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J Cancer
2020 Feb 03;118:2241-2251. doi: 10.7150/jca.31989.
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Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma.
Ding X
,
Huang T
,
Peng C
,
Ahn KS
,
Andersen JB
,
Lewinska M
,
Cao Y
,
Xu G
,
Chen G
,
Kong B
,
Friess H
,
Shen S
,
Roberts LR
,
Wang L
,
Zou X
.
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Background: Cholangiocarcinoma is a highly lethal neoplasm for which the currently available chemotherapeutic agents are suboptimal. Numerous studies show that alterations in expression of genes related to mitotic spindle and mitotic checkpoint are involved in chromosomal instability and tumor progression in various malignancies. This study aimed to evaluate these genes in cholangiocarcinoma patients. Material and methods: Different public datasets were analyzed to examine the expression of 76 selected mitotic spindle checkpoint genes including Aurora Kinase A (AURKA) in cholangiocarcinoma. Afterwards, cell number counting, CCK-8 assay, and Caspase 3/7 assay were used to explore the antitumor effect of AURKA inhibitor Alisertib in vitro. In addition, xenograft model was used to evaluate the antitumor effect of Alisertib in vivo. Furthermore, siRNA mediated silencing of AURKA was used to verify the function of AURKA in cholangiocarcinoma. Results: Components of the mitotic spindle checkpoint, including AURKA, were broadly dysregulated in human cholangiocarcinoma. High AURKA mRNA expression was associated with poor survival in cholangiocarcinoma patients within different datasets. AURKA specific inhibitor Alisertib, inhibited cell growth, induced cell cycle arrest in G2/M phase, and promoted apoptosis in cholangiocarcinoma cell lines. Additionally, Alisertib also inhibited tumor growth in a cholangiocarcinoma xenograft mouse model. Furthermore, AURKA knockdown by siRNA recapitulated the antitumor effect of Alisertib. AURKA expression was also highly correlated with its interaction proteins Polo-like kinase 1(PLK1) and Targeting protein for xenopus kinesin-like protein2 (TPX2) in different cholangiocarcinoma datasets. Conclusions: Highly expressed AURKA confers poor outcomes in cholangiocarcinoma and may represent a rational therapeutic target.
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32127951
???displayArticle.pmcLink???PMC7052919 ???displayArticle.link???J Cancer
Figure 1. Mitotic spindle checkpoint genes were broadly overexpressed in human cholangiocarcinoma. A) A heat map was drawn to show the differentially expressed gene transcripts related to the mitotic spindle checkpoint in cholangiocarcinoma tissues and normal bile duct tissues in the TCGA RNA sequencing data. B-C) Heat maps were drawn to show the differentially expressed gene transcripts related to the mitotic spindle checkpoint in cholangiocarcinoma tissues, normal surrounding liver tissues and normal bile duct tissues in the GSE107943 and GSE26566 datasets. D) Venn diagram of dysregulated genes in TCGA, GSE107943, and GSE26566 datasets.
Figure 2. AURKA expression was upregulated in cholangiocarcinoma and correlated with cell proliferation. A) AURKA mRNA expression was markedly upregulated in cholangiocarcinoma in TCGA, GSE107943, and GSE26566 datasets. B) The expression level of AURKA showed a significant positive correlation with Ki-67 expression in the dataset of TCGA, GSE107943, and GSE26566. The r and P values were determined by Pearson correlation analysis.
Figure 3. High AURKA expression correlated with poor survival in cholangiocarcinoma tumors. A) Kaplan-Meier survival curves showing the relationship between AUKRA mRNA expression and disease free survival and overall survival in the Korea cohort GSE107943 (n = 30). B) Kaplan-Meier survival curves showing the relationship between AURKA mRNA expression and overall survival in the Copenhagen cohort GSE26566 (n = 102). C) Kaplan-Meier survival curves showing the relationship between AURKA mRNA expression and overall survival in the Japan cohort EGAD00001001693 (n=111).
Figure 4. Effect of Alisertib on tumor growth in vitro and in vivo. A) Cells were treated with Alisertib at different concentrations (10nM-10 μM) for 72 h and cell proliferation was determined by cell number counting. B) IC50 values of Alisertib in cholangiocarcinoma cells following 72 h of treatment. C) Time-response curves of HCCC9810 and HuCCT1 cell lines to Alisertib treatment (100 nM). D) HCCC9810 and HuCCT1 were treated with Alisertib at different concentrations for 72 h and cell viability was determined by CCK-8 assay. E) Plated HCCC9810 and HuCCT1 were treated with Alisertib for 7 days and colonies were stained with 0.5% crystal violet. F) HuCCT1 cells were injected subcutaneously into the right flanks of athymic nude mice. When tumors reached a size of approximately150- 200 mm3, mice were randomized to receive vehicle (n=6) or Alisertib (n=6) by oral gavage. Tumor volume was measured every 3-4 days. Values shown are the mean difference in tumor volume ± SEM. G) Tumor volume in each group on day 25. Data represented are mean ± min/max group values. H) Change of body weight in mice treated with vehicle control or Alisertib. All results are presented as mean ± SEM from 3 independent experiments unless otherwise pointed, * P < 0.05, ** P < 0.01, compared with control.
Figure 5. AURKA inhibition induced cell cycle arrest and apoptosis. A) Quantification of percentage of HCCC9810 and HuCCT1 cells in different cell cycle phases following treatment with Alisertib for 48 h. B) Apoptosis analysis via Annexin V/propidium iodide staining of cholangiocarcinoma cells at 100 nM Alisertib following 72 h of treatment. C) Apoptosis analysis via Caspase 3/7 activity of cholangiocarcinoma cells at various concentrations of Alisertib following 48 h of treatment. All data shown were Mean ± SEM from 3 independent experiments, * P < 0.05, ** P < 0.01, compared with control.
Figure 6. Knockdown of AURKA diminished cell proliferation, viability, and increased G2/M phase arrest and apoptosis. A) Western immunoblotting analysis of AURKA protein expression 48 h post-siRNA knockdown of AURKA in cholangiocarcinoma cells. B) Cell proliferation following 72 h AUKRA knockdown in cholangiocarcinoma cells. Cell proliferation was determined by cell number counting. Cells number was normalized to siControl (siCont). C) CCK-8 cell viability assay following 72 h AURKA knockdown in HCCC9810 and HuCCT1 cells (n= 3). Cell viability was normalized to siControl. D) Cell cycle analysis following 48 h AURKA knockdown in HCCC9810 cells. E) Annexin V-PI assay and Caspase 3/7 activity analysis of apoptosis following 72 h AURKA knockdown in HCCC9810 cells. All data shown were Mean ± SEM from 3 independent experiments, * P < 0.05, ** P < 0.01, compared with control.
Figure 7. AURKA correlated with TPX2 and PLK1. A) Genetic interaction network of AURKA generated with the help of the GeneMANIA online tool. The top 20 genes were shown. Blue and pink lines denote pathways and physical interactions, respectively. B) Top 20 correlated genes with AURKA in the TCGA dataset of cholangiocarcinoma based on the Person's analysis. C) The expression level of AURKA showed a significant positive correlation with TPX2 and PLK1 expression in the dataset of GSE107943 and GSE26566. The r and P values were determined by Pearson correlation analysis.
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