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Oncol Lett. 2019 Feb;17(2):1865-1876. doi: 10.3892/ol.2018.9762. Epub 2018 Nov 26.

Overexpression of the ASPM gene is associated with aggressiveness and poor outcome in bladder cancer.

Xu Z1,2, Zhang Q3, Luh F4,5, Jin B1, Liu X4,5.

Author information

1
Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China.
2
Department of Urologic Surgery, Affiliated Dongyang People's Hospital of Wenzhou Medical University, Dongyang, Zhejiang 322100, P.R. China.
3
Department of Bioinformatics and Statistics, Hangzhou Hope Biotechnology, Inc., Hangzhou, Zhejiang 310015, P.R. China.
4
Sino-American Cancer Foundation, California Cancer Institute, Temple City, CA 91780, USA.
5
Tumor Biomarker Development, California Cancer Institute, Temple City, CA 91780, USA.

Abstract

Abnormal spindle-like microcephaly-associated (ASPM) protein is essential for mitotic spindle function during cell replication. The present study aimed to evaluate the hypothesis that ASPM serves a critical role in cancer invasiveness and may act as a prognostic biomarker in bladder cancer. In total, 6 independent worldwide bladder cancer microarray mRNA expression datasets (n=1,355) with clinical and follow-up annotations were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Reverse transcription-quantitative polymerase chain reaction analysis revealed that ASPM mRNA expression was higher in bladder cancer tissue compared with adjacent normal bladder mucosae in 10 paired human tissue samples (P=0.004). ASPM overexpression in human bladder cancer samples was consistent with the mRNA expression datasets from GEO and TCGA. Bioinformatics analysis indicated that ASPM mRNA expression was significantly associated with grade and tumor node metastasis (TNM) stage in bladder cancer, based on pooled GEO and TCGA datasets (P<0.05). Stratification analysis indicated that the clinical significance of ASPM was particularly pronounced in low-grade or papillary subtypes of bladder cancer. Individual Cox and pooled Kaplan-Meier analyses suggested that ASPM expression was significantly directly correlated with poor overall (OS) and progression-free survival (PFS) in bladder cancer. Multivariate and stratification analyses demonstrated that the prognostic significance of ASPM was evident in low-grade or papillary bladder cancers, yet not in high-grade or non-papillary subgroups. Increased expression of ASPM was associated with poor OS in muscle-invasive bladder cancer and with poor PFS in non-muscle-invasive bladder cancer (P<0.05). Bioinformatics analysis identified the top 11 ASPM-related genes on STRING-DB.org. The expression of the majority of these genes was associated with poor outcomes of bladder cancer with statistical significance. Gene set enrichment analysis indicated that the high expression of ASPM could enrich gene signatures involved in mitosis, differentiation and metastasis in bladder cancer. Further analysis of TCGA datasets indicated that increased ASPM expression was significantly associated with higher Gleason score, T stage, N stage and poor clinical outcome in prostate cancer. It was also significantly associated with late TNM stage and poor PFS in renal cell carcinoma. In summary, ASPM may serve as a novel prognostic biomarker for low-grade or papillary bladder cancer.

KEYWORDS:

abnormal spindle-like microcephaly-associated protein; bladder cancer; cancer survival; gene set enrichment analysis; prognostic biomarker

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