Publications (2)18.66 Total impact
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ABSTRACT: Chromosomal instability (CIN) is widely considered a hallmark of cancer but its precise roles in cancer stem cells (CSCs) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis and poor prognosis. Here we report that BMI1 mediates its diverse effects through upregulatiion of the mitotic kinase Aurora A which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed microRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exert several effects, including centrosomal amplification and aneuploidy, anti-apoptosis and cell cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that co-amplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT and CIN through the BMI1-AURKA axis and suggest therapeutic utility from inhibiting Aurora A in head and neck cancers which overexpress BMI1.
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ABSTRACT: Proinflammatory cytokines produced in the tumor microenvironment facilitate tumor development and metastatic progression. In particular, TNF-α promotes cancer invasion and angiogenesis associated with epithelial-mesenchymal transition (EMT); however, the mechanisms underlying its induction of EMT in cancer cells remain unclear. Here we show that EMT and cancer stemness properties induced by chronic treatment with TNF-α are mediated by the upregulation of the transcriptional repressor Twist1. Exposure to TNF-α rapidly induced Twist1 mRNA and protein expression in normal breast epithelial and breast cancer cells. Both IKK-β and NF-κB p65 were required for TNF-α-induced expression of Twist1, suggesting the involvement of canonical NF-κB signaling. In support of this likelihood, we defined a functional NF-κB-binding site in the Twist1 promoter, and overexpression of p65 was sufficient to induce transcriptional upregulation of Twist1 along with EMT in mammary epithelial cells. Conversely, suppressing Twist1 expression abrogated p65-induced cell migration, invasion, EMT, and stemness properties, establishing that Twist1 is required for NF-κB to induce these aggressive phenotypes in breast cancer cells. Taken together, our results establish a signaling axis through which the tumor microenvironment elicits Twist1 expression to promote cancer metastasis. We suggest that targeting NF-κB-mediated Twist1 upregulation may offer an effective a therapeutic strategy for breast cancer treatment.
- Cancer Research (2)
National Yang Ming University
T’ai-pei, Taipei, Taiwan
- Institute of Clinical Medicine