Abstract
PurposeB-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior.MethodsBTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression.ResultsBTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data.ConclusionsBTG3 expression might contribute to CRC carcinogenesis. BTG3 knockdown might strengthen the aggressive colorectal cancer behavior.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide and the third most frequently diagnosed malignancy (Cassidy and Syed 2017)
B-cell translocation gene 3 (BTG3) is downregulated in human CRC tissues and correlated with clinicopathological parameters and prognosis
The results revealed that the BTG3/small hairpin RNA (shRNA) groups in both HCT116 and LoVo cells showed a significant decrease in the percentage of cells in the G2 peak compared with the negative control (NC) group (BTG3/shRNA1 p < 0.01; BTG3/shRNA2 p < 0.05, Fig. 2d)
Summary
Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide and the third most frequently diagnosed malignancy (Cassidy and Syed 2017). The CRC incidence and mortality rates have declined in recent decades, largely attributed to the contribution of preventive screening and early detection (Siegel et al 2014). Journal of Cancer Research and Clinical Oncology (2018) 144:295–308 and economic burden worldwide, especially in developing countries (Alefan et al 2017). Effective therapies for CRC are needed urgently. To achieve this goal, it is important to explore the genetic and molecular abnormalities underlying CRC
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