scholarly journals Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling

2021 ◽  
Vol 22 (16) ◽  
pp. 8485
Author(s):  
Iranzu Gómez de Segura ◽  
Patricia Ahechu ◽  
Javier Gómez-Ambrosi ◽  
Amaia Rodríguez ◽  
Beatriz Ramírez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Extracellular Matrix ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Mrna Levels ◽  
Expression Levels ◽  
The Impact ◽  
Ht 29 ◽  
Gene Expression Levels

Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.

scholarly journals Codon usage is an important determinant of gene expression levels largely through its effects on transcription

2016 ◽  
Vol 113 (41) ◽  
pp. E6117-E6125 ◽  
Author(s):  
Zhipeng Zhou ◽  
Yunkun Dang ◽  
Mian Zhou ◽  
Lin Li ◽  
Chien-hung Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Codon Usage ◽  
Important Determinant ◽  
Mrna Translation ◽  
Mrna Levels ◽  
Protein Coding ◽  
Expression Levels ◽  
Highly Expressed Genes ◽  
The Impact ◽  
Gene Expression Levels

Codon usage biases are found in all eukaryotic and prokaryotic genomes, and preferred codons are more frequently used in highly expressed genes. The effects of codon usage on gene expression were previously thought to be mainly mediated by its impacts on translation. Here, we show that codon usage strongly correlates with both protein and mRNA levels genome-wide in the filamentous fungus Neurospora. Gene codon optimization also results in strong up-regulation of protein and RNA levels, suggesting that codon usage is an important determinant of gene expression. Surprisingly, we found that the impact of codon usage on gene expression results mainly from effects on transcription and is largely independent of mRNA translation and mRNA stability. Furthermore, we show that histone H3 lysine 9 trimethylation is one of the mechanisms responsible for the codon usage-mediated transcriptional silencing of some genes with nonoptimal codons. Together, these results uncovered an unexpected important role of codon usage in ORF sequences in determining transcription levels and suggest that codon biases are an adaptation of protein coding sequences to both transcription and translation machineries. Therefore, synonymous codons not only specify protein sequences and translation dynamics, but also help determine gene expression levels.

Molecular profiling in patients (pts) with upper gastrointestinal (UGI) cancers correlated with clinical outcome

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22042-e22042
Author(s):  
N. Virk ◽  
D. Yang ◽  
H. J. Lenz ◽  
A. B. El-Khoueiry ◽  
K. D. Danenberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Clinical Outcome ◽  
Excision Repair ◽  
Statistical Significance ◽  
Molecular Profiling ◽  
Cytotoxic Agents ◽  
Mrna Levels ◽  
Expression Levels ◽  
Gene Expression Levels

e22042 Background: Recent efforts have expanded our understanding of the molecular pathogenesis of UGI cancers and how oncogenes and tumor suppressor genes play a role in both carcinogenic and metastatic processes. These markers may serve as prognostic and/or predictive factors for recurrence following resection and resistance to radiotherapy and chemotherapy. Gene expression levels of thymidylate synthase (TS), thymidylate phosphorylase (TP), epidermal growth factor receptor (EGFR) and excision repair cross complementing (ERCC-1) have been shown to be associated with outcomes in lung, gastric and colon cancer. We evaluated TS, ERCC-1, EGFR and TP gene expression levels in patients with UGI cancers. Methods: This was a retrospective study of 80 pts with UGI cancers evaluated at USC who underwent molecular profiling. The primary objective was to determine a correlation between TS, TP, ERCC1 and EGFR and correlate with clinical outcome. Characteristics of these 80 pts: (16 females, 64 males ); median age 61 years (range 34–85); tumor types evaluated - 32 (40%) esophageal, 24(30%) gastric, 24(30%) GE junction; stages- 53 % IV, 21% III, 12% II, 2% I were evaluated for intratumoral gene expression of TS, TP, ERCC-1, & EGFR by real time quantitative PCR using Taqman technology from microdisected paraffin-embedded tumor sections. Results: High TS expression was associated with shorter OS (12.8 months vs. 23.7 months p=0.036). A significant correlation was found between TP & ERCC-1 (p=0.0078, r=0.37); TP & TS (p=0.0128, r=0.35); TP & EGFR (p=0.0065, r=0.39); TS & ERCC-1 (p=0.0004, r=0.39); ERCC-1 & EGFR (p=0.025, r=0.30). No statistically significant relationship was found between TS & EGFR (p=0.06,r=0.25). There was no correlation of ERCC-1, TP, & EGFR with OS that reached statistical significance. Conclusions: TS mRNA levels were shown to be associated with OS in UGI tumors, consistent with data reported in colon cancer. TS gene expression was significantly associated with expression levels of ERCC-1. In addition, ERCC1 was associated with EGFR. These data show for the first time that molecular pathways of cytotoxic agents are linked to the EGFR pathway suggesting that sensitivity to fluoropyrimidines, oxaliplatin, and EGFR inhibitors may be associated. No significant financial relationships to disclose.

scholarly journals Prognostic and Predictive Value of BGN in Colon Cancer Outcomes and Response to Immunotherapy

2022 ◽  
Vol 11 ◽  
Author(s):  
Zi-Xuan He ◽  
Sheng-Bing Zhao ◽  
Xue Fang ◽  
Ji-Fu E ◽  
Hong-Yu Fu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Immune Response ◽  
Cancer Patients ◽  
Immune Cells ◽  
Matrix Protein ◽  
Cox Regression ◽  
Extracellular Matrix Protein ◽  
Great Promise ◽  
Clinical Prognosis ◽  
Expression Levels

BackgroundColon cancer is one of the most frequent malignancies and causes high mortality worldwide. Exploring the tumor-immune interactions in the tumor microenvironment and identifying new prognostic and therapeutic biomarkers will assist in decoding the novel mechanism of tumor immunotherapy. BGN is a typical extracellular matrix protein that was previously validated as a signaling molecule regulating multiple processes of tumorigenesis. However, its role in tumor immunity requires further investigation.MethodsThe differentially expressed genes in three GEO datasets were analyzed, and BGN was identified as the target gene by intersection analysis of PPIs. The relevance between clinical outcomes and BGN expression levels was evaluated using data from the GEO database, TCGA and tissue microarray of colon cancer samples. Univariable and multivariable Cox regression models were conducted for identifying the risk factors correlated with clinical prognosis of colon cancer patients. Next, the association between BGN expression levels and the infiltration of immune cells as well as the process of the immune response was analyzed. Finally, we predicted the immunotherapeutic response rates in the subgroups of low and high BGN expression by TIS score, ImmuCellAI and TIDE algorithms.ResultsBGN expression demonstrated a statistically significant upregulation in colon cancer tissues than in normal tissues. Elevated BGN was associated with shorter overall survival as well as unfavorable clinicopathological features, including tumor size, serosa invasion and length of hospitalization. Mechanistically, pathway enrichment and functional analysis demonstrated that BGN was positively correlated with immune and stromal scores in the TME and primarily involved in the regulation of immune response. Further investigation revealed that BGN was strongly expressed in the immunosuppressive phenotype and tightly associated with the infiltration of multiple immune cells in colon cancer, especially M2 macrophages and induced Tregs. Finally, we demonstrated that high BGN expression presented a better immunotherapeutic response in colon cancer patients.ConclusionBGN is an encouraging predictor of diagnosis, prognosis and immunotherapeutic response in patients with colon cancer. Assessment of BGN expression represents a novel approach with great promise for identifying patients who may potentially benefit from immunotherapy.

Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 383-383
Author(s):  
Martin K. H. Maus ◽  
Craig Stephens ◽  
Stephanie H. Astrow ◽  
Peter Philipp Grimminger ◽  
Dongyun Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Mrna Expression ◽  
Advanced Colorectal Cancer ◽  
Expression Patterns ◽  
Mrna Levels ◽  
Expression Levels ◽  
Mutational Status ◽  
Mrna Expression Levels ◽  
Gene Expression Levels

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.

scholarly journals Evaluation of UHRF1 and P16INK4A expression levels in newly diagnosed AML patients

2018 ◽  
Vol 5 (9) ◽  
pp. 2658-2663 ◽  
Author(s):  
Vahid Amiri ◽  
Mohamadhossein Mohammadi ◽  
Mohammad Reza Khosravi Farsani ◽  
Arshia Gharehbaghian ◽  
Abbas Hajifathali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Negative Correlation ◽  
Leukemic Cells ◽  
Control Group ◽  
Newly Diagnosed ◽  
Expression Levels ◽  
Age Related ◽  
P16ink4a Gene ◽  
The Impact ◽  
Gene Expression Levels

Introduction: Gene mutation is an infrequent cause of tumor suppressor gene (TSG) defect in de novo AML patients. Instead, it seems that leukemic cells employ epigenetic tricks to attenuate the negative impacts of intact TSGs. Ordinarily, critical TSGs, such as p16INK4A, is hyper-methylated in AML blasts under the impact of master epigenetic regulators, such as UHRF1. In this study, we investigated the correlation between UHRF1 and p16INK4A gene expression levels in newly diagnosed AML patients. Methods: Bone marrow and peripheral blood samples were obtained from 50 newly diagnosed AML patients and 18 healthy normal control subjects. Gene expression levels of UHRF1 and P16INK4A were surveyed using SYBR Green Quantitative Real-time PCR. Statistical analyses were done using SPSS statistical software 21.0. Results: P16INK4A gene expression showed reduced levels in 80.64% of patients above 45 years of age, while only 32% of patients below 45 years had reduced expression levels. The Spearman correlation test also demonstrated a significant negative correlation between UHRF1 and p16INK4A gene expression levels in AML patients, which was not observed in the control group (r=0.343 and P= 0.015). Conclusion: Regarding the age-related patterns of UHRF1 and p16INK4A gene expression, and also the presence of negative correlation between them, we conclude that UHRF1 may potentially be involved in p16INK4A down-regulation in elderly AML patients, which may subsequently facilitate the progression of AML in older ages.  

scholarly journals Dynamics Affect Nitrogen Retention, Ileal Amino Acid Digestibility, and Gene Expression Levels of Digestive Enzymes at Three Stages in Pigs Fed Two Levels of Low-Protein Diets

2019 ◽  
Author(s):  
Li Wu ◽  
Qinghua He ◽  
Wen Zhen ◽  
Tiejun Li ◽  
Peng Liao
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Treatment Group ◽  
Protein Intake ◽  
Digestive Enzymes ◽  
Growing Pigs ◽  
Mrna Levels ◽  
Expression Levels ◽  
Three Stages ◽  
Gene Expression Levels

This study was conducted to determine the dynamic effects of dietary crude protein (CP) intake on nitrogen (N) balance, ileal amino acid digestibility, and gene expression levels of digestive enzymes at three stages in pigs. In Experiment 1, 18 growing pigs (average body weight (BW) = 9.5 kg) were randomly assigned to one of three treatments (n = 6/treatment group), including normal (20% CP), low (17% CP), and very low (14% CP) protein intake. In Experiment 2, 18 growing pigs (average BW = 30 kg) were allotted randomly to one of three treatments (n = 6/treatment group), including normal (18% CP), low (15% CP), and very low (12% CP) protein intake. In Experiment 3, 18 growing pigs (average BW = 45 kg) were assigned randomly to one of three treatments (n = 6/treatment group), including normal (16% CP), low (13% CP), and very low (10% CP) protein intake. Growing pigs fed the 14% CP and 17% CP diets had lower final BW (P &lt; 0.05) and average daily gain (ADG) (P &lt; 0.05) compared to pigs fed the 20% CP diet. Reducing the dietary CP level from 20 to 14% decreased urinary N excretion by 52.8% (P &lt; 0.001) in Experiment 1. Reducing the dietary CP level from 18 to 12% decreased urinary N excretion by 55.3% (P &lt; 0.001) and reduced fecal N excretion by 34% (P &lt; 0.05) in Experiment 2. Reducing the dietary CP level from 16 to 10% decreased urinary N excretion by 56.4% (P &lt; 0.001) and fecal N excretion by 47.1% (P &lt; 0.001) in Experiment 3. Pigs fed the very low (14%, 12%, and 10% CP) diets showed higher digestibility for CP (P &lt; 0.05), His (P &lt; 0.05), Ile (P &lt; 0.05), Phe (P &lt; 0.05), Thr (P &lt; 0.05), Trp (P &lt; 0.05), Glu (P &lt; 0.05), and Ser (P &lt; 0.05) compared to pigs fed the normal (20%, 18%, and 16% CP) diets among the three experiments. Pigs fed the very low (14%, 12%, and 10% CP) diets showed higher mRNA levels for chymotrypsin C (P &lt; 0.01 in Experiment 1 and 2; P &lt; 0.05 in Experiment 3) compared to pigs fed the normal (20%, 18%, and 16% CP) diets among the three experiments. These results indicated that a reduction in dietary CP by 6% limited the growth performance of growing pigs, and a reduction of dietary CP by 3% supplemented with essential amino acids could reduce the excretion of N into the environment without affecting weight gain.

Use of multidrug-resistance gene (MDR1) expression levels to predict outcome to adjuvant cisplatin/gemcitabine based chemotherapy in patients with with locally advanced urothelial cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22081-e22081
Author(s):  
T. Gauler ◽  
A. C. Hoffman ◽  
P. Wild ◽  
C. Leicht ◽  
S. Bertz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Urothelial Cancer ◽  
Locally Advanced ◽  
Mdr1 Gene ◽  
Mrna Levels ◽  
Expression Levels ◽  
Mdr1 Gene Expression ◽  
Mdr1 Expression ◽  
Advanced Urothelial Cancer ◽  
Gene Expression Levels

e22081 Background: The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. MDR1 mRNA levels have been shown to influence metabolism of cancer drugs. We tested whether MDR1 gene expression is associated with outcome in patients with locally advanced bladder cancer. Methods: 43 formalin fixed paraffin embedded (FFPE) tumor samples from patients with locally advanced and/or lymph node-positive bladder cancer undergoing treatment with cisplatin/gemcitabine were analyzed.FFPE tissues were dissected using laser-captured microdissection and analyzed for MDR1 expression using a quantitative real- time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: MDR1 was significantly correlated to overall survival. We included tumor stage (pT), lymph node status (pN) and the blood vessel invasion along with the measured gene expression in a stepwise multivariate Cox proportional hazards regression model. The overall model fit had a significance level of p=0.04 (<0.05). The relative risk for shorter survival in patients with High MDR1 expression was 1.9. Conclusions: These results suggest that MDR1 gene expression levels predict response and overall survival in patients with locally advanced urothelial cancer. MDR1 gene expression levels may allow the selection of patients who benefit likely from adjuvant cisplatin/gemcitabine based chemotherapy. Further studies are warranted to study this association. [Table: see text]

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