ABSTRACT: Integrative Transcriptomic Profiling reveals Hepatic Stem-like Phenotype and Interplay of EMT and miR-200c in Intrahepatic Cholangiocarcinoma [miRNA]
Project description:This SuperSeries is composed of the following subset Series: GSE32879: Integrative Transcriptomic Profiling reveals Hepatic Stem-like Phenotype and Interplay of EMT and miR-200c in Intrahepatic Cholangiocarcinoma [mRNA] GSE32957: Integrative Transcriptomic Profiling reveals Hepatic Stem-like Phenotype and Interplay of EMT and miR-200c in Intrahepatic Cholangiocarcinoma [miRNA] Refer to individual Series
Project description:Integrative Transcriptomic Profiling reveals Hepatic Stem-like Phenotype and Interplay of EMT and miR-200c in Intrahepatic Cholangiocarcinoma
Project description:Integrative Transcriptomic Profiling reveals Hepatic Stem-like Phenotype and Interplay of EMT and miR-200c in Intrahepatic Cholangiocarcinoma [mRNA]
Project description:We compared transcriptomic profiles of ICC tumor specimens to hepatocellular carcinoma (HCC) specimens using Affymetrix mRNA array and the miRNA array platforms to search for unique gene signatures linked to patient prognosis. ICC and HCC share common stem-like molecular characteristics and stem-like tumor features associated with poor prognosis. Gene expression profiling of 16 intrahepatic cholangiocarcinoma (ICC), 7 mixed type of combined hepatocellular cholangiocarcinoma (CHC), 2 Hepatic adenoma, 3 focal nodular hyperplasia (FNH), 5 non-tumor liver tissues, and 2 CCA cell lines were performed.
Project description:Macrophages constitute a major part of the tumor-infiltrating immune cells and within the tumor microenvironment acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of miR-200c in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed a substantial transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and found numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. The miR-200c-mediated reduction of infiltration further correlated well with a miR-200c migration signature comprised of four miR-200c-repressed targets (PPM1F, RAB11FIB2, RDX, MSN).
Project description:MircoRNAs are small RNAs which regulate a pleiotropy of cellular processes and are also involved in tumorigenesis, cancer progression and therapy resistance. We investigated the influence of miRNA-200c on chemoresistance of tumor cells. A proteomic approach identified glutathione S-transferases to be differentially expressed when miR-200c was knocked out and cells were treated with the chemotherapeutic drug doxorubicin.
Project description:Here we analyzed mouse and human samples to characterize origin, subtypes, functions and cell-cell interactions of cancer-associated fibroblasts in cholangiocarcinoma, a highly desmoplastic tumor of the liver. Hepatic stellate cell-derived cancer-associated fibroblasts were isolated from two different models of murine intrahepatic cholangiocarcinoma, induced by overexpression of YAP+AKT or KRASG12D in combination with sg-p19, and compared by bulk RNA-sequencing to hepatic stellate cells from two models of liver fibrosis, induced by bile duct ligation or DDC diet. CAF-enriched fractions of from YAP+AKT or KRAS/sg-p19-induced intrahepatic cholangiocarcinoma, were analyzed by single-cell RNA sequencing. A cell suspension from human cholangiocarcinoma, containing all cell populations, was analyzed by single cell RNA-sequencing.
Project description:We compared transcriptomic profiles of 23 ICC tumor specimens to hepatocellular carcinoma (HCC) specimens using Affymetrix mRNA array and the miRNA array platforms to search for unique gene signatures linked to patient prognosis. ICC and HCC share common stem-like molecular characteristics and stem-like tumor features associated with poor prognosis. Gene expression profiling of 16 intrahepatic cholangiocarcinoma (ICC), 7 mixed type of combined HCC and ICC (CHC), 2 Hepatic Adenoma, 5 Focal Nodular Hyperplasia, and 7 Non-Tumor Tissues were performed.
Project description:Members of the miR-200 family are critical gatekeepers of the epithelial state, restraining expression of pro-mesenchymal genes that drive epithelial-mesenchymal transition (EMT) and contribute to metastatic cancer progression. Here, we show that miR-200c and another epithelial-enriched miRNA, miR-375, exert widespread control of alternative splicing in cancer cells. This is achieved by their strong suppression of the RNA binding protein Quaking (QKI), which is required to mediate the splicing changes regulated by these miRNAs. During EMT, QKI-5 directly binds to and regulates hundreds of alternative splicing events and exerts pleiotropic effects, such as increasing cell migration and invasion and restraining tumour growth, without appreciably affecting mRNA levels. QKI-5 is both necessary and sufficient to direct EMT alternative splicing changes, and this splicing signature is broadly conserved across many epithelial-derived cancer types. Importantly, several actin cytoskeleton-associated genes are directly targeted both by QKI and miR-200c, revealing coordinated control of alternative splicing and mRNA abundance during EMT. These findings demonstrate the existence of a miR-200/miR-375/QKI axis that impacts cancer-associated epithelial cell plasticity through widespread control of alternative splicing. The purpose of the CLIP experiment was to determine direct targets of QKI.
Project description:variant MCC cell lines show lower expression levels of the EMT-related microRNAs miR-200c-141 and miR-183-96-182 in contrast to classcial MCC cell lines
