Abstract
Background:Cholangiocarcinoma(CCA),a malignancy that arises from biliary epithe-lial cells,has a dismal prognosis,and few targeted therapies are available.Aurora B,a key mitotic regulator,has been reported to be involved in the progression of various tumors,yet its role in CCA is still unclarified.Methods:Human CCA tissues and murine spontaneous CCA models were used to assess Aurora B expression in CCA.A loss-of-function model was constructed in CCA cells to determine the role of Aurora B in CCA progression.Subcutaneous and liver orthotopic xenograft models were used to assess the therapeutic potential of Aurora B inhibitors in CCA.Results:In murine spontaneous CCA models,Aurora B was significantly upregu-lated.Elevated Aurora B expression was also observed in 62.3％of human speci-mens in our validation cohort(143 CCA specimens),and high Aurora B expression was positively correlated with pathological parameters of tumors and poor sur-vival.Knockdown of Aurora B by siRNA and heteroduplex oligonucleotide(HDO)or an Aurora B kinase inhibitor(AZD1152)significantly suppressed CCA progres-sion via G2/M arrest induction.An interaction between Aurora B and c-Myc was found in CCA cells.Targeting Aurora B significantly reduced this interaction and accelerated the proteasomal degradation of c-Myc,suggesting that Aurora B pro-moted the malignant properties of CCA by stabilizing c-Myc.Furthermore,sequen-tial application of AZD1152 or Aurora B HDO drastically improved the efficacy of gemcitabine in CCA.Conclusions:Aurora B plays an essential role in CCA progression by modulating c-Myc stability and represents a new target for treatment and chemosensitization in CCA.
维普
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