| 1. |
- Ibrahim, Ahmed, et al.
(författare)
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Colitis-induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 144:12, s. 3086-3098
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Tidskriftsartikel (refereegranskat)abstract
- Chronic inflammation of the colon (colitis) is a risk factor for colorectal cancer (CRC). Hormone-replacement therapy reduces CRC incidences, and the estrogen receptor beta (ERβ/ESR2) has been implicated in this protection. Gut microbiota is altered in both colitis and CRC and may influence the severity of both. Here we test the hypothesis that intestinal ERβ impacts the gut microbiota. Mice with and without intestine-specific deletion of ERβ (ERβKOVil ) were generated using the Cre-LoxP system. Colitis and CRC were induced with a single intraperitoneal injection of azoxymethane (AOM) followed by administration of three cycles of dextran sulfate sodium (DSS) in drinking water. The microbiota population were characterized by high-throughput 16S rRNA gene sequencing of DNA extracted from fecal samples (N = 39). Differences in the microbiota due to AOM/DSS and absence of ERβ were identified through bioinformatic analyses of the 16S-Seq data, and the distribution of bacterial species was corroborated using qPCR. We demonstrate that colitis-induced CRC reduced the gut microbiota diversity and that loss of ERβ enhanced this process. Further, the Bacteroidetes genus Prevotellaceae_UCG_001 was overrepresented in AOM/DSS mice compared to untreated controls (3.5-fold, p = 0.004), and this was enhanced in females and in ERβKOVil mice. Overall, AOM/DSS enriched for microbiota impacting immune system diseases and metabolic functions, and lack of ERβ in combination with AOM/DSS enriched for microbiota impacting carbohydrate metabolism and cell motility, while reducing those impacting the endocrine system. Our data support that intestinal ERβ contributes to a more favorable microbiome that could attenuate CRC development.
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| 2. |
- Katona, Borbala, et al.
(författare)
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Antibody Validation Strategy for Nuclear Receptors.
- 2019
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Ingår i: Methods in Molecular Biology. - New York, NY : Springer New York. - 1064-3745 .- 1940-6029. ; 1966, s. 79-99
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies are invaluable biological tools that we can use to detect the presence, location, or alteration of nuclear receptors. However, antibodies frequently cross-react with other proteins and their performance can vary from batch to batch, from application to application and from lab to lab. When each lot of antibody is not thoroughly validated for each assay, each sample type, and each lab and user, antibody-based assays can lead to flawed interpretations and reproducibility problems. In this chapter, we describe a scheme for thorough antibody validation, suitable for nuclear receptors. The method is based on using highly characterized positive and negative controls assembled into a validation tissue microarray (TMA). Through correlation of immunohistochemical staining (IHC) and mRNA levels over multiple tissues, use of current public databases, and assessment of binding to intended and nonintended targets using western blotting (WB), immunoprecipitation (IP), and mass spectrometry (MS), we describe a path for thoroughly validation of antibodies.
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| 3. |
- Mesmar, Fahmi, et al.
(författare)
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Clinical candidate and genistein analogue AXP107-11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein-coupled estrogen receptor signaling
- 2019
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 8:18, s. 7705-7719
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Tidskriftsartikel (refereegranskat)abstract
- Despite advances in cancer therapeutics, pancreatic cancer remains difficult to treat and often develops resistance to chemotherapies. We have evaluated a bioavailable genistein analogue, AXP107-11 which has completed phase Ib clinical trial, as an approach to sensitize tumor cells to chemotherapy. Using organotypic cultures of 14 patient-derived xenografts (PDX) of pancreatic ductal adenocarcinoma, we found that addition of AXP107-11 indeed sensitized 57% of cases to gemcitabine treatment. Results were validated using PDX models in vivo. Further, RNA-Seq from responsive and unresponsive tumors proposed a 41-gene treatment-predictive signature. Functional and molecular assays were performed in cell lines and demonstrated that the effect was synergistic. Transcriptome analysis indicated activation of G-protein-coupled estrogen receptor (GPER1) as the main underlying mechanism of action, which was corroborated using GPER1-selective agonists and antagonists. GPER1 expression in pancreatic tumors was indicative of survival, and our study proposes that activation of GPER1 may constitute a new avenue for pancreatic cancer therapeutics.
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| 4. |
- Zheng, Daoshan, et al.
(författare)
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Sexual dimorphism in the incidence of human cancers
- 2019
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Ingår i: BMC Cancer. - : BMC. - 1471-2407 .- 1471-2407. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSex differences in the incidences of cancers become a critical issue in both cancer research and the development of precision medicine. However, details in these differences have not been well reported. We provide a comprehensive analysis of sexual dimorphism in human cancers.MethodsWe analyzed four sets of cancer incidence data from the SEER (USA, 1975-2015), from the Cancer Registry at Mayo Clinic (1970-2015), from Sweden (1970-2015), and from the World Cancer Report in 2012.ResultsWe found that all human cancers had statistically significant sexual dimorphism with male dominance in the United States and mostly significant in the Mayo Clinic, Sweden, and the world data, except for thyroid cancer, which is female-dominant.ConclusionsSexual dimorphism is a clear but mostly neglected phenotype for most human cancers regarding the clinical practice of cancer. We expect that our study will facilitate the mechanistic studies of sexual dimorphism in human cancers. We believe that fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of individualized precision medicine beginning from the sex-specific diagnosis, prognosis, and treatment.
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