Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2016; 22(9): 2789-2798
Published online Mar 7, 2016. doi: 10.3748/wjg.v22.i9.2789
Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer
Zhen-Zhai Cai, Jian-Gang Xu, Yu-Hui Zhou, Ji-Hang Zheng, Ke-Zhi Lin, Shu-Zhi Zheng, Meng-Si Ye, Yun He, Chang-Bao Liu, Zhan-Xiong Xue
Zhen-Zhai Cai, Yu-Hui Zhou, Shu-Zhi Zheng, Meng-Si Ye, Yun He, Zhan-Xiong Xue, Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Jian-Gang Xu, Chang-Bao Liu, Department of Surgical Oncology, Wenzhou Central Hospital, Wenzhou 325035, Zhejiang Province, China
Ji-Hang Zheng, Department of General Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Ke-Zhi Lin, Department of Pathology, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Author contributions: Cai ZZ and Xu JG equally contributed to this paper; Xu JG and Xue ZX designed the research studies; Cai ZZ and Zhou YH performed the majority of the experiments and wrote the manuscript; Lin KZ performed immunohistochemistry; Zheng JH performed the statistical analysis; Zheng SZ, Ye MS and He Y performed some experiments; and Liu CB collected specimens.
Supported by The Zhejiang Provincial Natural Science Foundation of China, No. LY15H160059; Zhejiang Provincial Medical and Health Science and Technology Project, No. 2016KYB192; and the Wenzhou Municipal Science and Technology Bureau, No. Y20140691.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Zhan-Xiong Xue, MD, Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou 325000, Zhejiang Province, China. xuezhanxiong2015@sina.com
Telephone: +86-577-88002715 Fax: +86-577-88002725
Received: September 29, 2015
Peer-review started: October 1, 2015
First decision: November 13, 2015
Revised: December 14, 2015
Accepted: December 30, 2015
Article in press: December 30, 2015
Published online: March 7, 2016
Processing time: 154 Days and 17.8 Hours
Abstract

AIM: To assess human cytomegalovirus-encoded US28 gene function in colorectal cancer (CRC) pathogenesis.

METHODS: Immunohistochemical analysis was performed to determine US28 expression in 103 CRC patient samples and 98 corresponding adjacent noncancerous samples. Patient data were compared by age, sex, tumor location, histological grade, Dukes’ stage, and overall mean survival time. In addition, the US28 gene was transiently transfected into the CRC LOVO cell line, and cell proliferation was assessed using a cell counting kit-8 assay. Cell cycle analysis by flow cytometry and a cell invasion transwell assay were also carried out.

RESULTS: US28 levels were clearly higher in CRC tissues (38.8%) than in adjacent noncancerous samples (7.1%) (P = 0.000). Interestingly, elevated US28 amounts in CRC tissues were significantly associated with histological grade, metastasis, Dukes’ stage, and overall survival (all P < 0.05); meanwhile, US28 expression was not significantly correlated with age, sex or tumor location. In addition, multivariate Cox regression data revealed US28 level as an independent CRC prognostic marker (P = 0.000). LOVO cells successfully transfected with the US28 gene exhibited higher viability, greater chemotherapy resistance, accelerated cell cycle progression, and increased invasion ability.

CONCLUSION: US28 expression is predictive of poor prognosis and may promote CRC.

Keywords: Human cytomegalovirus; US28; Colorectal cancer; Prognosis; Proliferation; Invasion

Core tip: Human cytomegalovirus (HCMV) is strongly correlated to colorectal cancer (CRC), although it remains unclear whether the virus contributes to CRC pathogenesis. We examined the expression of HCMV-encoded US28 protein in 103 CRC patient samples and 98 corresponding adjacent noncancerous samples using immunohistochemistry; the relationship between US28 expression and clinicopathological features was also analyzed. We found that US28 expression differed significantly between colorectal carcinoma and adjacent noncancerous colorectal tissues and that US28 expression was correlated with histological grade, metastasis, Dukes’ stage, and survival. After successful transfection with the US28 gene, LOVO cells exhibited higher viability, greater chemotherapy resistance, accelerated cell cycle progression, and increased invasion. These findings indicate that US28 expression predicts a poor prognosis and may promote the pathogenesis of CRC. Thus, targeting specific HCMV proteins (e.g., US28) in endogenously infected CRC may constitute a novel antitumor approach.