Abstract
Copy number alterations (CNAs) are crucial for colorectal cancer (CRC) development. In this study, DEAD box polypeptide 27 (DDX27) was identified to be highly amplified in both TCGA CRC (474/615) and primary CRC (47/103), which was positively correlated with its mRNA overexpression. High DDX27 mRNA (N = 199) and protein expression (N = 260) predicted poor survival in CRC patients. Ectopic expression of DDX27 increased CRC cells proliferation, migration and invasion, but suppressed apoptosis. Conversely, silencing of DDX27 exerted opposite effects in vitro and significantly inhibited murine xenograft tumor growth and lung metastasis in vivo. Up-regulation of DDX27 enhanced and prolonged TNF-α-mediated NF-κB signaling. Nucleophosmin (NPM1) was identified as a binding partner of DDX27. DDX27 increased nuclear NPM1 and NF-κB-p65 interaction to enhance DNA binding activity of NF-κB. Silencing NPM1 abrogated DDX27-activating NF-κB signaling and its tumor-promoting function. Together, DDX27 is overexpressed and plays a pivotal oncogenic role in CRC.
Highlights
These authors contributed : Jieting Tang, Huarong Chen.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide, accounting for 1.4 million new cases and 0.7 million deaths in 2012 [1]
To identify novel genes with copy number alterations (CNAs) that are associated with CRC, we comprehensively examined gene-level frequency of copy number gain and loss in 615 human CRC samples from The Cancer Genome Atlas (TCGA) [10]
In the Beijing cohort, Kaplan–Meier curves revealed that higher DEAD box polypeptide 27 (DDX27) mRNA expression was significantly associated with worse relapse-free survival in patients with CRC (N = 199, P < 0.05; Fig. 1f)
Summary
Emerging evidence indicates that CRC is a heterogeneous disease, arising through accumulation of genetic and epigenetic alterations with three major molecular pathways involved: chromosomal instability (CIN) (50–60%), microsatellite instability and the CpG island methylator phenotype [2]. CIN is a hallmark of CRC, resulting in copy number alterations (CNAs) [3]. CNAs are somatic changes of chromosome structure that lead to gain or loss in copies of DNA sections ranging in size from kilobases to megabases [4]. DNA copy number gain frequently activates oncogenes [6, 7], whereas tumor suppressors are often found in deleted genomic segments [8, 9]. It is of great importance to identify gains or losses of specific genes that contribute to CRC development
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