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The miRNAome of O. viverrini induced cholangiocarcinoma by microarray:

ABSTRACT: Cholangiocarcinoma is the second most common primary hepatic malignancy worldwide, with intrahepatic cholangiocarcinoma (ICC) a particularly significant public health problem in Southeast Asia, due to its strong association with the food-borne parasite Opisthorchis viverrini (OV). This manuscript represents the first comprehensive miRNA expression profiling by microarray of the three most common histological grades of OV-induced ICC: moderately differentiated, papillary, and well differentiated tumor tissue. No cohort of miRNAs emerged as commonly dysregulated among these histological grades of OV-induced ICC. Instead, each histological grade of ICC tissue showed a distinct miRNA profile. Moderately differentiated tumor tissue showed both the greatest number and the highest magnitude of miRNA dysregulation, followed by papillary ICC tumor tissue, and differentiated ICC tumor tissue. When ICC tumor tissue was compared to adjacent non-tumor tissue, a remarkable similarity in miRNA dysregulation was observed between these samples, indicative of intrahepatic metastasis. These findings indicate the possibility of determining the histological grade of ICC by profiling miRNA dysregulation, which not only would greatly enhance the molecular diagnosis of ICC, but could even lead to the personalized the treatment for ICC by the early classification of histological grade.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53992 | GEO | 2014/07/17

SECONDARY ACCESSION(S): PRJNA234298

REPOSITORIES: GEO

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Project description:Background: microRNAs (miRNAs) are approximately 21 nucleotide non-coding transcripts capable of regulating gene expression. The most widely studied mechanism of regulation involves binding of the miRNA to a target mRNA, usually in its 3â untranslated region (UTR). As a result, translation of the target mRNA is inhibited and sometimes the mRNA itself can be de-stabilized. The inhibitory effects of miRNAs have been linked to many diverse cellular processes including malignant proliferation and apoptosis, development and differentiation, metabolic processes and neural plasticity. We asked whether endogenous fluctuations in a set of mRNA and miRNA profiles contain correlated changes that are statistically distinguishable from the many other fluctuations in the data set. Methodology/Principal Findings: Biopsies from 12 human primary brain tumors were used to extract RNA. These samples were used to determine genome-wide mRNA expression levels by microarray analysis and a miRNA profile by real-time reverse transcription PCR (RT-PCR). Correlation coefficients were determined for all possible mRNA-miRNA pairs and the distribution of these correlations compared to the random distribution. An excess of high positive and negative correlation pairs were observed at the tails of these distributions. Most of these highest correlation pairs do not contain sufficiently complementary sequences to predict a target relationship; nor do they lie in physical proximity to each other. However, by examining pairs in which the significance of the correlation coefficients is modestly relaxed, negative correlations do tend to predict targets and positive correlations do tend to predict physically proximate pairs. A subset of high correlation pairs were experimentally validated by over-expressing or suppressing a miRNA and measuring the correlated mRNAs. Conclusions/Significance: Sufficient information exists within a set of tumor samples to detect endogenous correlations between miRNA and mRNA levels. Based on the validations of the correlations the causal arrow for these correlations is likely to be directed from the miRNAs to the mRNAs. From these data sets, we inferred and validated a tumor suppression pathway linked to miR-181c. Experiment Overall Design: Microarray data were obtained from the 12 tumors using Affymetrics HG-U133A array platforms. Tissue from glioma resections were obtained and collected at UCLA under approval from the Institutional Review Board. Categorization into high or low grade was based on the formal pathology report, with WHO grades III and IV being termed "high grade" and grades I and II termed "low grade". Histological diagnoses fell into the following categories: two low grade anaplastic mixed gliomas, one low grade oligodendroglioma, six high grade glioblastomas, two high grade gliosarcomas, and one high grade glioblastoma/gliosarcoma.

Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling we demonstrated that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 non-redundant genes that significantly discriminate the tumor stroma from non tumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix and Transforming Growth Factor beta (TGFM-NM-2) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increase expression of Collagen 4, Laminin, Osteopontin/SPP1, KIAA0101 and TGFM-NM-22 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of Osteopontin, TGFM-NM-22 and Laminin in the stroma of ICC was significantly correlated with patient overall survival. More importantly, multivariate analysis demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidates biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. 20 RNA samples were analyzed, from 10 patients with ICC. For each patient, RNA were isolated from laser capture microdissected (LCM) stroma from tumor and non tumor areas.

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The miRNAome of O. viverrini induced cholangiocarcinoma by microarray:

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