Abstract
Polypyrimidine tract-binding protein (PTBP1) is an RNA-binding protein with various molecular functions related to RNA metabolism and a major repressive regulator of alternative splicing, causing exon skipping in numerous alternatively spliced pre-mRNAs. Here, we have investigated the role of PTBP1 in colorectal cancer. PTBP1 expression levels were significantly overexpressed in cancerous tissues compared with corresponding normal mucosal tissues. We also observed that PTBP1 expression levels, c-MYC expression levels, and PKM2:PKM1 ratio were positively correlated in colorectal cancer specimens. Moreover, PTBP1 expression levels were positively correlated to poor prognosis and lymph node metastasis. In analyses of colorectal cancer cells using siRNA for PTBP1, we observed that PTBP1 affects cell invasion, which was partially correlated to CD44 splicing, and this correlation was also confirmed in clinical samples. PTBP1 expression also affected anchorage-independent growth in colorectal cancer cell lines. PTBP1 expression also affected cell proliferation. Using time-lapse imaging analysis, PTBP1 was implicated in prolonged G2-M phase in HCT116 cells. As for the mechanism of prolonged G2-M phase in HCT116 siPTBP1 cells, Western blotting revealed that PTBP1 expression level was correlated to CDK11(p58) expression level, which was reported to play an important role on progression to complete mitosis. These findings indicated that PTBP1 is a potential therapeutic target for colorectal cancer.
Highlights
Colorectal cancer is a leading cause of cancer-related death in the western world and is estimated to be one of the most frequently diagnosed cancers; estimated new cases of colorectal cancer were 142,820 and corresponding expected mortality was 50,830 in the United States in 2013 [1]
The expression of PTBP1 mRNA seemed to correlate with protein expression
PTBP1 serves as a repressor of alternative splicing in mammalian cells [24,25,26,27,28,29] and contains RNA-binding domains, each of which binds to CU-rich elements [30]
Summary
Colorectal cancer is a leading cause of cancer-related death in the western world and is estimated to be one of the most frequently diagnosed cancers; estimated new cases of colorectal cancer were 142,820 and corresponding expected mortality was 50,830 in the United States in 2013 [1]. Monoclonal antibodies, including bevacizumab, an inhibitor of vascular endothelial growth factor, and cetuximab, an epidermal growth factor receptor inhibitor [2, 3], are currently feasible as novel molecular-based therapies, many patients with colorectal cancer still die from disease recurrence, mainly because of liver metastasis. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Nishimura share first authorship of this article
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