scholarly journals Differential Notch and TGFβ Signaling in Primary Colorectal Tumors and Their Corresponding Metastases

2008 ◽  
Vol 30 (1) ◽  
pp. 1-11
Author(s):  
Liesbeth M. Veenendaal ◽  
Onno Kranenburg ◽  
Niels Smakman ◽  
Annemarie Klomp ◽  
Inne H. M. Borel Rinkes ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Lung Metastases ◽  
Tumor Development ◽  
Distant Metastases ◽  
Normal Mucosa ◽  
Normal Colonic Mucosa ◽  
Colorectal Tumors ◽  
Vimentin Expression ◽  
Aberrant Expression ◽  
Tissue Samples

Background: Loss of epithelial morphology and the acquisition of mesenchymal characteristics may contribute to metastasis formation during colorectal tumorigenesis. The Wnt, Notch and TGFβ signaling pathways control tissue homeostasis and tumor development in the gut. The relationship between the activity of these pathways and the expression of epithelial and mesenchymal markers was investigated in a series of primary colorectal tumors and their corresponding metastases.Methods: Tissue samples of primary colorectal tumors, normal colonic mucosa, and regional and systemic metastases were processed for immunohistochemistry in a tissue microarray format. The expression of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin) markers was related to markers of Wnt (β-catenin), Notch (HES1) and TGFβ (phospho-SMAD2) signalling. In addition, the KRAS mutation status was assessed.Results: When compared to normal mucosa, primary colorectal tumors showed a marked increase in the levels of cytoplasmic vimentin and nuclear β-catenin, phospho-SMAD2 and HES1. Increased vimentin expression correlated with the presence of oncogenic KRAS and with nuclear β-catenin. The corresponding liver, lymph node, brain and lung metastases did not express vimentin and displayed significantly lower levels of nuclear phospho-SMAD2 and HES1, while retaining nuclear β-catenin.Conclusions: Primary colorectal carcinomas display aberrant expression of vimentin, and have activated Notch and TGFβ signaling pathways. Surprisingly, many regional and distant metastases have lost nuclear HES1 and pSMAD2, suggesting that the activity of the Notch and TGFβ pathways is reduced in secondary colorectal tumors.

scholarly journals MicroRNA Analysis of Human Stroke Brain Tissue Resected during Decompressive Craniectomy/Stroke-Ectomy Surgery

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1860
Author(s):  
Andrew P. Carlson ◽  
William McKay ◽  
Jeremy S. Edwards ◽  
Radha Swaminathan ◽  
Karen S. SantaCruz ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Brain Tissue ◽  
Stroke Patient ◽  
Mirna Expression ◽  
Strong Association ◽  
Bioinformatic Analysis ◽  
Experimental Models ◽  
Aberrant Expression ◽  
Tissue Samples ◽  
Human Stroke

Background: Signaling pathways mediated by microRNAs (miRNAs) have been identified as one of the mechanisms that regulate stroke progression and recovery. Recent investigations using stroke patient blood and cerebrospinal fluid (CSF) demonstrated disease-specific alterations in miRNA expression. In this study, for the first time, we investigated miRNA expression signatures in freshly removed human stroke brain tissue. Methods: Human brain samples were obtained during craniectomy and brain tissue resection in severe stroke patients with life-threatening brain swelling. The tissue samples were subjected to histopathological and immunofluorescence microscopy evaluation, next generation miRNA sequencing (NGS), and bioinformatic analysis. Results: miRNA NGS analysis detected 34 miRNAs with significantly aberrant expression in stroke tissue, as compared to non-stroke samples. Of these miRNAs, 19 were previously identified in stroke patient blood and CSF, while dysregulation of 15 miRNAs was newly detected in this study. miRNA direct target gene analysis and bioinformatics approach demonstrated a strong association of the identified miRNAs with stroke-related biological processes and signaling pathways. Conclusions: Dysregulated miRNAs detected in our study could be regarded as potential candidates for biomarkers and/or targets for therapeutic intervention. The results described herein further our understanding of the molecular basis of stroke and provide valuable information for the future functional studies in the experimental models of stroke.

scholarly journals The Clinicopathological Significance of miR-133a in Colorectal Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Timothy Ming-Hun Wan ◽  
Colin Siu-Chi Lam ◽  
Lui Ng ◽  
Ariel Ka-Man Chow ◽  
Sunny Kit-Man Wong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Negative Correlation ◽  
Target Genes ◽  
Distant Metastases ◽  
Normal Mucosa ◽  
Tnm Staging ◽  
Tissue Samples ◽  
Qrt Pcr ◽  
Endogenous Expression ◽  
Clinicopathological Significance

This study determined the expression of microRNA-133a (MiR-133a) in colorectal cancer (CRC) and adjacent normal mucosa samples and evaluated its clinicopathological role in CRC. The expression of miR-133a in 125 pairs of tissue samples was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and correlated with patient’s clinicopathological data by statistical analysis. Endogenous expression levels of several potential target genes were determined by qRT-PCR and correlated using Pearson’s method. MiR-133a was downregulated in 83.2% of tumors compared to normal mucosal tissue. Higher miR-133a expression in tumor tissues was associated with development of distant metastasis, advanced Dukes and TNM staging, and poor survival. The unfavorable prognosis of higher miR-133a expression was accompanied by dysregulation of potential miR-133a target genes, LIM and SH3 domain protein 1 (LASP1), Caveolin-1 (CAV1), and Fascin-1 (FSCN1). LASP1 was found to possess a negative correlation (γ=-), whereas CAV1 exhibited a significant positive correlation (γ=), and a stronger correlation was found in patients who developed distant metastases (γ=). In addition, a negative correlation of FSCN1 was only found in nonmetastatic patients. In conclusion, miR-133a was downregulated in CRC tissues, but its higher expression correlated with adverse clinical characteristics and poor prognosis.

scholarly journals Epigenetic-Mediated Downregulation of μ-Protocadherin in Colorectal Tumours

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Bujko Mateusz ◽  
Kober Paulina ◽  
Statkiewicz Małgorzata ◽  
Mikula Michal ◽  
Ligaj Marcin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Rna Polymerase Ii ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Normal Mucosa ◽  
Colorectal Carcinogenesis ◽  
Cellular Interaction ◽  
Mrna Levels ◽  
Aberrant Expression ◽  
Tissue Samples

Carcinogenesis involves altered cellular interaction and tissue morphology that partly arise from aberrant expression of cadherins. Mucin-like protocadherin is implicated in intercellular adhesion and its expression was found decreased in colorectal cancer (CRC). This study has compared MUPCDH (CDHR5) expression in three key types of colorectal tissue samples, for normal mucosa, adenoma, and carcinoma. A gradual decrease of mRNA levels and protein expression was observed in progressive stages of colorectal carcinogenesis which are consistent with reports of increasing MUPCDH 5′ promoter region DNA methylation. High MUPCDH methylation was also observed in HCT116 and SW480 CRC cell lines that revealed low gene expression levels compared to COLO205 and HT29 cell lines which lack DNA methylation at the MUPCDH locus. Furthermore, HCT116 and SW480 showed lower levels of RNA polymerase II and histone H3 lysine 4 trimethylation (H3K4me3) as well as higher levels of H3K27 trimethylation at the MUPCDH promoter. MUPCDH expression was however restored in HCT116 and SW480 cells in the presence of 5-Aza-2′-deoxycytidine (DNA methyltransferase inhibitor). Results indicate that μ-protocadherin downregulation occurs during early stages of tumourigenesis and progression into the adenoma-carcinoma sequence. Epigenetic mechanisms are involved in this silencing.

Activity of Matrix Metalloproteinases-2 and -9 in Advanced Laryngeal Cancer

2003 ◽  
Vol 128 (1) ◽  
pp. 132-136 ◽  
Author(s):  
Michal Bogusiewicz ◽  
Marta Stryjecka-Zimmer ◽  
Marcin Szymanski ◽  
Tomasz Rechberger ◽  
Wieslaw Golabek
Keyword(s):  
Matrix Metalloproteinases ◽  
Laryngeal Cancer ◽  
Malignant Tumors ◽  
Proteolytic Enzymes ◽  
Distant Metastases ◽  
Normal Mucosa ◽  
Collagen Type Iv ◽  
Primary Therapy ◽  
Tissue Samples ◽  
Type Iv

OBJECTIVES: Matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) are proteolytic enzymes that digest collagen type IV and other components of the basement membrane. They play a key role in local invasion and the formation of distant metastases by malignant tumors. The aim of this study was to evaluate the activity of MMP-2 and MMP-9 in stage III and IV laryngeal cancers. STUDY DESIGN: In the study we used specimens of laryngeal cancer and surrounding normal mucosa obtained from 23 patients undergoing surgical treatment as a primary therapy. After extraction of MMP-2 and MMP-9 from tissue samples, their activity was assessed with zymography. RESULTS: Greater activity of MMP-2 and MMP-9 and a higher active/latent MMP-2 ratio were found in cancer compared with normal mucosa. Moreover, N2 tumors revealed greater activity of MMP-2 in comparison with N1 and N0 tumors. CONCLUSIONS: Results of the study indicate that both MMP-2 and MMP-9 may be involved in the expansion of laryngeal cancer. MMP-2 may also play an important role in the lymphatic spread of some laryngeal tumors.

scholarly journals Elevated miRNA Inversely Correlates with E-cadherin Gene Expression in Tissue Biopsies from Crohn Disease Patients in contrast to Ulcerative Colitis Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Małgorzata Guz ◽  
Tomasz Dworzański ◽  
Witold Jeleniewicz ◽  
Marek Cybulski ◽  
Joanna Kozicka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Crohn Disease ◽  
Normal Tissue ◽  
Normal Mucosa ◽  
Normal Colonic Mucosa ◽  
Adjacent Normal Tissue ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
E Cadherin

Inflammatory bowel disease (IBD) comprises ulcerative colitis (UC) and Crohn disease (CD). Similar symptoms, but different treatment procedures for both diseases require precise diagnosis. MicroRNAs (miRNAs) are major posttranscriptional players that regulate the expression of genes during the inflammation and thus could be appropriate biomarkers for differentiation between UC and CD. For this purpose, we analyzed the expression of miR-21-3p, miR-31-3p, miR-125b-1-3p, miR-146a-3p, miR-155-5p, and E-cadherin (CDH1) genes associated with IBD, in 67 tissue samples: 28 inflamed mucosa samples (n=16 UC, n=12 CD), 28 adjacent normal colonic mucosa (n=16 UC, n=12 CD), and 11 normal mucosa from healthy patients using reverse transcription real-time RT-PCR. We found all analyzed miRNAs were significantly overexpressed in UC tissue as compared to adjacent normal tissue of patients with UC, as well as to normal mucosa from healthy controls. Four miRNAs (except miR-125b-1-3p) were significantly upregulated in CD lesions as compared to adjacent normal tissue of patients with CD, and four miRNAs, except miR-146a-3p, were significantly higher in CD samples compared to normal mucosa from healthy individuals. In the CD group, we found an inverse correlation between miR-155-5p or miR-146a-3p expressions and CDH1expression in inflamed mucosa. This type of correlation was also detected for miR-213p in adjacent normal tissue and CDH1 in inflamed mucosa, as well as between miR-155-5p and CDH1 in adjacent normal tissue. Elevated miRNA expression is characteristic for IBD-mediated inflammation process and inversely correlated with CDH1 gene expression, which suggest involvement of epithelial to mesenchymal transition (EMT) in IBD development.

scholarly journals IL-19 Promotes Nasal Mucosal Tissue Remodeling in Chronic Rhinosinusitis Patients By Upregulating Fibronectin and Collagen Ι Expressions in Fibroblasts Via NF-κB-Smad2/3 Signaling Pathways

2021 ◽  
Author(s):  
Hongwei Bao ◽  
Xia Li ◽  
Xiaoping Lai ◽  
Xiaoping Chen ◽  
Yue Li ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Chronic Sinusitis ◽  
Interstitial Fibrosis ◽  
Tissue Remodeling ◽  
Control Group ◽  
Mucosal Tissue ◽  
Aberrant Expression ◽  
Tissue Samples

Abstract BackgroundChronic sinusitis without nasal polyps (CRSsNP), a subtype of chronic rhinosinusitis, is characterized by tissue remodeling, mainly by interstitial fibrosis. Fibroblasts are essential effectors of tissue remodeling, mainly expressing fibronectin (FN), collagen Ι (Col Ι), and other extracellular matrices. Our previous study found that IL-19 can promote the aberrant expression of extracellular matrix, and pre-experiments revealed that the Smad2/3 pathway plays a crucial role in tissue remodeling. However, the exact mechanism how IL-19 participants in tissue remodeling remains unclear. This study aimed to determine the roles of IL-19 in regulating the expression of FN and Col Ι, and the roles of Smad2/3 and NF-κB signaling pathways in fibroblasts.MethodsNasal mucosal tissue samples were collected from patients with chronic sinusitis with nasal polyps (CRSwNP), patients with CRSsNP, and controls to analyze the expression of IL-19, FN, and Col Ι by RT-qPCR, immunohistochemistry, immunofluorescence, or western blotting. Cultured primary human nasal mucosal fibroblasts were treated with human recombinant IL-19 with or without Smad2/3 and NF-κB pathway inhibitor or agonist. They were analyzed for Smad2/3 and NF-κB pathway activation, and FN and Col Ι expression in fibroblasts by western blot, immunohistochemistry, and immunofluorescence.ResultsIL-19 co-localized with FN and Col Ι in nasal mucosal tissues and the expression levels of FN and Col Ι were elevated in CRSsNP, compared with CRSwNP and the control group. IL-19 activated the Smad2/3 and NF-κB pathways and promoted FN and Col Ι production in fibroblasts. NF-κB functions as an upstream pathway of the Smad2/3 pathway. The inhibitors of Smad2/3 and NF-κB could significantly attenuate the expression of FN and Col Ι induced by IL-19. ConclusionIL-19 promotes FN and Col Ι expression in fibroblasts via the NF-κB-Smad2/3 signaling pathway, leading to fibrosis and collagen deposition in patients with CRSsNP.

scholarly journals Comparison of matrix proteinase mRNA expression in morphologically normal, neoplastic, and metastatic colon tissue and colon biopsies from healthy donors

2018 ◽  
Vol 64 (1) ◽  
pp. 46-52 ◽  
Author(s):  
V.K. Bozhenko ◽  
U.S. Stanojevic ◽  
I.D. Trotsenko ◽  
M.V. Zakharenko ◽  
Y.Y. Kiseleva ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Liver Metastases ◽  
Normal Mucosa ◽  
Normal Colonic Mucosa ◽  
Matrix Remodeling ◽  
Proliferation Marker ◽  
Healthy Individuals ◽  
Ki 67 ◽  
Tissue Samples ◽  
Primary Tumors

Matrix metalloproteinases (MMPs) responsible for the extracellular matrix remodeling, the activation of various growth factors, and angiogenesis play an important role in the colorectal cancer (CRC) development. In the present work the comparative analysis of MMP-7, -8, -9, and -11 mRNA as well mRNA of the Ki-67 proliferation marker in tissue samples obtained from CRC patients and healthy individuals. Employing the real time PCR method the expression levels of several MMPs (MMP-7, -8, -9, and -11) and cell proliferation marker, Ki-67, were simultaneously measured in 256 tissue samples obtained from 112 patients with CRC: 112 samples of the primary tumor (CRC), 112 samples of the most distant border of morphologically normal colonic mucosa (MNT), 16 samples of liver metastases) and from 16 healthy volunteers who underwent colonoscopy and biopsy. The expression of both MMPs studied and Ki-67 was found to be elevated in CRC primary tumors and liver metastases compared with the normal mucosa. CRC tumor and metastatic cells exhibited similar proliferative activity. The metastases are characterized by the highest cross-correlation of MMPs among tissue types tested. For the first time it was shown that normal mucosa from healthy individuals and CRC patients varied in the MMP-8 expression level. They also had dissimilar MMP correlation patterns thus suggesting that epithelial cells adjusted to CRC tumor differ from mucosal epithelial cells of healthy individuals.

scholarly journals Association between colorectal cancer and Fusobacterium nucleatum and Bacteroides fragilis bacteria in Iranian patients: a preliminary study

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Aref Shariati ◽  
Shabnam Razavi ◽  
Ehsanollah Ghaznavi-Rad ◽  
Behnaz Jahanbin ◽  
Abolfazl Akbari ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Relative Abundance ◽  
Normal Tissue ◽  
Bacteroides Fragilis ◽  
Fusobacterium Nucleatum ◽  
Normal Mucosa ◽  
Clinicopathologic Characteristics ◽  
Tissue Samples ◽  
Adjacent Normal Mucosa ◽  
Iranian Patients

Abstract Background and aim Recent studies have proposed that commensal bacteria might be involved in the development and progression of gastrointestinal disorders such as colorectal cancer (CRC). Therefore, in this study, the relative abundance of Fusobacterium nucleatum, Bacteroides fragilis, Streptococcus bovis/gallolyticus, and Enteropathogenic Escherichia coli (EPEC) in CRC tissues, and their association with clinicopathologic characteristics of CRC was investigated in Iranian patients. Moreover, the role of these bacteria in the CRC-associated mutations including PIK3CA, KRAS, and BRAF was studied. Method To these ends, the noted bacteria were quantified in paired tumors and normal tissue specimens of 30 CRC patients, by TaqMan quantitative Real-Time Polymerase Chain Reaction (qPCR). Next, possible correlations between clinicopathologic factors and mutations in PIK3CA, KRAS, and BRAF genes were analyzed. Results In studied samples, B. fragilis was the most abundant bacteria that was detected in 66 and 60% of paired tumor and normal samples, respectively. Furthermore, 15% of the B. fragilis-positive patients were infected with Enterotoxigenic B. fragilis (ETBF) in both adenocarcinoma and matched adjacent normal samples. F. nucleatum was also identified in 23% of tumors and 13% of adjacent normal tissue samples. Moreover, the relative abundance of these bacteria determined by 2-ΔCT was significantly higher in CRC samples than in adjacent normal mucosa (p < 0.05). On the other hand, our findings indicated that S. gallolyticus and EPEC, compared to adjacent normal mucosa, were not prevalent in CRC tissues. Finally, our results revealed a correlation between F. nucleatum-positive patients and the KRAS mutation (p = 0.02), while analyses did not show any association between bacteria and mutation in PIK3CA and BRAF genes. Conclusion The present study is the first report on the analysis of different bacteria in CRC tissue samples of Iranian patients. Our findings revealed that F. nucleatum and B. fragilis might be linked to CRC. However, any link between gut microbiome dysbiosis and CRC remains unknown.

scholarly journals The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Mohammad Burhan Uddin ◽  
Zhishan Wang ◽  
Chengfeng Yang
Keyword(s):  
Signaling Pathways ◽  
Malignant Transformation ◽  
Noncoding Rna ◽  
Rna Modification ◽  
Oncogenic Signaling ◽  
Aberrant Expression ◽  
Rna Methylation ◽  
Rna Molecules ◽  
M6a Rna Methylation ◽  
Oncogenic Signaling Pathways

AbstractThe m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes. Dysregulations of the m6A modification due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer. Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms. Accumulating evidence showing regulation of oncogenic signaling pathways at the epitranscriptomic level has added an extra layer of the complexity. In particular, recent studies demonstrated that, in many types of cancers various oncogenic signaling pathways are modulated by the m6A modification in the target mRNAs as well as noncoding RNA transcripts. m6A modifications in these RNA molecules control their fate and metabolism by regulating their stability, translation or subcellular localizations. In this review we discussed recent exciting studies on oncogenic signaling pathways that are modulated by the m6A RNA modification and/or their regulators in cancer and provided perspectives for further studies. The regulation of oncogenic signaling pathways by the m6A modification and its regulators also render them as potential druggable targets for the treatment of cancer.

scholarly journals Nomogram based on homogeneous and heterogeneous associated factors for predicting distant metastases in patients with colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tianwen Luo ◽  
Yutong Wang ◽  
Xuefeng Shan ◽  
Ye Bai ◽  
Chun Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Lung Metastases ◽  
Roc Curves ◽  
Distant Metastases ◽  
Good Prediction ◽  
Operating Characteristics ◽  
Good Prediction Performance ◽  
Different Types ◽  
Associated Risk Factors

Abstract Background The identification of the homogeneous and heterogeneous risk factors for different types of metastases in colorectal cancer (CRC) may shed light on the aetiology and help individualize prophylactic treatment. The present study characterized the incidence differences and identified the homogeneous and heterogeneous risk factors associated with distant metastases in CRC. Methods CRC patients registered in the SEER database between 2010 and 2016 were included in this study. Logistic regression was used to analyse homogeneous and heterogeneous risk factors for the occurrence of different types of metastases. Nomograms were constructed to predict the risk for developing metastases, and the performance was quantitatively assessed using the receiver operating characteristics (ROC) curve and calibration curve. Results A total of 204,595 eligible CRC patients were included in our study, and 17.07% of them had distant metastases. The overall incidences of liver metastases, lung metastases, bone metastases, and brain metastases were 15.34%, 5.22%, 1.26%, and 0.29%, respectively. The incidence of distant metastases differed by age, gender, and the original CRC sites. Poorly differentiated grade, more lymphatic metastasis, higher carcinoembryonic antigen (CEA), and different metastatic organs were all positively associated with four patterns of metastases. In contrast, age, sex, race, insurance status, position, and T stage were heterogeneously associated with metastases. The calibration and ROC curves exhibited good performance for predicting distant metastases. Conclusions The incidence of distant metastases in CRC exhibited distinct differences, and the patients had homogeneous and heterogeneous associated risk factors. Although limited risk factors were included in the present study, the established nomogram showed good prediction performance.

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