Original research
Cytoplasmic Poly(A) Binding Protein 4 Is Highly Expressed in Human Colorectal Cancer and Correlates with Better Prognosis

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Abstract

Cytoplasmic poly(A) binding protein 4 (PABPC4) is an RNA-processing protein that plays an important role in the regulation of gene expression. The aim of this study was to investigate the expression pattern and identify the potential clinical significance of PABPC4 in colorectal cancer. Immunohistochemical analysis revealed that 26.7% (27/101 patients) of primary colorectal tumors and 60.5% (23/38 patients) of corresponding adjacent, normal tissues showed high cytoplasmic expression of PABPC4, whereas expression was absent in 98% (43/44 patients) of distant, normal tissues. Using Kaplan–Meier analysis, we observed that the expression of PABPC4 was significantly correlated with disease-free survival and overall survival in patients with stage II and stage III colorectal cancer (P = 0.022 and P = 0.020, respectively). PABPC4 expression was positively associated with survival outcome, and may have predictive value in the prognosis of patients with colorectal cancer. Taken together, our findings indicate that PABPC4 may play a role in the pathogenesis of colorectal cancer.

Introduction

Poly(A) tails are permanently attached to almost all eukaryotic mRNAs and are necessary for efficient translation initiation. The effects of the poly(A) tail on translation appear to be mediated predominantly by the cytoplasmic poly(A) binding protein (PABPC) family of RNA-processing proteins (Gorgoni et al., 2011; Villalba et al., 2011). Previous studies have shown that PABPC promotes translation via multiple mechanisms. One mechanism by which PABPC stimulates the initiation of translation involves binding to the eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) protein, thus promoting recruitment of the small ribosomal subunit (40S), in a similar manner to eIF4E (Decker and Parker, 2002; Jackson et al., 2010) (Fig. 1A). In addition to regulating translation initiation, PABPC also controls the rate of mRNA deadenylation and participates in mRNA decay (Villalba et al., 2011). Previous studies have shown that dysregulation of RNA-processing proteins can affect oncogenic progression in multiple human cancers. The initiation factor, eIF4B, increases ribosomal recruitment, and targeted knockdown leads to apoptosis, indicating a critical role in cell cycle regulation (Shahbazian et al., 2010). The cap protein, eIF4E, which facilitates mRNA translation by forming a complex with eIF4G and PABPC, was shown to be activated in prostate cancer and expression was associated with a significantly worse prognosis (Graff et al., 2009). Despite this, the expression profile and clinical significance of PABPC in human cancers remain largely unknown.

PABPC4, initially described as inducible poly(A) binding protein, is a homolog of PABPC (Fig. 1B). Unlike PABPC1, which is expressed in most cell types, PABPC4 upregulation is dependent on the status of cells, such as during T-cell activation (Yang et al., 1995) and in thrombin-activated rabbit platelets (Houng et al., 1997). Given the recent evidence that PABPC4 expression regulates telomerase activity and cell growth in cervical cancer cell lines (Katzenellenbogen et al., 2010), it is tempting to speculate that PABPC4 expression may underlie the pathogenesis of other malignancies, including colorectal cancer.

In this context, we explored the expression of PABPC4 and its clinical significance in human colorectal cancer. Using a combination of immunohistochemistry (IHC) and Western blot analysis, we showed that PABPC4 is expressed in cancerous tissues and corresponding adjacent normal glands. Further analysis revealed that the expression of PABPC4 in cancerous tissues is closely correlated with a survival advantage in patients with stage II and stage III colorectal cancer.

Section snippets

Patient specimens

Primary colorectal cancer tissue specimens were obtained from 101 patients (61 men and 40 women; mean age 62 years, range: 28–90 years), who underwent radical surgery at the Peking Union Medical College hospital between March 2003 and March 2008. Written, informed consent was obtained from all patients and this study was approved by the local ethics committee. Patients with pre-surgically treated cancer, recurrent colorectal cancer, or other known malignancies were excluded from this study.

Cytoplasmic expression of PABPC4 in colorectal cancer patients

To examine the expression pattern of PABPC4 in colorectal cancer, IHC was performed in 101 primary colorectal cancer tissues, 38 corresponding adjacent, normal colorectal samples and 44 matched, distant, normal colorectal samples (located at least 10 cm from the primary tumor) (Fig. 2A). PABPC4 expression was restricted to the cytoplasm of both tumor and normal cells, and was significantly expressed in primary tumors (26.7%, 27/101 patients) compared with distant, normal colorectal tissue (2%,

Discussion

Colorectal cancer is one of the most common malignancies worldwide, and it is estimated that more than one million individuals develop colorectal cancer each year (Jemal et al., 2010; Loconte et al., 2011). While significant progress has been made in both the surgical and adjuvant treatment of colorectal cancer, the prognosis of patients remains poor. The disease-specific mortality is related to metastases at diagnosis, developing local recurrence or metachronous metastases after resection of

Acknowledgements

This work was funded by the Ph.D. Programs Foundation of the Ministry of Education of China (No. 20070023003 to C-M Lu).

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