Elsevier

Human Pathology

Volume 39, Issue 1, January 2008, Pages 80-86
Human Pathology

Original contribution
Overexpression of EIF-5A2 is associated with metastasis of human colorectal carcinoma

https://doi.org/10.1016/j.humpath.2007.05.011Get rights and content

Summary

Our previous study has suggested an oncogenic role of eIF-5A2 in ovarian tumorigenesis. Abnormalities of eIF-5A2, however, in colorectal carcinoma are unclear. In this study, amplification and overexpression of eIF-5A2 in colorectal carcinoma were studied by fluorescence in situ hybridization and immunohistochemistry using colorectal carcinoma tissue microarrays, including 139 primary colorectal carcinomas and their adjacent normal mucosa, 22 paired premalignant adenomas, and 42 metastatic tumors. The immunohistochemistry results showed that overexpression of EIF-5A2 was detected in none of normal epithelial mucosa, 35.3% of colorectal adenomas, 53.2% of primary colorectal carcinomas, and 67.6% of metastases. Amplification of eIF-5A2 was detected in 15.8% (16/101) of informative colorectal carcinomas, and most of them showed overexpression of EIF-5A2. In primary colorectal carcinomas, the frequency of EIF-5A2 overexpression was significantly higher in colorectal carcinomas with lymphovascular invasion (61.2%) than that in colorectal carcinomas without lymphovascular invasion (36.6%, P < .05). In addition, significant positive associations were found between EIF-5A2 overexpression and the tumors' later pN and pM stages, as well as increased tumor cell proliferation (P < .05). These findings suggest that overexpression of EIF-5A2 in colorectal carcinomas may be important in the acquisition of a metastatic phenotype and plays an important role in colorectal carcinoma development and progression.

Introduction

Colorectal carcinoma (CRC) is the fourth most common human malignancy and a major cause of cancer-related death in developed countries [1]. The incidence of CRC in China increased rapidly during the past 2 decades [2]. The pathogenesis of CRC is believed to be a multistep process that involves multiple genetic changes, including inactivation of tumor suppressor genes and activation of oncogenes. Although CRC has been widely studied, the precise genetic changes underlying the development and progression of this neoplasm are not thoroughly understood. Amplification of 3q is one the most frequent chromosomal aberrations in CRC detected by comparative genomic hybridization [3], [4]. Amplification of 3q also has been detected frequently in many other human cancers including ovarian [5], lung [6], esophagus [7], gastric [8] carcinomas, and others [9], [10], [11]. These studies strongly suggest that the existence of oncogene(s) at 3q plays an important role in the pathogenesis and progression of a number of different human solid tumors.

Using a chromosome microdissection-hybrid selection method, we have previously isolated a novel candidate oncogene, eIF-5A2 (eukaryotic initiation factor 5A2), from a primary ovarian cancer containing high–copy-number amplification of 3q26 [12]. EIF-5A2 protein shares 82% identical amino acid sequence with EIF-5A including the minimum domain needed for EIF-5A maturation by hypusine modification at lysine-50 residue. Previous study showed that intracellular depletion of eIF-5A could cause the inhibition of cell growth [13]. Other studies indicated that the inhibition of deoxyhypusine synthase (DHPS), the enzyme involved in the hypusination reaction of eIF-5A, could inhibit Chinese hamster ovary cells proliferation [14], suppress the growth of HeLa cells, and induce apoptosis [15]. Recently, the tumorigenic characteristics of eIF-5A2 have also been demonstrated by both in vitro and in vivo assays [12], [16], [17]. In addition, overexpression of EIF-5A2 has been observed to correlate with late clinical stage in ovarian cancer [17]. Because amplification of 3q was also frequently detected in CRC, we hypothesized that eIF-5A2 may also play an important role in the development and progression of CRC. In the present study, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to examine the distribution and frequency of protein expression and amplification of eIF-5A2 in a large group of human CRCs by tissue microarray (TMA).

Section snippets

Patients and tissue specimens

In this study, 139 patients with CRC who underwent partial coloproctectomy were selected consecutively from the surgical pathology archives of the Department of Pathology, Cancer Center and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, between 1995 and 2003. Patients with mucinous carcinoma and/or familial CRC were excluded from this study. All CRCs selected were conventional adenocarcinoma, in which the 22 cases encountered were colorectal adenomatous polyps in the

EIF-5A2 expression in colorectal tissues

In the present study, the protein expression of EIF-5A2 was investigated by IHC in colorectal tissue TMAs, which contained 139 cases of adjacent normal colorectal mucosa and different colorectal lesions including 139 cases of primary CRC, 22 premalignant colorectal adenomas, and 42 metastases from the same patients with CRC. EIF-5A2 expression could be evaluated informatively in 102 (73.4%) of 139 normal colorectal mucosa, 17 (77.3%) of 22 colorectal adenomas, 126 (90.6%) of 139 primary CRCs,

Discussion

Our previous studies provide evidence that the eIF-5A2 gene, located at human chromosome 3q26, has an oncogenic function in ovarian carcinoma [12], [17]. Because amplification of 3q was frequently detected in human CRCs [3], [4], it is highly possible that the abnormalities of eIF-5A2 may play a critical role in colorectal tumorigenesis.

In the present study, the expression of EIF-5A2 was first investigated by IHC using TMA containing a series of normal colorectal and tumor tissues (benign and

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    This study was supported by grants from 985-II Project of State Key Laboratory of Oncology in Southern China, the Foundation of Guangzhou Science and Technology Bureau (2005J1-C0311), the National Nature Science Foundation of China (30300401), and the Sun Yat-sen University “Hundred Talents Program” (85000-3171311).

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