miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is upregulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNAmRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting IntroductionKaposi sarcoma-associated herpesvirus (KSHV) was identified in 1994. 1 KSHV is also associated with 2 other human B-cell leukemias, primary effusion lymphoma (PEL) and multicentric Castleman disease. 2 Kaposi sarcoma (KS) is one of the few human cancers derived from a lymphatic endothelial cell (LEC) lineage, 3,4 and typically appears as colored lesions or patches on the skin, although it can spread to internal organs. 2 This disease has been recognized as a highly disseminated and angiogenic tumor. 4 Analyzing KSHV clonality at different stages of KS has shown that KS begins as a polyclonal disease and then evolves into a mono/oligoclonal disease involving infected spindle cells. 5 This model therefore implies that the spreading of a few malignant spindle cells in patients' bodies occurs during tumor progression. Moreover, distal metastasis, such as pulmonary KS, can be observed in AIDS-KS patients and causes diffused lung disease. Tumor cells of KSHV-associated B-cell neoplasias (PEL and multicentric Castleman disease) are also able to migrate into body cavities. 6 The ability of KSHV to induce cell migration and invasion is therefore important to disease progression.In vitro, KSHV infects both micro-and macrovascular endothelial cells (ECs), and these cells are useful when studying the role of KSHV in the pathogenesis of KS. 7,8 KSHV has also become a powerful tool that aids in the study of EC biology. 9 KSHV infects both LECs and blood vessel ECs (BECs) of microvascular origin in vitro. 3,4 After infection, KSHV stimulates EC invasiveness by inducing extracellular matrix metalloproteinases (MMPs) such as MMP-1, MMP-2, and MMP-9. 10 Because the majority of cells in KS lesions and in KSHV-infected...

BackgroundIt has been recognized cancer cells acquire characters reminiscent of those of normal stem cells, and the degree of stem cell gene expression correlates with patient prognosis. Lgr5(+) or CD133(+) epithelial stem cells (EpiSCs) have recently been identified and these cells are susceptible to neoplastic transformation. It is unclear, however, whether genes enriched in EpiSCs also contribute in tumor malignancy. Endometrial endometrioid carcinoma (EEC) is a dominant type of the endometrial cancers and is still among the most common female cancers. Clinically endometrial carcinoma is classified into 4 FIGO stages by the degree of tumor invasion and metastasis, and the survival rate is low in patients with higher stages of tumors. Identifying genes shared between advanced tumors and stem cells will not only unmask the mechanisms of tumor malignancy but also provide novel therapeutic targets.ResultsTo identify EpiSC genes in late (stages III-IV) EECs, a molecular signature distinguishing early (stages I-II) and late EECs was first identified to delineate late EECs at the genomics level. ERBB2 and CCR1 were genes activated in late EECs, while APBA2 (MINT2) and CDK inhibitor p16 tumor suppressors in early EECs. MAPK pathway was significantly up in late EECs, indicating drugs targeting this canonical pathway might be useful for treating advanced EECs. A six-gene mini-signature was further identified to differentiate early from advanced EECs in both the training and testing datasets. Advanced, invasive EECs possessed a clear EpiSC gene expression pattern, explaining partly why these tumors are more malignant.ConclusionsOur work provides new insights into the pathogenesis of EECs and reveals a previously unknown link between adult stem cells and the histopathological traits of EECs. Shared EpiSC genes in late EECs may contribute to the stem cell-like phenotypes shown by advanced tumors and hold the potential of being candidate therapeutic targets and novel prognosis biomarkers.