| 1. |
- Jiang, Shu-Heng, et al.
(författare)
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Modeling of cancer-related body-wide effects identifies LTB4 as a diagnostic biomarker for pancreatic cancer
- 2022
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 80, s. 104050-104050
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cancer elicits a complex adaptive response in an organism. Limited information is available for the body-wide effects induced by cancer. Here, we evaluated multiorgan changes in mouse models of pancreatic ductal adenocarcinoma (PDAC) and its precursor lesions (pancreatic intraepithelial neoplasia, PanIN) to decipher changes that occur during PDAC development.METHODS: RNA-sequencing was employed in the brain, colon, stomach, kidney, heart, liver, and lung tissues of mice with PanIN and PDAC. A combination of differential expression analysis and functional-category enrichment was applied for an in-depth understanding of the multiorgan transcriptome. Differentially expressed genes were verified by quantitative real-time polymerase chain reaction. Neutrophil and macrophage infiltration in multiple organs was analyzed by immunohistochemical staining. Leukotriene B4 (LTB4) levels in mouse and human serum samples were determined by enzyme-linked immunosorbent assay.FINDINGS: Transcriptional changes within diverse organs during PanIN and PDAC stages were identified. Using Gene Ontology enrichment analysis, increased neutrophil infiltration was discovered as a central and prominent affected feature, which occurred in the liver, lung, and stomach at the PanIN stage. The brain appeared to be well protected from the sequels of PanIN or PDAC. Importantly, serum LTB4 was able to discriminate PDAC from normal controls, chronic pancreatitis, and intraductal papillary mucinous neoplasms with high performance.INTERPRETATION: Our study provides a high-resolution cartographic view of the dynamic multiorgan transcriptomic landscape of mice with PDAC and its precursor lesions. Our findings suggest that LTB4 could serve as a biomarker for the early detection of PDAC.FUNDING: The complete list of funders can be found in the Acknowledgement section.
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| 2. |
- Nie, Huizhen, et al.
(författare)
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The short isoform of PRLR suppresses the pentose phosphate pathway and nucleotide synthesis through the NEK9-Hippo axis in pancreatic cancer
- 2021
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Ingår i: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 11:8, s. 3898-3915
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Tidskriftsartikel (refereegranskat)abstract
- Prolactin binding to the prolactin receptor exerts pleiotropic biological effects in vertebrates. The prolactin receptor (PRLR) has multiple isoforms due to alternative splicing. The biological roles and related signaling of the long isoform (PRLR-LF) have been fully elucidated. However, little is known about the short isoform (PRLR-SF), particularly in cancer development and metabolic reprogramming, a core hallmark of cancer. Here, we reveal the role and underlying mechanism of PRLR-SF in pancreatic ductal adenocarcinoma (PDAC). Methods: A human PDAC tissue array was used to investigate the clinical relevance of PRLR in PDAC. The in vivo implications of PRLR-SF in PDAC were examined in a subcutaneous xenograft model and an orthotopic xenograft model. Immunohistochemistry was performed on tumor tissue obtained from genetically engineered KPC (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) mice with spontaneous tumors. 13C-labeled metabolite measures, LC-MS, EdU incorporation assays and seahorse analyses were used to identify the effects of PRLR-SF on the pentose phosphate pathway and glycolysis. We identified the molecular mechanisms by immunofluorescence, coimmunoprecipitation, proximity ligation assays, chromatin immunoprecipitation and promoter luciferase activity. Public databases (TCGA, GEO and GTEx) were used to analyze the expression and survival correlations of the related genes. Results: We demonstrated that PRLR-SF is predominantly expressed in spontaneously forming pancreatic tumors of genetically engineered KPC mice and human PDAC cell lines. PRLR-SF inhibits the proliferation of PDAC cells (AsPC-1 and BxPC-3) in vitro and tumor growth in vivo. We showed that PRLR-SF reduces the expression of genes in the pentose phosphate pathway (PPP) and nucleotide biosynthesis by activating Hippo signaling. TEAD1, a downstream transcription factor of Hippo signaling, directly regulates the expression of G6PD and TKT, which are PPP rate-limiting enzymes. Moreover, NEK9 directly interacts with PRLR-SF and is the intermediator between PRLR and the Hippo pathway. The PRLR expression level is negatively correlated with overall survival and TNM stage in PDAC patients. Additionally, pregnancy and lactation increase the ratio of PRLR-SF:PRLR-LF in the pancreas of wild-type mice and subcutaneous PDAC xenograft tumors. Conclusion: Our characterization of the relationship between PRLR-SF signaling, the NEK9-Hippo pathway, PPP and nucleotide synthesis explains a mechanism for the correlation between PRLR-SF and metabolic reprogramming in PDAC progression. Strategies to alter this pathway might be developed for the treatment or prevention of pancreatic cancer.
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| 3. |
- Wen, Rongjia, et al.
(författare)
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Effects of temperature on ion transport in C–A–S–H gel nanopores: insights from molecular dynamics simulations
- 2022
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Ingår i: Journal of Materials Science. - : Springer Nature. - 0022-2461 .- 1573-4803. ; 57:39, s. 18437-18455
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, molecular dynamics simulations are used to study the effects of temperature on the transport of chloride and sulfate in the nanopores of aluminum-doped cement-based materials (i.e., CASH gels) exposed to aqueous solutions of NaCl and Na2SO4 at 283, 293, 303, 333, and 363 K. It is shown that high temperatures increase the initial transport rates of water molecules and ions while weakening the hydration layer around ions. This increases the probability of ion–ion and ion–substrate contact and thus makes ions more likely to cluster in solution and be captured by the substrate. Both cluster formation and substrate capture can significantly restrict the free movement of ions in solution and thus gradually reduce the ion transport rate. In addition, since sulfate ions have four oxygen atoms that can capture other ions, large ion clusters form more readily in Na2SO4 solution than in NaCl solution. The capture of these large ion clusters at the interface can cause a “necking” phenomenon that hinders the subsequent transport of water molecules and ions into the nanopore. These results provide a nanoscale basis for designing aluminum-doped cement-based materials with enhanced durability at high temperatures.
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| 4. |
- Zhou, Kai-Xia, et al.
(författare)
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Increased Nuclear Transporter KPNA2 Contributes to Tumor Immune Evasion by Enhancing PD-L1 Expression in PDAC
- 2021
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Ingår i: Journal of Immunology Research. - : Hindawi Limited. - 2314-7156 .- 2314-8861. ; 2021, s. 6694392-6694392
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is known for its high resistance and low response to treatment. Tumor immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Karyopherin alpha 2 (KPNA2), a member of the nuclear transporter family, is elevated in multiple human cancers and accelerates carcinogenesis. However, the specific role of KPNA2 in PDAC remains unclear. In this study, we found that expression of KPNA2 was significantly upregulated in PDAC compared to adjacent nontumor tissue and its high expression was correlated with poor survival outcome by analyzing the GEO datasets. Similar KPNA2 expression pattern was also found in both human patient samples and KPC mouse models through IHC staining. Although KPNA2 knockdown failed to impair the vitality and migration ability of PDAC cells in vitro, the in vivo tumor growth was significantly impeded and the expression of immune checkpoint ligand PD-L1 was reduced by silencing KPNA2. Furthermore, we uncovered that KPNA2 modulated the expression of PD-L1 by mediating nuclear translocation of STAT3. Collectively, our data suggested that KPNA2 has the potential to serve as a promising biomarker for diagnosis in PDAC.
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