ZIA BC 010876 (ZIA) | |||
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Title | The role of cancer stem cells in liver cancer heterogeneity and subtypes | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Wang, Xin Wei | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $675,351 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (100.0%) |
Liver Cancer (100.0%) | ||
Research Type | |||
Cancer Initiation: Alterations in Chromosomes Cancer Progression & Metastasis |
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Abstract | |||
In a gene expression array study comparing signatures of chronic liver diseases with hepatocellular carcinoma (HCC), we found a molecular signature that separates patients for their risk of developing advanced disease. Epithelial cell adhesion molecule (EpCAM) was identified as the lead gene and its silencing resulted in growth suppression of HCC cells. EpCAM could significantly differentiate HCC into two subtypes. HCC could be further stratified into four distinct subtypes with the additional assessment of alpha-fetoprotein (AFP) status. These four subtypes were associated with HCC prognostic outcome and cells double positive for EpCAM and AFP had the worst prognosis. Furthermore, these subtypes resembled certain stages of liver lineages and EpCAM/AFP-positive cells displayed a distinct molecular signature with features of hepatic stem/progenitor cells. Moreover, these cells, characterizing a poor prognostic HCC subtype, were capable of initiating highly invasive HCC in in-vitro and in-vivo models. Thus, EpCAM and AFP are useful diagnostic markers for HCC which can be used as a convenient classification system for prognosis. Furthermore, EpCAM and AFP may act as downstream molecules to maintain HCC stemness and as markers for HCC initiating cells. We have also recently explored whether integrative genomic profiling of a well-defined HCC subset of extreme EpCAM+ AFP+ could uncover survival-related driver genes in HCC. We found that YY1-associated protein 1 (YY1AP1) is a critical oncoprotein specifically activated in EpCAM+AFP+ HCC. YY1AP1 silencing eliminates oncogene addiction by altering the chromatin landscape while YY1AP1 expression promotes HCC proliferation and is required for the maintenance of stem cell features. Thus YY1AP1 may serve as a key molecular target for EpCAM+ AFP+ HCC subtype. We also investigated the mechanism by which EpCAM is elevated in HCC subtypes with stem/progenitor cell features. We found that the activation of wnt-beta-catenin pathway regulates EpCAM expression. In fact, EpCAM is a biosensor for wnt-beta-catenin signaling and is transcriptionally up-regulated by this pathway through direct Tcf binding element interactions. Inhibition of HCC cell growth could be achieved through blockade of EpCAM/wnt-beta-catenin signaling in EpCAM-positive HCC cells. We propose that EpCAM/wnt-beta-catenin signaling functions to maintain HCC stem cell growth and that EpCAM expression-based classification of HCC could be useful in clinical settings to stratify HCC patients who may benefit from beta-catenin/EpCAM adjuvant therapies. We recently developed a high-throughput screening assay to identify inhibitors of EpCAM-dependent growth of HCC cells. EpCAM(+) and EpCAM(-) HCC cell lines were assessed for differential sensitivity to Wnt/beta-catenin pathway inhibitors. Libraries comprising 22 668 pure compounds and 107 741 crude or partially purified natural product extracts were tested, and 12 pure compounds and 67 natural product extracts were identified for further study. Three active compounds and the positive control were further characterized by effects on EpCAM expression. Treatment of EpCAM(+) Hep3B cells resulted in loss of EpCAM expression by flow cytometry. The identification of compounds with a variety of possible molecular targets suggests a likelihood of multiple mechanisms for modulation of EpCAM-dependent cell growth. Recently, we found that an FDA-approved psychiatric drug, pimozide (PMZ), has anti-cancer properties in HCC cell lines that express EpCAM. We demonstrate that PMZ effectively inhibits cell growth of HCC cells by disrupting the wnt/beta-catenin signaling pathway and reducing EpCAM expression. Thus, PMZ may be a useful molecular entity that could be repurposed as an anti-cancer therapy for treatment of HCC. A global microRNA microarray approach was used to explore whether certain microRNAs were associated with HCC stem cells. We found that microRNA-181 family members were up-regulated in HCC |