An Assessment of Database-Validated microRNA Target Genes in Normal Colonic Mucosa: Implications for Pathway Analysis

Background: Determination of functional pathways regulated by microRNAs (miRNAs), while an essential step in developing therapeutics, is challenging. Some miRNAs have been studied extensively; others have limited information. In this study, we focus on 254 miRNAs previously identified as being associated with colorectal cancer and their database-identified validated target genes. Methods: We use RNA-Seq data to evaluate messenger RNA (mRNA) expression for 157 subjects who also had miRNA expression data. In the replication phase of the study, we replicated associations between 254 miRNAs associated with colorectal cancer and mRNA expression of database-identified target genes in normal colonic mucosa. In the discovery phase of the study, we evaluated expression of 18 miRNAs (those with 20 or fewer database-identified target genes along with miR-21-5p, miR-215-5p, and miR-124-3p which have more than 500 database-identified target genes) with expression of 17 434 mRNAs to identify new targets in colon tissue. Seed region matches between miRNA and newly identified targeted mRNA were used to help determine direct miRNA-mRNA associations. Results: From the replication of the 121 miRNAs that had at least 1 database-identified target gene using mRNA expression methods, 97.9% were expressed in normal colonic mucosa. Of the 8622 target miRNA-mRNA associations identified in the database, 2658 (30.2%) were associated with gene expression in normal colonic mucosa after adjusting for multiple comparisons. Of the 133 miRNAs with database-identified target genes by non-mRNA expression methods, 97.2% were expressed in normal colonic mucosa. After adjustment for multiple comparisons, 2416 miRNA-mRNA associations remained significant (19.8%). Results from the discovery phase based on detailed examination of 18 miRNAs identified more than 80 000 miRNA-mRNA associations that had not previously linked to the miRNA. Of these miRNA-mRNA associations, 15.6% and 14.8% had seed matches for CRCh38 and CRCh37, respectively. Conclusions: Our data suggest that miRNA target gene databases are incomplete; pathways derived from these databases have similar deficiencies. Although we know a lot about several miRNAs, little is known about other miRNAs in terms of their targeted genes. We encourage others to use their data to continue to further identify and validate miRNA-targeted genes.

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Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.7229 ◽

2009 ◽

Vol 27 (2) ◽

pp. 186-192 ◽

Cited By ~ 603

Author(s):

Paul Salama ◽

Michael Phillips ◽

Fabienne Grieu ◽

Melinda Morris ◽

Nik Zeps ◽

...

Keyword(s):

Colorectal Cancer ◽

Colonic Mucosa ◽

Tumor Tissue ◽

Early Stage ◽

Prognostic Significance ◽

High Density ◽

Prognostic Indicators ◽

Normal Colonic Mucosa ◽

Solid Cancer ◽

Histopathologic Features

Purpose To determine the prognostic significance of FOXP3+ lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8+ and CD45RO+ lymphocyte densities. Patients and Methods Tissue microarrays and immunohistochemistry were used to assess the densities of CD8+, CD45RO+, and FOXP3+ lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. Results FOXP3+ Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8+ and CD45RO+ cell densities were lower. FOXP3+ Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3+ Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8+ and CD45RO+. High FOXP3+ Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3+ Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). Conclusion FOXP3+ Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8+ and CD45RO+ lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3+ Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3+ Treg density may help to improve the prognostication of early-stage colorectal cancer.

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The different immune profiles of normal colonic mucosa in cancer-free Lynch syndrome carriers and Lynch syndrome colorectal cancer patients

Gastroenterology ◽

10.1053/j.gastro.2021.11.029 ◽

2021 ◽

Author(s):

Lena Bohaumilitzky ◽

Klaus Kluck ◽

Robert Hüneburg ◽

Richard Gallon ◽

Jacob Nattermann ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Cancer Patients ◽

Colonic Mucosa ◽

Normal Colonic Mucosa ◽

Colorectal Cancer Patients

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The integrative knowledge base for miRNA-mRNA expression in colorectal cancer

Scientific Reports ◽

10.1038/s41598-019-54358-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Daša Jevšinek Skok ◽

Nina Hauptman ◽

Emanuela Boštjančič ◽

Nina Zidar

Keyword(s):

Colorectal Cancer ◽

Knowledge Base ◽

Mrna Expression ◽

Web Application ◽

Mirna Target ◽

Target Gene ◽

The Cancer Genome Atlas ◽

Gene Expressions ◽

Mirna Target Gene ◽

Colon And Rectum

Abstract“miRNA colorectal cancer” (https://mirna-coadread.omics.si/) is a freely available web application for studying microRNA and mRNA expression and their correlation in colorectal cancer. To the best of our knowledge, “miRNA colorectal cancer” has the largest knowledge base of miRNA-target gene expressions and correlations in colorectal cancer, based on the largest available sample size from the same source of data. Data from high-throughput molecular profiling of 295 colon and rectum adenocarcinoma samples from The Cancer Genome Atlas was analyzed and integrated into our knowledge base. The objective of developing this web application was to help researchers to discover the behavior and role of miRNA-target gene interactions in colorectal cancer. For this purpose, results of differential expression and correlation analyses of miRNA and mRNA data collected in our knowledge base are available through web forms. To validate our knowledge base experimentally, we selected genes FN1, TGFB2, RND3, ZEB1 and ZEB2 and miRNAs hsa-miR-200a/b/c-3p, hsa-miR-141-3p and hsa-miR-429. Both approaches revealed a negative correlation between miRNA hsa-miR-200b/c-3p and its target gene FN1 and between hsa-miR-200a-3p and its target TGFB2, thus supporting the usefulness of the developed knowledge base.

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Antioxidant Agents and Colorectal Carcinogenesis: Role of β-Carotene, Vitamin E and Vitamin C

Tumori Journal ◽

10.1177/030089169608200102 ◽

1996 ◽

Vol 82 (1) ◽

pp. 6-11 ◽

Cited By ~ 7

Author(s):

Giuseppe Pappalardo ◽

Antonio Guadalaxara ◽

Giuseppe Maiani ◽

Giovanni Illomei ◽

Mauro Trifero ◽

...

Keyword(s):

Colorectal Cancer ◽

Vitamin E ◽

Vitamin C ◽

Colonic Mucosa ◽

Genetic Alterations ◽

Colorectal Carcinogenesis ◽

Normal Colonic Mucosa ◽

Antioxidant Agents ◽

Β Carotene

In consideration of findings reported in the literature and of our study, we examined the correlation between antioxidants (β-carotene, vitamin C, vitamin E) and colorectal carcinogenesis. Although diagnostic progress has been made in the last decades, no significant improvements in death rates have been achieved in the western world. Exogenous factors might be responsible for a complex alteration process of normal colonic mucosa into adenoma and carcinoma. Free radicals and reactive oxygen metabolites, due to increased production or to reduced inactivation, following a decrease in the antioxidant burden in the mucosa, might cause damage to DNA, thereby resulting in genetic alterations. This might represent the cause of the transformation process: normal mucosa→ adenoma→ carcinoma. In a prospective study, we observed a reduction of β-carotene levels in normal colonic mucosa in patients with polyps and colorectal cancer. We also showed that β-carotene supplementation raises levels of this micronutrient in the colonic mucosa of these patients. Findings from the literature and our trials show a significant decrease in the antioxidant capacity of colorectal mucosa in patients affected by colorectal cancer, although there is a significant interindividual variability. Such results suggest a possible chemopreventive role of antioxidant agents in colorectal cancer.

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MGMT methylation is associated primarily with the germline C>T SNP (rs16906252) in colorectal cancer and normal colonic mucosa

Modern Pathology ◽

10.1038/modpathol.2009.130 ◽

2009 ◽

Vol 22 (12) ◽

pp. 1588-1599 ◽

Cited By ~ 46

Author(s):

Nicholas J Hawkins ◽

James H-F Lee ◽

Justin J-L Wong ◽

Chau-To Kwok ◽

Robyn L Ward ◽

...

Keyword(s):

Colorectal Cancer ◽

Colonic Mucosa ◽

Normal Colonic Mucosa ◽

Mgmt Methylation

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Clinicopathologic Significance of CXCL12 and CXCR4 Expressions in Patients with Colorectal Cancer

Gastroenterology Research and Practice ◽

10.1155/2018/9613185 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Naomi Yoshuantari ◽

Didik Setyo Heriyanto ◽

Susanna Hilda Hutajulu ◽

Johan Kurnianda ◽

Ahmad Ghozali

Keyword(s):

Colorectal Cancer ◽

Mrna Expression ◽

Messenger Rna ◽

Histological Grade ◽

Expression Patterns ◽

Distant Metastases ◽

Lymphatic Invasion ◽

Patients Âgés ◽

Response To Chemotherapy ◽

National Burden

Background. Colorectal cancer (CRC) is both a global and national burden, being the third most common malignancy in men and the second in women, worldwide. The prognosis of CRC is affected by various factors like the histological grade, angiolymphatic invasion, and distant metastases. Metastasis is an intricate process; one of the possible mechanisms is through the interaction of the chemokines CXCL12 and CXCR4. This study aims to reveal the expression patterns of CXCL12 and CXCR4 in CRC. Methods. The quantitative expressions of CXCL12 and CXCR4 messenger RNA (mRNA) were evaluated in 32 patients with adenocarcinoma-type CRC. Real-time polymerase chain reaction (qRT-PCR) was performed on formalin-fixed tissues. CXCL12 and CXCR4’s expressions, clinicopathologic features, and the treatment response to the CRC were analysed. Results. All tumour tissues showed higher levels of both chemokines compared to normal colonic tissue. The expression of CXCL12 mRNA was higher in rectal location (p=0.04) with a tendency to be higher in later stages (p=0.15), while the expression of CXCR4 was lower in tumours with a lymphatic invasion (p=0.02), compared to their counterparts. There was no difference in the expression of CXCL12 and CXCR4 according to the patients’ ages, gender, tumour differentiation, or response to chemotherapy. Conclusion. Our study demonstrated that the mRNA expression of CXCL12 was significantly correlated with rectal location. CXCR4 mRNA expression was inversely correlated in tumours with a lymphatic invasion.

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