Background: Cholangiocarcinoma(CCA), a malignancy that arises from biliary epithelial cells, has a dismal prognosis, and few targeted therapies are available. Aurora B, a key mitotic regulator, has been reported to be...Background: Cholangiocarcinoma(CCA), a malignancy that arises from biliary epithelial 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 upregulated. Elevated Aurora B expression was also observed in 62.3% of human specimens in our validation cohort(143 CCA specimens), and high Aurora B expression was positively correlated with pathological parameters of tumors and poor survival. Knockdown of Aurora B by siRNA and heteroduplex oligonucleotide(HDO)or an Aurora B kinase inhibitor(AZD1152) significantly suppressed CCA progression 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 promoted the malignant properties of CCA by stabilizing c-Myc. Furthermore, sequential 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.展开更多
The expression of Aurora B in normal endometria and endometrial carcinomas and its relation with clinicopathologic parameters of endometrial carcinomas were investigated. Streptavidin-biotin peroxidase （SP） immunohi...The expression of Aurora B in normal endometria and endometrial carcinomas and its relation with clinicopathologic parameters of endometrial carcinomas were investigated. Streptavidin-biotin peroxidase （SP） immunohistochemical technique was used to detect the expression of Aurora B in 10 cases of normal proliferative phase endometria, 10 cases of normal secretory phase endometria and 72 cases of endometrial carcinomas respectively. According to the 1988 International Federation of Gynecology and Obstetrics （FIGO） grade, there were 37 patients in grade 1, 23 in grade 2 and 12 in grade 3 respectively. According to the FIGO stage, there were 59 patients in stage Ⅰ-Ⅱ and 13 patients in stage Ⅲ-Ⅳ. Aurora B was expressed in both normal proliferative phase endometria, secretory phase endometria and endometrial carcinomas, but its positive labeling index （PLI） in proliferative phase endometria was significantly higher than that in secretory phase endometria （P〈0.01） and endometrial carcinomas （P〈0.01）. The PLI of Aurora B was lower in tumors with well differentiation （G1）, low surgical staging （Ⅰ-Ⅱ）, and ≤1/2 myometrial invasion than that in tumors with moderate and low differentiation （G2--G3）, higher surgical staging （Ⅲ-Ⅳ）, and 〉1/2 myometrial invasion （all P〈0.01）. Aurora B exerts its functions in the replication of normal endometrial glandular cells; Expression of Aurora B is significantly correlated with biologic behavior of endometrial carcinoma, indicating that Aurora B may be a promising prognostic factor in endometrial carcinoma.展开更多
Accurate chromosome segregation in mitosis depends on kinetochores that connect centromeric chromatin to spindle microtubules.Centromeres are captured by individual microtubules via a kinetochore constitutive centrome...Accurate chromosome segregation in mitosis depends on kinetochores that connect centromeric chromatin to spindle microtubules.Centromeres are captured by individual microtubules via a kinetochore constitutive centromere-associated network(CCAN)during chromosome segregation.CCAN contains 16 subunits,including CENP-W and CENP-T.However,the molecular recognition and mitotic regulation of the CCAN assembly remain elusive.Here,we revealed that CENP-W binds to the histone fold domain and an uncharacterized N-terminal region of CENP-T.Aurora B phosphorylates CENP-W at threonine 60,which enhances the interaction between CENP-W and CENP-T to ensure robust metaphase chromosome alignment and accurate chromosome segregation in mitosis.These findings delineate a conserved signaling cascade that integrates protein phosphorylation with CCAN integrity for the maintenance of genomic stability.展开更多
基金supported by National Natural Science Foundation of ChinaGrant/Award Number:82172602+1 种基金Guang Dong Basic and Applied Basic Research FoundationGrant/Award Number:2023A1515011892。
文摘Background: Cholangiocarcinoma(CCA), a malignancy that arises from biliary epithelial 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 upregulated. Elevated Aurora B expression was also observed in 62.3% of human specimens in our validation cohort(143 CCA specimens), and high Aurora B expression was positively correlated with pathological parameters of tumors and poor survival. Knockdown of Aurora B by siRNA and heteroduplex oligonucleotide(HDO)or an Aurora B kinase inhibitor(AZD1152) significantly suppressed CCA progression 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 promoted the malignant properties of CCA by stabilizing c-Myc. Furthermore, sequential 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.
文摘The expression of Aurora B in normal endometria and endometrial carcinomas and its relation with clinicopathologic parameters of endometrial carcinomas were investigated. Streptavidin-biotin peroxidase （SP） immunohistochemical technique was used to detect the expression of Aurora B in 10 cases of normal proliferative phase endometria, 10 cases of normal secretory phase endometria and 72 cases of endometrial carcinomas respectively. According to the 1988 International Federation of Gynecology and Obstetrics （FIGO） grade, there were 37 patients in grade 1, 23 in grade 2 and 12 in grade 3 respectively. According to the FIGO stage, there were 59 patients in stage Ⅰ-Ⅱ and 13 patients in stage Ⅲ-Ⅳ. Aurora B was expressed in both normal proliferative phase endometria, secretory phase endometria and endometrial carcinomas, but its positive labeling index （PLI） in proliferative phase endometria was significantly higher than that in secretory phase endometria （P〈0.01） and endometrial carcinomas （P〈0.01）. The PLI of Aurora B was lower in tumors with well differentiation （G1）, low surgical staging （Ⅰ-Ⅱ）, and ≤1/2 myometrial invasion than that in tumors with moderate and low differentiation （G2--G3）, higher surgical staging （Ⅲ-Ⅳ）, and 〉1/2 myometrial invasion （all P〈0.01）. Aurora B exerts its functions in the replication of normal endometrial glandular cells; Expression of Aurora B is significantly correlated with biologic behavior of endometrial carcinoma, indicating that Aurora B may be a promising prognostic factor in endometrial carcinoma.
基金supported by the National Key Research and Development Program of China(2022YFA1303100,2022YFA0806800,2022YFA1302700,and 2017YFA0503600)the National Natural Science Foundation of China(32090040,92254302,92153302,92253301,22137007,32170733,and 31871359)+3 种基金the Ministry of Education(IRT_17R102)the Plans for Major Provincial Science&Technology Projects of Anhui Province(202303a0702003)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19040000)the Fundamental Research Funds for the Central Universities(WK2070000066 and WK2070000194).
文摘Accurate chromosome segregation in mitosis depends on kinetochores that connect centromeric chromatin to spindle microtubules.Centromeres are captured by individual microtubules via a kinetochore constitutive centromere-associated network(CCAN)during chromosome segregation.CCAN contains 16 subunits,including CENP-W and CENP-T.However,the molecular recognition and mitotic regulation of the CCAN assembly remain elusive.Here,we revealed that CENP-W binds to the histone fold domain and an uncharacterized N-terminal region of CENP-T.Aurora B phosphorylates CENP-W at threonine 60,which enhances the interaction between CENP-W and CENP-T to ensure robust metaphase chromosome alignment and accurate chromosome segregation in mitosis.These findings delineate a conserved signaling cascade that integrates protein phosphorylation with CCAN integrity for the maintenance of genomic stability.
