It thereby enhances the self-renewal ability of EpCAM+ liver CSCs. Conversely targeting the activation of the differentiation of CDX2 and GATA6 by miR-181s can maintain EpCAM+ liver CSCs in their undifferentiated www.selleckchem.com/products/LDE225(NVP-LDE225).html state.43,44 More recently, studies from our group have also demonstrated a similar finding, whereby liver CSCs are regulated by dysregulated miRNA expression. By comparing the miRNA profiles of CD133+ and CD133- cells isolated from HCC primary

tumors and experimental cell lines, significantly elevated miR-130b expression was identified in CD133+ liver CSCs. miR-130b was found to be preferentially expressed in CD133+ spheres derived from HCC clinical samples and in chemotherapy-treated unsorted spheres enriched for CD133. Functional studies found that miR-130b was required for self-renewal, tumorigenicity and chemoresistance. CD133- cells overexpressing miR-130b displayed enhanced proliferation, superior resistance to chemotherapeutic agents, elevated expression of stem cell-associated genes, enhanced tumorigenicity in vivo and greater potential for

self-renewal in serial passages than control cells transduced with the empty vector alone. Conversely, the antagonization of miR-130b in CD133+ cells was shown to result in the opposite effect. Furthermore, the increased amount of miR-130b paralleled a reduction in TP53INP1, a known miR-130b target. The silencing of TP53INP1 in CD133- cells enhanced both self-renewal and tumorigenicity in vivo. Thus, our findings suggested that miR-130b regulates CD133+ liver CSCs by PF-2341066 silencing TP53INP1.15 In addition to resistance to chemo-

and radiation therapies, CSCs seem Dipeptidyl peptidase to be particularly adept in stimulating angiogenesis to promote tumor growth and increase the overall tumor aggressiveness before and after therapy. In fact, recent clinical studies have shown enhanced antitumor cell effects when anti-angiogenic therapy is combined with radiation or chemotherapy, suggesting that possibly radioresistance, chemotherapy resistance and angiogenesis in CSCs work in concert to initiate tumor recurrence in advanced or aggressive tumors. Given the evidence for the CSC dependence on tumor vasculature, combining radiation therapy or chemotherapy with anti-angiogenic therapies has promise in possibly mediating targeted anti-CSC effects in the promotion of prolonged recurrence-free survival. In HCC, there are currently two original articles that have documented a link between liver CSCs and angiogenesis. The first report, by Yang et al., found that high expression levels of hepatic stem/progenitor cell biomarkers, such as cytokeratin 19, ABCG2, CD133, nestin and CD44, are related to tumor angiogenesis and are indicative of high tumor recurrence and poor prognosis of surgically resected HCC.