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Expression profile‑driven discovery of AURKA as a treatment target for liposarcoma.

Abstract：

:Liposarcoma (LPS) is one of the most frequently reported type of soft‑tissue sarcoma (STS). Well‑differentiated (WD) LPS and dedifferentiated (DD) LPS are the two most common subtypes. Chemotherapy has been considered to be ineffective in LPS, and novel treatment agents are thus necessary. In this study, we reanalyzed two published microarray data sets of LPS. By comparing the top 50 upregulated genes in DD LPS in both sets of data, we identified 12 overlapping genes. Of note, the top five gene sets enriched in DD LPS in both sets of data were involved in cell cycle regulation. Among the 12 overlapping genes, aurora kinase A (AURKA) is a well‑known gene involved in cell cycle regulation; we thus further investigated this gene. AURKA was significantly upregulated in DD LPS, compared with WD LPS. Among 40 cases of DD LPS in GSE30929, patients with high AURKA expression in tumors had significantly worse distant recurrence‑free survival than those with low expression. In an in vitro model, MLN8237, an AURKA inhibitor, could inhibit AURKA in LPS cell lines with a resultant G2/M arrest. MLN8237 was also reported to exert a cytotoxic effect by inducing apoptosis in LPS cell lines. Furthermore, except for cisplatin, MLN8237 had a significantly synergistic effect with chemotherapy agents against LPS. MLN8237 induced cellular senescence in LPS cell lines with increased expression of DcR2, a senescence biomarker, and upregulated expression of cytokines associated with the senescence‑associated secretory phenotype, including interleukin (IL)‑1α, IL‑6 and IL‑8. Our study identified AURKA as a potential biomarker for predicting poor prognosis in LPS. The findings of the present study suggested the potential of AURKA as a therapeutic target in LPS cell line models, while the novel combination of AURKA inhibitors and chemotherapy requires further investigation.

journal_name

Int J Oncol

journal_title

International journal of oncology

authors

Yen CC,Chen SC,Hung GY,Wu PK,Chua WY,Lin YC,Yen CH,Chen YC,Wang JY,Yang MH,Chao Y,Chang MC,Chen WM

doi

10.3892/ijo.2019.4861

subject

Has Abstract

pub_date

2019-10-01 00:00:00

pages

938-948

issue

eissn

1019-6439

issn

1791-2423

journal_volume

pub_type

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Expression profile‑driven discovery of AURKA as a treatment target for liposarcoma.