BAG3-positive pancreatic stellate cells promote migration and invasion of pancreatic ductal adenocarcinoma.

BAG3 is constitutively expressed in multiple types of cancer cells and its high expression is associated with tumour progression and poor prognosis of PDAC. However, little is known about the role of BAG3 in the regulation of stromal microenvironment of PDAC. The current study demonstrated that beside PDAC tumour cells, BAG3 was also expressed in some activated stroma cells in PDAC tissue, as well as in activated PSCs. In addition, the current study demonstrated that BAG3 expression in PSCs was involved in maintenance of PSCs activation and promotion of PDACs invasion via releasing multiple cytokines. The current study demonstrated that BAG3-positive PSCs promoted invasion of PDACs via IL-8, MCP1, TGF-ß2 and IGFBP2 in a paracrine manner. Furthermore, BAG3 sustained PSCs activation through IL-6, TGF-ß2 and IGFBP2 in an autocrine manner. Thereby, the current study provides a new insight into the involvement of BAG3 in remodelling of stromal microenvironment favourable for malignant progression of PDAC, indicating that BAG3 might serve as a potential target for anti-fibrosis of PDAC.

MicroRNA-873 mediates multidrug resistance in ovarian cancer cells by targeting ABCB1.

Ovarian cancer is commonly treated with cisplatin and paclitaxel combination chemotherapy; however, ovarian cancer cells often develop resistance to these drugs. Increasingly, microRNAs (miRNAs) including miR-873 have been implicated in drug resistance in many cancers, but the role of miR-873 in ovarian cancer remains unknown. MTT cell viability assays revealed that the sensitivities of ovarian cancer lines to cisplatin and paclitaxel increased following transfection with miR-873 (P < 0.05). After predicting the miR-873 binding region in the 3'-untranslated region of ABCB1, dual-luciferase reporter assay confirmed this prediction. RT-PCR and Western blotting revealed that MDR1 expression was significantly downregulated after transfection with miR-873 and upregulated after transfection with anti-miR-873 at both mRNA and protein levels compared to negative controls (P < 0.05). Experiments in a mouse xenograft model confirmed that intratumoral administration of miR-873 could enhance the efficacy of cisplatin in inhibiting tumor growth in ovarian cancer in vivo (P < 0.05). ABCB1 overexpression reduced sensitivities of ovarian cancer lines OVCAR3 and A2780 to cisplatin and paclitaxel, which can be reversed by miR-873 mimic transfection (P < 0.05). In summary, we demonstrated that overexpression of miR-873 increased the sensitivity of ovarian cancer cells to cisplatin and paclitaxel by targeting MDR1 expression. Our findings suggest that combination therapies with chemotherapy agents and miR-873 may suppress drug resistance in ovarian cancer.

How does the digital economy affect the provincial "zero-waste city" construction? Evidence from China.

The digital economy is playing a crucial effect in the field of environmental governance. Digital and intelligent management is an essential means to fully realize the "zero-waste city" construction. The present paper investigates the impact of digital economy on China's provincial "zero-waste city" construction. The results indicate that digital economy can contribute to "zero-waste city" construction. The digital economy has a positive nonlinear effect on the construction of "zero-waste city," but the marginal effect is diminishing. The digital economy can facilitate "zero-waste city" construction by improving industrial structure upgrading and green technology innovation. Heterogeneity analysis reveals that digital economy contributes to the construction of "zero-waste city" in the eastern and western regions and high-level environmental regulation regions, while this impact is insignificant in the central region and low-level environmental regulation regions. The digital economy exerts the most significant positive influence on waste resource recycling followed by waste final disposal and then waste reduction at the source. These findings underscore the effect of digital economy in fostering "zero-waste city" construction and promoting sustainable waste management. The present study provides new ideas for the "zero-waste city" construction in emerging developing countries such as China.

[Changes to surfactant proteins in the bronchoalveolar lavage fluid and serum of children with Mycoplasma pneumoniae pneumonia].

OBJECTIVE: To study the changes to surfactant proteins in the serum and bronchoalveolar lavage fluids (BALF) of children with Mycoplasma pneumoniae pneumonia (MPP) and their significance. METHODS: Self-control method was used in the study. Forty-seven MPP children were divided into single lung infected (n=32) and bilateral lung infected groups (n=15) according to lung CT results. Surfactant proteins SP-A, B, C and D were measured using ELISA in the serum and BALF in the two groups. The correlations between SP-A, B, C and D content in the serum and BALF were evaluated by Spearman correlation analysis. RESULTS: SP-A, B, C and D content in BALF from the majorly infected or infected lung were significantly higher than from the opposite lung and serum (P<0.01). SP-A, B and C content in serum was significantly lower than in BALF from the non-infected lung in the single-side infected lung group (P<0.01 or 0.05), but there was no significant difference between serum SP-D content and BALF SP-D content from the non-infected lung. There were no significant differences in SP-A, B, C and D content in serum and BALF from the minorly infected lung in the bilateral lung infected group. Serum SP-D content was positively correlated with BALF SP-D content from the majorly infected lung in the bilateral lung infected group (P<0.01). CONCLUSIONS: Serum SP-D content may serve as a biomarker for evaluating the severity of pulmonary infection in children with community-acquired pneumonia.

Can industrial collaborative agglomeration reduce carbon intensity? Empirical evidence based on Chinese provincial panel data.

The collaborative agglomeration of manufacturing and producer services is an essential tool for the green transformation of China's economic model. This paper explores the impact of industrial collaborative agglomeration on carbon intensity, using the spatial Durbin model (SDM) based on China's provincial panel data from 2012 to 2019. The empirical results indicate that there is an inverted N-shaped relationship between industrial collaborative agglomeration and carbon intensity, with the turning points of 2.5255 and 2.8575. Regional industrial collaborative agglomeration tends to initially reduce carbon intensity, then aggravates to carbon emission, then finally inhibits carbon intensity. There is an obvious heterogeneity in the impact of producer-service subsectors and manufacturing collaborative agglomeration on carbon intensity. When the industrial collaborative agglomeration level exceeds a certain threshold, the clustering of information transmission, software and information technology service, and financial intermediation service have the greatest emission reduction potential. Industrial collaborative agglomeration has obvious spatial spillover effect, and carbon intensity has obvious spatial convergence effect. This paper provides some novelties for research perspectives on carbon intensity reduction and theoretical references for the development and implementation of differentiated industrial collaborative agglomeration policies.

Energy consumption, environmental pollution, and technological innovation efficiency: taking industrial enterprises in China as empirical analysis object.

Facing increasingly serious environmental problems, technological innovation has become the key for industrial enterprises to coordinate energy conservation and emission reduction constraints and achieve steady growth of the industrial economy. Considering the impact of energy consumption and environmental pollution on the technological innovation efficiency of industrial enterprises, this paper incorporates industrial energy consumption, pollution control, and wastewater and exhaust emissions into the technical inefficiency equation. Based on the panel data of industrial enterprises in 30 provinces and autonomous regions in China from 2009 to 2016, the stochastic frontier analysis (SFA) model is used to study the effect of energy consumption and environmental pollution on technological innovation efficiency of industrial enterprises. The research results show that reducing energy consumption and increasing pollution treatment investment both have a significant driving effect on the improvement of industrial enterprises' technological innovation efficiency. Industrial wastewater and exhaust emissions have the opposite effect; unreasonable input mode of pollution control and personnel allocation have hindered the improvement of industrial enterprises' technological innovation efficiency. The average annual trend of technological innovation efficiency in industrial enterprises shows a curve of first rising, then falling, and rising again. The average values of Chongqing, Zhejiang, and Hunan rank in the top three, and the average values of Qinghai, Heilongjiang, and Inner Mongolia rank the bottom three. The average values of other provinces are higher than 0.9, and the difference is small. A suitable incentive mechanism should be established for industrial enterprises to save energy and reduce emissions and strengthen pollution control, improve the training program for environmental protection technical personnel, and provide important support for improving the green competitiveness of industrial enterprises.

Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation.

TRIM family proteins are defined as E3 ubiquitin ligases because of their RING-finger domains. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the posttranslational modification of diverse proteins. Both TRIM29 and ISG15 play both pro-tumoral and anti-tumoral functions in cancer cells derived from different histology. In the current study, we demonstrated that correlation expression of TRIM29 and ISG15 in pancreatic ductal adenocarcinomas (PDACs). The current study demonstrated that TRIM29 knockdown destabilized ISG15 protein via promoting its processing by calpain 3 (CAPN3). Importantly, the current study found that TRIM29 knockdown suppressed cancer stem cell-like features of PDACs, which can be rescued by ISG15 independent of its conjugation function. In addition, the current study demonstrated that extracellular free ISG15 played an important role in maintenance of cancer stem cell-like features of PDACs. Thereby, the current study displayed a novel mechanism by which TRIM29 modulates ISG15 stability via CAPN3-mediated processing, and subsequently extracellular ISG15 maintains the cancer stem cell-like features of PDAC via autocrine mode of action.

BAG3 promotes autophagy and glutaminolysis via stabilizing glutaminase.

Bcl-2 associated athanogene 3 (BAG3) is an important molecule that maintains oncogenic features of cancer cells via diverse mechanisms. One of the important functions assigned to BAG3 is implicated in selective macroautophagy/autophagy, which attracts much attention recently. However, the mechanism underlying regulation of autophagy by BAG3 has not been well defined. Here, we describe that BAG3 enhances autophagy via promotion of glutamine consumption and glutaminolysis. Glutaminolysis initiates with deamination of glutamine by glutaminase (GLS), by which yields glutamate and ammonia in mitochondria. The current study demonstrates that BAG3 stabilizes GLS via prohibition its interaction with SIRT5, thereby hindering its desuccinylation at Lys158 and Lys164 sites. As an underlying molecular mechanism, we demonstrate that BAG3 interacts with GLS and decreases SIRT5 expression. The current study also demonstrates that occupation by succinyl at Lys158 and Lys164 sites prohibits its Lys48-linked ubiquitination, thereby preventing its subsequent proteasomal degradation. Collectively, the current study demonstrates that BAG3 enhances autophagy via stabilizing GLS and promoting glutaminolysis. For the first time, this study reports that succinylation competes with ubiquitination to regulate proteasomal GLS degradation.

BAG3 deletion suppresses stem cell-like features of pancreatic ductal adenocarcinoma via translational suppression of ISG15.

BAG3 is a member of the cochaperone BAG family and often highly expressed in various cancers. Recently, evidences show that BAG3 promotes stemness of human cancer cells. IFN-stimulated genes 15 (ISG15) is an ubiquitin-like molecule, which is covalently conjugated with substrates to form ISGylated proteins. Global screening BAG3 interacting partners demonstrated that ISG15 might be a potential binding partner. The current study revealed that BAG3 did not interact with ISG15, but positively regulated ISG15 expression in pancreatic ductal adenocarcinoma cancer (PDAC). It was further found that BAG3 deletion stabilized ISG15 mRNAs, while suppressed its translation via increasing Serine phosphorylation of Ago2 at position 387 (S387). Both BAG3 deletion and ISG15 knockdown suppressed stem cell-like phenotypes of PDAC cells, including clonogenicity, invasiveness and spheroid formation. In addition, ectopic ISG15 expression rescued the suppressive role of BAG3 deletion in cancer stem cell (CSC)-like phenotypes of PDAC cells, and this effect of ISG15 was independent of its ISGylation function. The current study implies that BAG3 and ISG15 may provide a therapeutic advantage for PDAC.

BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.

Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.

MiR-23b targets cyclin G1 and suppresses ovarian cancer tumorigenesis and progression.

BACKGROUND: It has been proposed that cyclin G1 (CCNG1) participates in p53-dependent G1-S and G2 checkpoints and might function as an oncogenic protein in the initiation and metastasis of ovarian carcinoma. MicroRNA 23b (miR-23b) is a critical regulatory factor in the progression of many cancer cell types that targets the relevant genes. METHODS: MiR-23b expression in ovarian tissues was quantified by quantitative reverse transcription-PCR. The ovarian cancer cell lines OVCAR3, HO8910-PM, and SKOV3/DDP were transfected with miR-23b, after we assayed the cell phenotype and expression of the relevant molecules. Dual-luciferase reporter assay and a xenograft mouse model were used to examine the expression of miR-23b and its target gene CCNG1. RESULTS: MIR23B mRNA expression was significantly lower in epithelial ovarian carcinoma and borderline tumors than in normal ovarian tissues and benign tumors, and miR-23b expression among ages and pathological subtypes was significantly different. CCNG1 mRNA expression was significantly lower in normal ovarian tissues than in benign tumors, borderline tumors, and ovarian carcinomas, and expression among pathological subtypes was significantly different. MiR-23b overexpression inhibited ovarian cancer cell proliferation, invasion, and migration, and induced apoptosis. Dual-luciferase reporter assay showed that miR-23b bound with the 3' untranslated region of CCNG1. MiR-23b overexpression significantly downregulated CCNG1, urokinase, survivin, Bcl-xL, P70S6K, and matrix metallopeptidase-9 (MMP9) mRNA and protein expression. Furthermore, miR-23b inhibited tumor growth and suppressed CCNG1 expression in vitro. CONCLUSIONS: Our findings show that miR-23b may inhibit ovarian cancer tumorigenesis and progression by downregulating CCNG1 and the expression of the relevant genes. MiR-23b is a potentially novel application for regulating ovarian carcinoma progression.

[Alterations of SP-A, SP-D and KL-6 in serum and bronchoalveolar lavage fluid in children with Mycoplasma pneumoniae pneumonia].

OBJECTIVE: To study the alterations and relationship of surfactant protein (SP)-A, SP-D and KL-6 in serum and bronchoalveolar lavage fluids (BALF) in children with Mycoplasma pneumoniae pneumonia (MPP). METHOD: Self-control method was used for the study on SP-A, SP-D and KL-6 in serum, infected and non-infected BALFs in 32 MMP children with only one side of MPP. RESULT: The contents of SP-A, SP-D and KL-6 in infected BALF were [mg/L;M (IQR) ]: 243 (90-468) , 187 (43-333) , 148 (47-426) ;104 (37-257) , 56 (25-131) , 35 (12-147) in non-infected BALF; 35 (25-69) , 33 (9-149) and 24 (15-62) in serum. The correlation coefficient of KL-6 between serum and infected BALF were -0.534 and -0.378 (P < 0.05). CONCLUSION: There were significant correlation between the alterations of SP-A, SP-D and KL-6 in serum and lung infection in children with CAP. KL-6 in serum may be more sensitive than SP-A and SP-D.