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Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Human Cytomegalovirus | Research

Detection of Human cytomegalovirus UL55 Gene and IE/E Protein Expression in Colorectal Cancer Patients in Egypt

Authors: May Raouf, Ahmed A. Sabry, Mahinour A. Ragab, Samar El Achy, Amira Amer

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

A possible relation between Human cytomegalovirus (HCMV) and colorectal cancer (CRC) has been widely explored with an unclear role yet speculated.

Aim

The study aimed at detecting HCMV UL55 gene, immediate early and early (IE/E) proteins in colorectal tumor tissues and adjacent non neoplastic tissues (ANNT). Also, it aimed to correlate HCMV presence with CRC clinicopathological features.

Subjects and methods

A prospective study of 50 HCMV seropositive patients with resectable CRC were enrolled in the study. Demographic, clinical, and radiological findings were recorded. Pathological assessment was done. Paired CRC tumorous and ANNT were examined for HCMV UL55 by PCR and for IE/ E proteins by immunohistochemistry (IHC).

Results

70% of CRC patients enrolled were females and 36% were elderly (> 60y). Adenocarcinoma was the prevalent histopathological type (92%) with Grade 2, higher stages, and nodal involvement accounting for (64%, 64% and 56%) respectively.
HCMV detection was significantly higher in tumoral tissue versus ANNT by PCR and IHC (P < 0.001, P < 0.008) respectively. Moderate agreement was found between the two techniques (κ = 0.572, P < 0.001).
Univariate analysis identified HCMV presence to be significantly higher in elderly patients, in tumors with higher stage and with nodal involvement (P = 0.041, P = 0.008, P = 0.018 respectively). In multivariate analysis, the latter two retained significance (P = 0.010, P = 0.008).

Conclusion

CRC tumor tissues are more infected by HCMV than ANNT. A significant association of HCMV presence with a higher CRC tumor stage and nodal involvement in an age-dependent manner was detected. HCMV oncomodulatory and a disease progression role is suspected.
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Literature
3.
go back to reference Nauclér CS, Geisler J, Vetvik K. The emerging role of human cytomegalovirus infection in human carcinogenesis : a review of current evidence and potential therapeutic implications. Oncotarget. 2019;10:4333–47.CrossRefPubMedPubMedCentral Nauclér CS, Geisler J, Vetvik K. The emerging role of human cytomegalovirus infection in human carcinogenesis : a review of current evidence and potential therapeutic implications. Oncotarget. 2019;10:4333–47.CrossRefPubMedPubMedCentral
5.
go back to reference Geisler J, Touma J, Rahbar A, Söderberg-Nauclér C, Vetvik K. A review of the potential role of human cytomegalovirus (HCMV) infections in breast cancer carcinogenesis and abnormal immunity. Cancers (Basel). 2019;11:1842.CrossRefPubMedPubMedCentral Geisler J, Touma J, Rahbar A, Söderberg-Nauclér C, Vetvik K. A review of the potential role of human cytomegalovirus (HCMV) infections in breast cancer carcinogenesis and abnormal immunity. Cancers (Basel). 2019;11:1842.CrossRefPubMedPubMedCentral
6.
go back to reference Cai ZZ, Xu JG, Zhou YH, Zheng JH, Lin KZ, Zheng SZ, et al. Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer. World J Gastroenterol. 2016;22:2789–98.CrossRefPubMedPubMedCentral Cai ZZ, Xu JG, Zhou YH, Zheng JH, Lin KZ, Zheng SZ, et al. Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer. World J Gastroenterol. 2016;22:2789–98.CrossRefPubMedPubMedCentral
7.
go back to reference El Baba R, Herbein G. Immune Landscape of CMV Infection in Cancer Patients: From “Canonical” Diseases Toward Virus-Elicited Oncomodulation. Front Immunol. 2021;12:1–17. El Baba R, Herbein G. Immune Landscape of CMV Infection in Cancer Patients: From “Canonical” Diseases Toward Virus-Elicited Oncomodulation. Front Immunol. 2021;12:1–17.
8.
go back to reference Andouard D, Gueye R, Hantz S, Fagnère C, Liagre B, Bernardaud L, et al. Impact of new cyclooxygenase 2 inhibitors on human cytomegalovirus replication in vitro. Antivir Ther. 2021;26:117–25.CrossRefPubMed Andouard D, Gueye R, Hantz S, Fagnère C, Liagre B, Bernardaud L, et al. Impact of new cyclooxygenase 2 inhibitors on human cytomegalovirus replication in vitro. Antivir Ther. 2021;26:117–25.CrossRefPubMed
9.
go back to reference Moussawi FA, Kumar A, Pasquereau S, Tripathy MK, Karam W, Diab-Assaf M, et al. The transcriptome of human mammary epithelial cells infected with the HCMV-DB strain displays oncogenic traits. Sci Rep. 2018;8:1–14.CrossRef Moussawi FA, Kumar A, Pasquereau S, Tripathy MK, Karam W, Diab-Assaf M, et al. The transcriptome of human mammary epithelial cells infected with the HCMV-DB strain displays oncogenic traits. Sci Rep. 2018;8:1–14.CrossRef
10.
go back to reference Ball CB, Parida M, Li M, Spector BM, Suarez GA, Meier JL, et al. Human Cytomegalovirus Infection Elicits Global Changes in Host Transcription by RNA Polymerases I, II, and III. Viruses. 2022;14:779.CrossRefPubMedPubMedCentral Ball CB, Parida M, Li M, Spector BM, Suarez GA, Meier JL, et al. Human Cytomegalovirus Infection Elicits Global Changes in Host Transcription by RNA Polymerases I, II, and III. Viruses. 2022;14:779.CrossRefPubMedPubMedCentral
12.
go back to reference Jackson SE, Redeker A, Arens R, van Baarle D, van den Berg SPH, Benedict CA, et al. CMV immune evasion and manipulation of the immune system with aging. GeroScience. 2017;39:273–91.CrossRefPubMedPubMedCentral Jackson SE, Redeker A, Arens R, van Baarle D, van den Berg SPH, Benedict CA, et al. CMV immune evasion and manipulation of the immune system with aging. GeroScience. 2017;39:273–91.CrossRefPubMedPubMedCentral
13.
go back to reference Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–64.CrossRefPubMed Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–64.CrossRefPubMed
14.
go back to reference Habbal W, Monem F, Gärtner BC. Comparative evaluation of published cytomegalovirus primers for rapid real-time PCR: Which are the most sensitive? J Med Microbiol. 2009;58:878–83.CrossRefPubMed Habbal W, Monem F, Gärtner BC. Comparative evaluation of published cytomegalovirus primers for rapid real-time PCR: Which are the most sensitive? J Med Microbiol. 2009;58:878–83.CrossRefPubMed
15.
go back to reference Mills AM, Guo FP, Copland AP, Pai RK, Pinsky BA. A comparison of cmv detection in gastrointestinal mucosal biopsies using immunohistochemistry and pcr performed on formalin-fixed, paraffin-embedded tissue. Am J Surg Pathol. 2013;37:995–1000.CrossRefPubMed Mills AM, Guo FP, Copland AP, Pai RK, Pinsky BA. A comparison of cmv detection in gastrointestinal mucosal biopsies using immunohistochemistry and pcr performed on formalin-fixed, paraffin-embedded tissue. Am J Surg Pathol. 2013;37:995–1000.CrossRefPubMed
17.
go back to reference Kim BH, Kim JM, Kang GH, Chang HJ, Kang DW, Kim JH, et al. Standardized pathology report for colorectal cancer, 2nd edition. J Pathol Transl Med. 2020;54:1–19.CrossRefPubMed Kim BH, Kim JM, Kang GH, Chang HJ, Kang DW, Kim JH, et al. Standardized pathology report for colorectal cancer, 2nd edition. J Pathol Transl Med. 2020;54:1–19.CrossRefPubMed
18.
go back to reference Chen HP, Jiang JK, Lai PY, Teo WH, Yang CY, Chou TY, et al. Serological and viraemic status of human cytomegalovirus infection in patients with colorectal cancer is not correlated with viral replication and transcription in tumours. J Gen Virol. 2016;97:152–9.CrossRefPubMed Chen HP, Jiang JK, Lai PY, Teo WH, Yang CY, Chou TY, et al. Serological and viraemic status of human cytomegalovirus infection in patients with colorectal cancer is not correlated with viral replication and transcription in tumours. J Gen Virol. 2016;97:152–9.CrossRefPubMed
19.
go back to reference Mielonen OI, Pratas D, Hedman K, Sajantila A, Perdomo MF. Detection of Low-Copy Human Virus DNA upon Prolonged Formalin Fixation. Viruses. 2022;14:1–12.CrossRef Mielonen OI, Pratas D, Hedman K, Sajantila A, Perdomo MF. Detection of Low-Copy Human Virus DNA upon Prolonged Formalin Fixation. Viruses. 2022;14:1–12.CrossRef
21.
go back to reference Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.CrossRefPubMed Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.CrossRefPubMed
22.
go back to reference Söderberg-Nauclér C. HCMV microinfections in inflammatory diseases and cancer. J Clin Virol. 2008;41:218–23.CrossRefPubMed Söderberg-Nauclér C. HCMV microinfections in inflammatory diseases and cancer. J Clin Virol. 2008;41:218–23.CrossRefPubMed
23.
go back to reference Lv YL, Han FF, An ZL, Jia Y, Xuan LL, Gong LL, et al. Cytomegalovirus Infection Is a Risk Factor in Gastrointestinal Cancer: A Cross-Sectional and Meta-Analysis Study. Intervirology. 2020;63(1–6):10–6.CrossRefPubMed Lv YL, Han FF, An ZL, Jia Y, Xuan LL, Gong LL, et al. Cytomegalovirus Infection Is a Risk Factor in Gastrointestinal Cancer: A Cross-Sectional and Meta-Analysis Study. Intervirology. 2020;63(1–6):10–6.CrossRefPubMed
25.
go back to reference Chelbi H, Jelassi R, Belfkih S, Amor AB, Saidi N, Krishna BA. Association of CCR5 Δ 32 deletion and human cytomegalovirus infection with colorectal cancer in tunisia. Front Genet. 2021;12:1–10.CrossRef Chelbi H, Jelassi R, Belfkih S, Amor AB, Saidi N, Krishna BA. Association of CCR5 Δ 32 deletion and human cytomegalovirus infection with colorectal cancer in tunisia. Front Genet. 2021;12:1–10.CrossRef
26.
go back to reference Akintola-Ogunremi O, Luo Q, He TC, Wang HL. Is cytomegalovirus associated with human colorectal tumorigenesis? Am J Clin Pathol. 2005;123:244–9.CrossRefPubMed Akintola-Ogunremi O, Luo Q, He TC, Wang HL. Is cytomegalovirus associated with human colorectal tumorigenesis? Am J Clin Pathol. 2005;123:244–9.CrossRefPubMed
27.
go back to reference Bender C, Zipeto D, Bidoia C, Costantini S, Zamo A, Menestrina F, et al. Analysis of colorectal cancers for human cytomegalovirus presence. Infect Agent Cancer. 2009;4:1–6.CrossRef Bender C, Zipeto D, Bidoia C, Costantini S, Zamo A, Menestrina F, et al. Analysis of colorectal cancers for human cytomegalovirus presence. Infect Agent Cancer. 2009;4:1–6.CrossRef
28.
go back to reference Knösel T, Schewe C, Dietel M, Petersen I. Cytomegalovirus is not associated with progression and metastasis of colorectal cancer. Cancer Lett. 2004;211:243–7.CrossRefPubMed Knösel T, Schewe C, Dietel M, Petersen I. Cytomegalovirus is not associated with progression and metastasis of colorectal cancer. Cancer Lett. 2004;211:243–7.CrossRefPubMed
29.
30.
go back to reference Taher C, Frisk G, Fuentes S, Religa P, Costa H, Assinger A, et al. High prevalence of human cytomegalovirus in brain metastases of patients with primary breast and colorectal cancers. Transl Oncol. 2014;7:732–40. Neoplasia Press, IncCrossRefPubMedPubMedCentral Taher C, Frisk G, Fuentes S, Religa P, Costa H, Assinger A, et al. High prevalence of human cytomegalovirus in brain metastases of patients with primary breast and colorectal cancers. Transl Oncol. 2014;7:732–40. Neoplasia Press, IncCrossRefPubMedPubMedCentral
31.
go back to reference Taher C, de Boniface J, Mohammad AA, Religa P, Hartman J, Yaiw KC, et al. High Prevalence of Human Cytomegalovirus Proteins and Nucleic Acids in Primary Breast Cancer and Metastatic Sentinel Lymph Nodes. PLoS One. 2013;8(2):e56795.CrossRefPubMedPubMedCentral Taher C, de Boniface J, Mohammad AA, Religa P, Hartman J, Yaiw KC, et al. High Prevalence of Human Cytomegalovirus Proteins and Nucleic Acids in Primary Breast Cancer and Metastatic Sentinel Lymph Nodes. PLoS One. 2013;8(2):e56795.CrossRefPubMedPubMedCentral
32.
go back to reference Yang Z, Tang X, Hasing ME, Pang X, Ghosh S, Mcmullen TPW, et al. Human Cytomegalovirus Seropositivity and Viral DNA in Breast Tumors Are Associated with Poor Patient Prognosis. Cancers (Basel). 2022;14:1–23. Yang Z, Tang X, Hasing ME, Pang X, Ghosh S, Mcmullen TPW, et al. Human Cytomegalovirus Seropositivity and Viral DNA in Breast Tumors Are Associated with Poor Patient Prognosis. Cancers (Basel). 2022;14:1–23.
33.
go back to reference Touma J, Pantalone MR, Rahbar A, Liu Y, Vetvik K, Sauer T, et al. Human Cytomegalovirus Protein Expression Is Correlated with Shorter Overall Survival in Breast Cancer Patients: A Cohort Study. Viruses. 2023;15:732.CrossRefPubMedPubMedCentral Touma J, Pantalone MR, Rahbar A, Liu Y, Vetvik K, Sauer T, et al. Human Cytomegalovirus Protein Expression Is Correlated with Shorter Overall Survival in Breast Cancer Patients: A Cohort Study. Viruses. 2023;15:732.CrossRefPubMedPubMedCentral
34.
go back to reference Chen HP, Jiang JK, Chen CY, Chou TY, Chen YC, Chang YT, et al. Human cytomegalovirus preferentially infects the neoplastic epithelium of colorectal cancer: A quantitative and histological analysis. J Clin Virol. 2012;54:240–4. Elsevier B.VCrossRefPubMed Chen HP, Jiang JK, Chen CY, Chou TY, Chen YC, Chang YT, et al. Human cytomegalovirus preferentially infects the neoplastic epithelium of colorectal cancer: A quantitative and histological analysis. J Clin Virol. 2012;54:240–4. Elsevier B.VCrossRefPubMed
35.
go back to reference Dimberg J, Trinh Hong T, Skarstedt M, Löfgren S, Zar N, Matussek A. Detection of cytomegalovirus DNA in colorectal tissue from Swedish and Vietnamese patients with colorectal cancer. Anticancer Res. 2013;33:4947–50.PubMed Dimberg J, Trinh Hong T, Skarstedt M, Löfgren S, Zar N, Matussek A. Detection of cytomegalovirus DNA in colorectal tissue from Swedish and Vietnamese patients with colorectal cancer. Anticancer Res. 2013;33:4947–50.PubMed
36.
go back to reference Chen HP, Jiang JK, Lai PY, Chen CY, Chou TY, Chen YC, et al. Tumoral presence of human cytomegalovirus is associated with shorter disease-free survival in elderly patients with colorectal cancer and higher levels of intratumoral interleukin-17. Clin Microbiol Infect. 2014;20:664–71.CrossRefPubMed Chen HP, Jiang JK, Lai PY, Chen CY, Chou TY, Chen YC, et al. Tumoral presence of human cytomegalovirus is associated with shorter disease-free survival in elderly patients with colorectal cancer and higher levels of intratumoral interleukin-17. Clin Microbiol Infect. 2014;20:664–71.CrossRefPubMed
37.
go back to reference El Shazly DF, Bahnassey AA, Omar OS, Elsayed ET, Al-Hindawi A, El-Desouky E, et al. Detection of Human Cytomegalovirus in Malignant and Benign Breast Tumors in Egyptian Women. Clin Breast Cancer. 2018;18:e629-42. Elsevier IncCrossRefPubMed El Shazly DF, Bahnassey AA, Omar OS, Elsayed ET, Al-Hindawi A, El-Desouky E, et al. Detection of Human Cytomegalovirus in Malignant and Benign Breast Tumors in Egyptian Women. Clin Breast Cancer. 2018;18:e629-42. Elsevier IncCrossRefPubMed
38.
go back to reference Harkins L, Volk AL, Samanta M, Mikolaenko I, Britt WJ, Bland KI, et al. Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet. 2002;360:1557–63. Elsevier B.VCrossRefPubMed Harkins L, Volk AL, Samanta M, Mikolaenko I, Britt WJ, Bland KI, et al. Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet. 2002;360:1557–63. Elsevier B.VCrossRefPubMed
39.
go back to reference Teo WH, Chen HP, Huang JC, Chan YJ. Human cytomegalovirus infection enhances cell proliferation, migration and upregulation of EMT markers in colorectal cancer-derived stem cell-like cells. Int J Oncol. 2017;51:1415–26.CrossRefPubMedPubMedCentral Teo WH, Chen HP, Huang JC, Chan YJ. Human cytomegalovirus infection enhances cell proliferation, migration and upregulation of EMT markers in colorectal cancer-derived stem cell-like cells. Int J Oncol. 2017;51:1415–26.CrossRefPubMedPubMedCentral
40.
go back to reference Wong MCS, Huang J, Huang JLW, Pang TWY, Choi P, Wang J, et al. Global Prevalence of Colorectal Neoplasia: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2020;18:553-561.e10 Elsevier, Inc.CrossRefPubMed Wong MCS, Huang J, Huang JLW, Pang TWY, Choi P, Wang J, et al. Global Prevalence of Colorectal Neoplasia: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2020;18:553-561.e10 Elsevier, Inc.CrossRefPubMed
41.
go back to reference Chen HP, Jiang JK, Chen CY, Yang CY, Chen YC, Lin CH, et al. Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients. J Gen Virol. 2016;97:2411–20.CrossRefPubMed Chen HP, Jiang JK, Chen CY, Yang CY, Chen YC, Lin CH, et al. Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients. J Gen Virol. 2016;97:2411–20.CrossRefPubMed
42.
go back to reference Pera A, Campos C, Corona A, Sanchez-Correa B, Tarazona R, Larbi A, et al. CMV latent infection improves CD8+ T response to SEB due to expansion of polyfunctional CD57+ cells in young individuals. PLoS ONE. 2014;9:1–7.CrossRef Pera A, Campos C, Corona A, Sanchez-Correa B, Tarazona R, Larbi A, et al. CMV latent infection improves CD8+ T response to SEB due to expansion of polyfunctional CD57+ cells in young individuals. PLoS ONE. 2014;9:1–7.CrossRef
44.
go back to reference Nagel B, Frankel L, Ardeljan A, Cardeiro M, Rashid S, Takabe K, et al. The Association of Human Cytomegalovirus Infection and Colorectal Cancer: A Clinical Analysis. World J Oncol. 2023;14:119–24.CrossRefPubMedPubMedCentral Nagel B, Frankel L, Ardeljan A, Cardeiro M, Rashid S, Takabe K, et al. The Association of Human Cytomegalovirus Infection and Colorectal Cancer: A Clinical Analysis. World J Oncol. 2023;14:119–24.CrossRefPubMedPubMedCentral
Metadata
Title
Detection of Human cytomegalovirus UL55 Gene and IE/E Protein Expression in Colorectal Cancer Patients in Egypt
Authors
May Raouf
Ahmed A. Sabry
Mahinour A. Ragab
Samar El Achy
Amira Amer
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11200-x

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