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Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma.

ABSTRACT: 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.

SUBMITTER: Ding X

PROVIDER: S-EPMC7052919 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma.

Ding Xiwei X Huang Tianlu T Peng Chunyan C Ahn Keun Soo KS Andersen Jesper B JB Lewinska Monika M Cao Yu Y Xu Guifang G Chen Gang G Kong Bo B Friess Helmut H Shen Shanshan S Roberts Lewis R LR Wang Lei L Zou Xiaoping X

Journal of Cancer 20200203 8

<b>Background</b>: 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. <b>Material and methods</b>: Different public datasets were analyzed to examine the expr ...[more]

PMID: 32127951

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Project description:Gastric cancer (GC) is the fifth most common cancer and GC has a high mortality rate worldwide. Circular (circ) RNAs serve an important role in cancer. The present study aimed to investigate the expression level of hsa_circ_0060975 in gastric cancer (GC) and to determine the clinical pathological significance of hsa_circ_0060975 in patients with GC. Reverse transcription-quantitative PCR was used to detect expression level of hsa_circ_0060975 in 192 GC and adjacent non-cancerous gastric tissues, in GC cell lines (MKN-45, HGC27 and AGS) and a human gastric epithelium cell line (GES-1), as well as in plasma samples from 126 patients with GC and 92 healthy volunteers. All plasma and tissue samples of were obtained from The First Affiliated Hospital of Anhui Medical University (Hefei, China). The relationship between hsa_circ_0060975 expression and clinical pathological factors was analyzed using the χ2 test. The diagnostic value of hsa_circ_0060975 was analyzed using the receiver operating characteristic curve (ROC curve), while the Kaplan-Meier method was used to analyze the relationship of hsa_circ_0060975 expression with the survival of patients with GC as determined by log-rank tests. Univariate and multivariate Cox regression analyses were used to identify the prognostic factors, including hsa_circ_0060975 expression and clinical pathological factors. In addition, the potential function of hsa_circ_0060975 was evaluated via bioinformatics analysis. The expression level of hsa_circ_0060975 was higher in GC tissues compared with adjacent non-cancerous gastric tissues, GC cell lines compared with GES-1 and plasma samples from patients with GC compared with plasma samples from healthy volunteers. In addition, higher hsa_circ_0060975 expression was associated with histological grade, pathological stage and tumor (T) classification in GC tissues and plasma samples (P<0.05). The area under the ROC curves of hsa_circ_0060975, the combination with hsa_circ_0060975 and carcinoembryonic antigen (CEA) or CEA alone were 0.804 (sensitivity, 0.746; specificity, 0.783; P<0.001); 0.931 (sensitivity, 0.937; specificity, 0.870; P<0.001) and 0.924 (sensitivity, 0.937; sspecificity, 0.804; P<0.001) respectively. The Kaplan-Meier survival analysis revealed that the overall survival (OS) and disease-free survival (DFS) time of patients with higher hsa_circ_0060975 expression were shorter compared with those in patients with lower hsa_circ_0060975 expression. Univariate and multivariate Cox regression analyses in OS and DFS time determined that the expression level of hsa_circ_0060975, histological grade and pathological stage were independent prognostic factors for patients with GC. In addition, the bioinformatics analysis results suggested that the abnormal expression of hsa_circ_0060975 may serve an important role in tumorigenesis. Hence, hsa_circ_0060975 expression may be an independent prognostic factor for patients with GC and may be a potential marker for biological malignancy.

Dataset Information

Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma.

Publications

Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma.

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