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Our previous study reported that Epstein-Barr virus(EBV)-encoded latent membrane protein 1 (LMP1) could induce development of CD44(+/High) stem-like cells in nasopharyngeal carcinoma (NPC). However, the molecular mechanisms that underlie modulation of cancer stem cells (CSCs) in NPC remain unclear. Here, we show that LMP1 induced CSC-like properties through promotion of the expression of epithelial-mesenchymal transition-like cellular markers and through alterations in differentiation markers. Furthermore, LMP1 activated and triggered phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, which subsequently stimulated expression of CSC markers, development of side population and tumor sphere formation. This suggests that PI3K/AKT pathway has an important role in the induction and maintenance of CSC properties in NPC. Similarly, PI3K/AKT pathway was also activated by phosphorylase in LMP1-induced CD44(+/High) cells. In addition, LMP1 greatly increased expression of miR-21 and downregulated expression of the miR-21 target, PTEN. Overexpression of miR-21 by transfection of miR-21 mimics into LMP1-transformed cells led to phosphorylase-mediated activation of the PI3K/AKT pathway and induction of CSCs. On the contrary, phosphorylation of the PI3K/AKT pathway and the expression of CSC were reversed by an miR-21 inhibitor. The specific inhibitor (Ly294002) of PI3K/AKT pathway significantly decreased expression of miR-21 and CSC markers and upregulated the expression of PTEN, which indicates that miR-21 and PTEN are the downstream effectors of PI3K/AKT and that expression of these two effectors are related to the development of NPC CSCs. Taken together, our novel findings indicate that LMP1, PI3K/AKT, miR-21 and PTEN constitute a positive feedback loop and have a key role in LMP1-induced CSCs in NPC.

Background: We aimed to systematically summarize the diagnostic and prognostic value of circulating/ tissue miR21 in patients with colorectal cancer.Methods: An original study was conducted to explore the potential value of circulating miR21 in colorectal cancer diagnosis and tissue miR21 in colorectal cancer prognosis. PUBMED and EMBASE were searched (to August, 2013) to identify eligible studies. To explore the diagnostic performance of circulating miR21, metaanalysis methods were used to pool sensitivity, specificity, positive and negative likelihood ratio, diagnostic OR and to construct a summary ROC curve. For prognostic meta-analysis, study-specific HRs of tissue miR21 for survival were summarized. Subgroup and sensitivity analyses were applied to explore heterogeneity.Results: Finally, 14 studies (including our study) were included in the meta-analyses. The pooled sensitivity, specificity, and AUC of circulating miR21 were 0.76 [95% confidence interval (CI), 0.59-0.88], 0.81 (95% CI, 0.76-0.85), and 0.81 (95% CI, 0.78-0.85) in diagnosing colorectal cancer. Patients with higher expression of tissue miR21 had significant inferior overall survival (OS; pooled HR, 1.56; 95% CI, 1.16-2.11) and disease-free survival (DFS; pooled HR, 1.35; 95% CI, 1.08-1.69). The individual participant data (IPD) meta-analysis demonstrated that tissue miR21 level was independently associated with worse colorectal cancer OS (HR, 1.69; 95% CI, 1.07-2.67; P ¼ 0.023), whereas this association seems to be confined to males (P ¼ 0.007) but not for females (P ¼ 0.845).Conclusions: Circulating miR21 level has potential value for colorectal cancer early detection, whereas high tissue miR21 level is associated with adverse colorectal cancer prognosis.Impact: miR21 is a promising biomarker for early detection and prognosis of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 23(12); 2783-92. Ó2014 AACR.

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