Dataset Information

Impact of miRNAs modulation on regulatory networks and pathways involved in colon cancer and metastasis development

ABSTRACT: Originally linked with development and differentiation, the role of microRNAs (miRNAs) in many important biological processes has emerged and dysregulation of miRNA expression has been connected with cancer pathogenesis. The association between abnormal expression levels of miRNAs and colon cancer has been mainly demonstrated in primary tumors; more recently, non-overlapping sets of oncomirs, tumour suppressor miRNAs and metastamirs have been associated with distinct stages of colo-rectal cancer (CRC) progression. In an attempt to identify changes in both miRNA and gene expression levels along the colon mucosa - primary tumor - liver metastasis- sequence and to classify miRNAs into distinct functional networks according to the expression of their anti-correlated and differentially expressed target genes, we analyzed a large set of sample-matched miRNA and mRNA expression profiles, including the complete non tumor tissue, primary carcinoma and liver metastasis sequence from 8 patients. Our study shows that the largest changes in miRNA and gene expression levels occur in normal mucosa to tumor transition and are almost stably maintained in the subsequent tumor to metastasis transition. Only a few miRNAs were differentially expressed between liver metastasis and primary carcinoma; however, miRNA expression profiles classified better primary tumors and metastases compared to mRNA profiles. By integration of miRNAs and target genes expression data, we were able to infer regulatory networks modulated by miRNAs during colorectal tumorigenesis and metastatic process, and associate them to the affected biological pathways. In particular, we identified a combination of interconnected miRNAs, up- or down-regulated during tumorigenesis, which are organized into distinct sub-networks, each of which includes several regulatory relationships with differentially expressed genes. Among them, the relationship between miR-182, up-regulated in colon cancer, and the anti-correlated ENTPD5 gene was identified for the first time and confirmed in an independent set of samples.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE35834 | GEO | 2014/01/16

SECONDARY ACCESSION(S): PRJNA151903

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Originally linked with development and differentiation, the role of microRNAs (miRNAs) in many important biological processes has emerged and dysregulation of miRNA expression has been connected with cancer pathogenesis. The association between abnormal expression levels of miRNAs and colon cancer has been mainly demonstrated in primary tumors; more recently, non-overlapping sets of oncomirs, tumour suppressor miRNAs and metastamirs have been associated with distinct stages of colo-rectal cancer (CRC) progression. In an attempt to identify changes in both miRNA and gene expression levels along the colon mucosa - primary tumor - liver metastasis- sequence and to classify miRNAs into distinct functional networks according to the expression of their anti-correlated and differentially expressed target genes, we analyzed a large set of sample-matched miRNA and mRNA expression profiles, including the complete non tumor tissue, primary carcinoma and liver metastasis sequence from 8 patients. Our study shows that the largest changes in miRNA and gene expression levels occur in normal mucosa to tumor transition and are almost stably maintained in the subsequent tumor to metastasis transition. Only a few miRNAs were differentially expressed between liver metastasis and primary carcinoma; however, miRNA expression profiles classified better primary tumors and metastases compared to mRNA profiles. By integration of miRNAs and target genes expression data, we were able to infer regulatory networks modulated by miRNAs during colorectal tumorigenesis and metastatic process, and associate them to the affected biological pathways. In particular, we identified a combination of interconnected miRNAs, up- or down-regulated during tumorigenesis, which are organized into distinct sub-networks, each of which includes several regulatory relationships with differentially expressed genes. Among them, the relationship between miR-182, up-regulated in colon cancer, and the anti-correlated ENTPD5 gene was identified for the first time and confirmed in an independent set of samples. We determined miRNA expression profile for 78 samples comprising 23 normal adjacent mucosa (N), 31 primitive colorectal cancer (T) and 24 liver metastases (M), obtained from 45 patients who underwent surgery at University of Padova (Surgery Branch, Department of Oncological and Surgical Sciences) between March 1994 and September 2008. This dataset included 24 samples belonging to 8 patients with matched samples (N, T and M) from the same patients. We also examined the expression profiles for 80 samples, comprising 23 N, 30 T, 27 M, and including 27 per-patient matched samples from 9 patients. Considering both miRNAs and genes expression experiments, we obtained a set of 77 samples (23N, 30T, 24M) with matched miRNAs and genes expression data from the same biological sample, to reconstruct post-transcriptional regulatory networks.

Project description:Liver metastasis is one of the major causes of death in colorectal cancer (CRC) patients. To understand this process, we investigated whether the gene expression profiling of matched colorectal carcinomas and liver metastases could reveal key molecular events involved in tumor progression and metastasis. We performed experiments using a cDNA microarray containing 17,104 genes with the following tissue samples: paired tissues of 25 normal colorectal mucosa, 27 primary colorectal tumors, 13 normal liver and 27 liver metastasis, and 20 primary colorectal tumors without liver metastasis. To remove the effect of normal cell contamination, we selected 4,583 organ-specific genes with a false discovery rate (FDR) of 0.0067% by comparing normal colon and liver tissues using significant analysis of microarray, and these genes were excluded from further analysis. We then identified and validated 46 liver metastasis-specific genes with an accuracy of 83.3% by comparing the expression of paired primary colorectal tumors and liver metastases using prediction analysis of microarray. The 46 selected genes contained several known oncogenes and 2 ESTs. To confirm that the results correlated with the microarray expression patterns, we performed RT-PCR with WNT5A and carbonic anhydrase II. Additionally, we observed that 21 of the 46 genes were differentially expressed (FDR = 2.27%) in primary tumors with synchronous liver metastasis compared with primary tumors without liver metastasis. We scanned the human genome using a cDNA microarray and identified 46 genes that may play an important role in the progression of liver metastasis in CRC. Keywords: gene expression profiling using cDNA microarray We performed 17K cDNA microarray with the amplified RNAs from the following tissue samples: normal colorectal mucosa, primary colorectal tumors, normal liver and liver metastasis tumors, and primary colorectal tumors without liver metastasis. Organ-specific genes in normal colon and liver tissues were excluded from the pre-filtered genes, and then we discovered and validated liver metastasis-specific genes commonly up-regulated in the primary colorectal tumors and liver metastasis tumors. To confirm the microarray data, we performed a RT-PCR of two genes (WNT5A and carbonic anhydrase II) in the primary colorectal tumors with and without liver metastases.

Project description:Colorectal cancer (CRC) is one of the most prevalent cancers, with over one million new cases per year. Overall, prognosis of CRC largely depends on the disease stage and metastatic status. As precision oncology for patients with CRC continues to improve, this study aimed to integrate genomic, transcriptomic, and proteomic analyses to identify significant differences in expression during CRC progression using a unique set of paired patient samples while considering tumour heterogeneity.We analysed fresh-frozen tissue samples prepared under strict cryogenic conditions of matched healthy colon mucosa, colorectal carcinoma, and liver metastasis from the same patients. Somatic mutations of known cancer-related genes were analysed using Illumina's TruSeq Amplicon Cancer Panel; the transcriptome was assessed comprehensively using Clariom D microarrays. The global proteome was evaluated by liquid chromatography-coupled mass spectrometry (LC‒MS/MS) and validated by two-dimensional difference in-gel electrophoresis. Subsequent unsupervised principal component clustering, statistical comparisons, and gene set enrichment analyses were calculated based on differential expression results.Although panomics revealed low RNA and protein expression of CA1, CLCA1, MATN2, AHCYL2, and FCGBP in malignant tissues compared to healthy colon mucosa, no differentially expressed RNA or protein targets were detected between tumour and metastatic tissues. Subsequent intra-patient comparisons revealed highly specific expression differences (e.g., SRSF3, OLFM4, and CEACAM5) associated with patient-specific transcriptomes and proteomes.Our research results highlight the importance of inter- and intra-tumour heterogeneity as well as individual, patient-paired evaluations for clinical studies. In addition to changes among groups reflecting CRC progression, we identified significant expression differences between normal colon mucosa, primary tumour, and liver metastasis samples from individuals, which might accelerate implementation of precision oncology in the future.

Dataset Information

Impact of miRNAs modulation on regulatory networks and pathways involved in colon cancer and metastasis development

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets