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Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma.

ABSTRACT: UNLABELLED:Therapies that target cancer stem cells (CSCs) hold promise in eliminating cancer burden. However, normal stem cells are likely to be targeted owing to their similarities to CSCs. It is established that epithelial cell adhesion molecule (EpCAM) is a biomarker for normal hepatic stem cells (HpSCs), and EpCAM(+) AFP(+) hepatocellular carcinoma (HCC) cells have enriched hepatic CSCs. We sought to determine whether specific microRNAs (miRNAs) exist in hepatic CSCs that are not expressed in normal HpSCs. We performed a pair-wise comparison of the miRNA transcriptome of EpCAM(+) and corresponding EpCAM(-) cells isolated from two primary HCC specimens, as well as from two fetal livers and three healthy adult liver donors by small RNA deep sequencing. We found that miR-150, miR-155, and miR-223 were preferentially highly expressed in EpCAM(+) HCC cells, which was further validated. Their gene surrogates, identified using miRNA and messenger RNA profiling in a cohort of 292 HCC patients, were associated with patient prognosis. We further demonstrated that miR-155 was highly expressed in EpCAM(+) HCC cells, compared to corresponding EpCAM(-) HCC cells, fetal livers with enriched normal hepatic progenitors, and normal adult livers with enriched mature hepatocytes. Suppressing miR-155 resulted in a decreased EpCAM(+) fraction in HCC cells and reduced HCC cell colony formation, migration, and invasion in vitro. The reduced levels of identified miR-155 targets predicted the shortened overall survival and time to recurrence of HCC patients. CONCLUSION:miR-155 is highly elevated in EpCAM(+) HCC cells and might serve as a molecular target to eradicate the EpCAM(+) CSC population in human HCCs.

SUBMITTER: Ji J

PROVIDER: S-EPMC4549211 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma.

Ji Junfang J Zheng Xin X Forgues Marshonna M Yamashita Taro T Wauthier Eliane L EL Reid Lola M LM Wen Xinyu X Song Young Y Wei Jun S JS Khan Javed J Thorgeirsson Snorri S SS Wang Xin Wei XW

Hepatology (Baltimore, Md.) 20150630 3

<h4>Unlabelled</h4>Therapies that target cancer stem cells (CSCs) hold promise in eliminating cancer burden. However, normal stem cells are likely to be targeted owing to their similarities to CSCs. It is established that epithelial cell adhesion molecule (EpCAM) is a biomarker for normal hepatic stem cells (HpSCs), and EpCAM(+) AFP(+) hepatocellular carcinoma (HCC) cells have enriched hepatic CSCs. We sought to determine whether specific microRNAs (miRNAs) exist in hepatic CSCs that are not exp ...[more]

PMID: 25953724

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Project description:Cell adhesion molecules can predict liver hepatocellular carcinoma (LIHC) metastasis and determine prognosis, while the mechanism of the role of cell adhesion molecules in LIHC needs to be further explored. LIHC-related expression data were sourced from The Cancer Genome Atlas (TCGA) and the gene expression omnibus (GEO) databases, and genes related to cell adhesion were sourced from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. First, the TCGA-LIHC dataset was clustered by the nonnegative matrix factorization (NMF) algorithm to find different subtypes of LIHC. Then the difference of prognosis and immune microenvironment between patients of different subtypes was evaluated. In addition, a prognostic risk model was obtained by least shrinkage and selection operator (LASSO) and Cox analysis, while a nomogram was drawn. Furthermore, functional enrichment analysis between high and low risk groups was conducted. Finally, the expressions of model genes were explored by quantitative real-time polymerase chain reaction (qRT-PCR). The 371 LIHC patients were classified into four subtypes by NMF clustering, and survival analysis revealed that disease-free survival (DFS) of these four subtypes were clearly different. Cancer-related pathways and immune microenvironment among these four subtypes were dysregulated. Moreover, 58 common differentially expressed genes (DEGs) between four subtypes were identified and were mainly associated with PPAR signaling pathway and amino acid metabolism. Furthermore, a prognostic model consisting of IGSF11, CD8A, ALCAM, CLDN6, JAM2, ITGB7, SDC3, CNTNAP1, and MPZ was built. A nomogram consisting of pathologic T and riskScore was built, and the calibration curve illustrated that the nomogram could better forecast LIHC prognosis. Gene Set Enrichment Analysis (GSEA) demonstrated that DEGs between high and low risk groups were mainly involved in cell cycle. Finally, the qRT-PCR illustrated the expressions of nine model genes between normal and LIHC tissue. A prognostic model consisting of IGSF11, CD8A, ALCAM, CLDN6, JAM2, ITGB7, SDC3, CNTNAP1, and MPZ was obtained, which provides an important reference for the molecular diagnosis of patient prognosis.

Dataset Information

Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma.

Publications

Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma.

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