Brief Article
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World J Gastroenterol. Aug 14, 2012; 18(30): 4051-4058
Published online Aug 14, 2012. doi: 10.3748/wjg.v18.i30.4051
Human papilloma virus 16 E6 oncoprotein associated with p53 inactivation in colorectal cancer
Tan-Hsia Chen, Chi-Chou Huang, Kun-Tu Yeh, Shu-Hau Chang, Shih-Wen Chang, Wen-Wei Sung, Ya-Wen Cheng, Huei Lee
Tan-Hsia Chen, Shu-Hau Chang, Wen-Wei Sung, Ya-Wen Cheng, Huei Lee, Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, China
Tan-Hsia Chen, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan, China
Chi-Chou Huang, Kun-Tu Yeh, Shih-Wen Chang, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, China
Chi-Chou Huang, Shih-Wen Chang, Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan, China
Kun-Tu Yeh, Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan, China
Ya-Wen Cheng, Huei Lee, Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan, China
Ya-Wen Cheng, Huei Lee, PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 115, Taiwan, China
Author contributions: Chen TH, Huang CC, Cheng YW, Lee H contributed equally to this work; Cheng YW, Lee H designed the study and wrote the paper; Cheng YW, Chen TH, Huang CC, Yeh KT and Chang SH conceived the experiments, wrote the paper, and prepared the figures; Huang CC and Yeh KT collected the colorectal tumor samples; Sung WW performed the p21 and Mdm2 mRNA detection; and all authors gave final approval for the manuscript to be submitted for publication.
Supported by Grants from the National Science Council of Taiwan, China, No. 99-2628-B-040-002-MY3 and No. 97-2314-B-040-027-MY3
Correspondence to: Huei Lee, Professor, PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, 12F., No.3, Sec. 4, Bade Rd., Nangang Dist., Taipei 115, Taiwan, China. hl@tmu.edu.tw
Telephone: +886-4-24759400 Fax: +886-4-24720407
Received: January 30, 2012
Revised: March 31, 2012
Accepted: April 9, 2012
Published online: August 14, 2012
Abstract

AIM: To investigate the association between human papilloma virus (HPV) infection and colorectal cancer.

METHODS: Sixty-nine patients with pathologically confirmed primary colorectal cancer including 6 stage I, 24 stage II, 21 stage III, and 18 stage IV patients were enrolled in this study to investigate whether HPV 16 could be involved in colorectal tumorigenesis. Nested-polymerase chain reaction (nested-PCR) was used to detect HPV16 DNA in colorectal tumor tissues and further confirmed by in situ hybridization (ISH). In addition, immunohistochemistry analysis was performed to examine the E6 oncoprotein in colorectal tumors. To verify whether E6 could inactivate the p53 transcriptional function, the levels of p21 and Mdm2 mRNA expression were evaluated by real-time reverse transcription (RT)-PCR.

RESULTS: Of the 69 colorectal tumors, HPV16 DNA was detected in 11 (16%) by nested-PCR, and HPV16 DNA was present in 8 of the 11 (73%) tumors which was confirmed by ISH. The presence of HPV16 DNA in colorectal tumors was not associated with patients’ clinical parameters including age, gender, smoking status, tumor site; however, HPV16 infection was more common in stage I patients than in late-stages patients (II, III and IV). We next asked whether HPV16 infection could be linked with colorectal cancer development. Immunohistochemical data indicated that 8 of the 11 HPV16 DNA-positive tumors had E6 oncoprotein expression. Moreover, we also observed that the adjacent normal tissues including endothelial cells, lymphocytes, fibroblasts, and gland cells in E6-positive tumors had E6 oncoprotein expression. In addition, 3 of the 4 (75%) E6-positive tumors carrying p53 wild-type had negative immunostaining, but one tumor had less p53 immunostaining. We further examined whether E6-positive and/or p53 mutated tumors reduce p53 transcriptional activity. Real-time RT-PCR analysis indicated that p21 and mdm2 mRNA expression levels in E6/p53-wildtype tumors were significantly lower than in their adjacent normal tissues; as expected, E6-positive/p53-mutated tumors had lower p21 and mdm2 mRNA expression levels compared with their adjacent normal tissues. These results clearly indicate that the E6 oncoprotein expressed in p53 wildtype tumors may reduce p21 and mdm2 expression via p53 inactivation.

CONCLUSION: These results suggest that HPV16 infection may be involved in a subset of colorectal cancer, and we suggest that the transmission of HPV to the colon and rectum might occur through peripheral blood lymphocytes.

Keywords: Human papilloma virus; Colorectal cancer; p53; p21; Blood lymphocytes