effect of Dex.

The mechanism and significance of synergistic induction of the expression of plasminogen activator inhibitor-1 by glucocorticoid and transforming growth factor beta in human ovarian cancer cells.

Plasminogen activator inhibitor-1 (PAI-1) plays a key role in tissue remodeling and tumor development by suppression of plasminogen activator function. Glucocorticoids (GCs) and transforming growth factor beta (TGF-ß) signal pathways cross-talk to regulate gene expression, but the mechanism is poorly understood. Here we investigated the mechanism and significance of co-regulation of PAI-1 by TGF-ß and dexamethasone (DEX), a synthetic glucocorticoid in ovarian cancer cells. We found that TGF-ß and DEX showed rapidly synergistic induction of PAI-1 expression, which contributed to the early pro-adhesion effects. The synergistic induction effect was accomplished by several signal pathways, including GC receptor (GR) pathway and TGF-ß-activated p38MAPK, ERK and Smad3 pathways. TGF-ß-activated p38MAPK and ERK pathways cross-talked with GR pathway to augment the expression of PAI-1 through enhancing DEX-induced GR phosphorylation at Ser211 in ovarian cancer cells. These findings reveal possible novel mechanisms by which TGF-ß pathways cooperatively cross-talk with GR pathway to regulate gene expression.