| 1. |
- Hases, Linnea, et al.
(författare)
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The importance of sex in colorectal cancer biomarker discovery
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is the third leading cause for cancer deaths, indicating the needfor new diagnostic and prognostic biomarkers. The advances in omics technologies andbioinformatics can speed up and improve current biomarker discovery strategies.Machine learning has been integrated for analysis of transcriptomic data for severalcancers. However, in addition to improved data-analysis, there is a need to investigate theimpact of sex in the biomarker discovery since there are several sex-differences in theincidence, mortality, prognosis and tumor characteristics of CRC. First we investigated ifthere are any sex-differences in the transcriptome of normal colon and CRC andinvestigated if there are any sex-differences in the differentially expressed genes betweenpaired-normal and CRC. In an attempt to study sex-specific biomarkers we used TCGAdata and performed feature selection with Vita, Boruta and MRMR in combination withmachine learning to identify top CRC biomarkers. Interestingly, we found stronger sexdifferencesin the normal colon compared to in CRC. Although the sex-differences werestronger in normal colon, sex showed to have a significant impact of the prognostic valueof the biomarkers. 13 of the selected features showed a sex-specific prognostic value. Thepreviously proposed prognostic biomarkers ESM1 and GUCA2A showed a male-specificprognostic value whereas CLDN1 was specific for females. Additionally, we found somenovel prognostic biomarkers including TSPAN7 (females), SLC25A23 (females) andC2orf88 (males). In conclusion, our data show the importance of sex in the discovery ofCRC biomarkers and proposes 13 sex-specific CRC prognostic biomarkers.
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| 2. |
- Hases, Linnea, et al.
(författare)
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The Importance of Sex in the Discovery of Colorectal Cancer Prognostic Biomarkers
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:3
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is the third leading cause of cancer deaths. Advances within bioinformatics, such as machine learning, can improve biomarker discovery and ultimately improve CRC survival rates. There are clear sex differences in CRC characteristics, but the impact of sex has not been considered with regards to CRC biomarkers. Our aim here was to investigate sex differences in the transcriptome of a normal colon and CRC, and between paired normal and tumor tissue. Next, we attempted to identify CRC diagnostic and prognostic biomarkers and investigate if they are sex-specific. We collected paired normal and tumor tissue, performed RNA-seq, and applied feature selection in combination with machine learning to identify the top CRC diagnostic biomarkers. We used The Cancer Genome Atlas (TCGA) data to identify sex-specific CRC diagnostic biomarkers and performed an overall survival analysis to identify sex-specific prognostic biomarkers. We found transcriptomic sex differences in both the normal colon tissue and in CRC. Forty-four of the top-ranked biomarkers were sex-specific and 20 biomarkers showed a sex-specific prognostic value. Our data show the importance of sex in the discovery of CRC biomarkers. We propose 20 sex-specific CRC prognostic biomarkers, including ESM1, GUCA2A, and VWA2 for males and CLDN1 and FUT1 for females.
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| 3. |
- 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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| 4. |
- 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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