HPV18 E7 induces the over-transcription of eIF4E gene in cervical cancer

Document Type : Original Article


1 Obstetrics and Gynecology Department of the first Affiliated Hospital of Guangdong Medical College, No. 57 Avenue of the people, Zhanjiang, Guangdong Province 524023, PR China

2 Cancer Institute of Guangdong Medical College, No. 1 Xincheng Road, Dongguan, Guangdong Province 523808, PR China

3 People's Hospital of Dongguan, No. 3 South of Wandao Road, Dongguan, Guangdong Province 523059, PR China

4 Pathology Department of Guangdong Medical College, No. 1 Xincheng Road, Dongguan, Guangdong Province 523808, PR China


Objective(s):Eukaryotic translation initiation factor 4E (eIF4E) is overexpressed in cervical cancer (CC). However, the molecular mechanisms are unclear. This study aimed to investigate the molecular mechanism of eIF4E gene overexpression in CC.
Materials andMethods:The human papillomavirus (HPV) type 18 E7 and eIF4E mRNAs were measured following knock down or overexpression of E7 gene by RT-PCR and real-time PCR. Cell counting kit-8 assay was used to determine the cell proliferation. Flow cytometry was used to analyze the cell cycle and apoptosis. Transwell system was employed to determine the cell migration.
Results:Overexpression of E7 gene increased eIF4E mRNA level by 24.3% (P<0.01) in HPV negative C33A cells. Knock down of E7 decreased markedly eIF4E mRNA by 73% (P<0.01) in HPV18 positive HeLa cells. Under the state of high expression of E7, 1) up-regulation of eIF4E drastically promoted the cell proliferation, cell cycle and cell migration, and inhibited the cell apoptosis.  2) down-regulation of eIF4E significantly inhibited the cell proliferation, cell cycle and the ability of cell  migration,  and  also  promoted  the  apoptosis  of  cervical  cancer  cells.
Conclusion: HPV E7 induced eIF4E gene over transcription which might be a new marker for CC. The finding broadens the understanding of the CC carcinogenesis.


1. Arbyn M, Castellsagué X, de Sanjosé S, Bruni L, Saraiya M, Bray F, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol 2011; 22: 2675-2686.
2. Hyacinth HI, Adekeye OA, Ibeh JN, Osoba T. Cervical Cancer and Pap Smear Awareness and Utilization of Pap Smear Test among Federal Civil Servants in North Central Nigeria. PLoS One 2012; 7:e46583.
3. Klingelhutz AJ, Roman A. Cellular transformation by human papillomaviruses, lessons learned by comparing high- and low-risk viruses. Virology 2012; 424: 77-98.
4. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine 2012; 30:F12-F23.
5. Huh K, Zhou X, Hayakawa H, Cho JY, Libermann TA, Jin J, et al. Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin Suppressor. J Virol 2007; 81:9737-9747.
6. Sonenberg N.EIF4E, the mRNA cap-binding protein, from basic discovery to translational research Biochem Cell Biol 2008; 86:178-183.
7. Graff JR, Konicek BW, Carter JH, Marcusson EG. Targeting the eukaryotic translation initiation factor 4E for cancer therapy.  Cancer Res 2008; 68:631-634.
8. Hsieh AC, Ruggero D.Targeting eukaryotic translation initiation factor 4E (EIF4E) in cancer. Clin Cancer Res 2010; 16:4914-4920.
9. Zimmer SG, DeBenedetti A, Graff JR. Translational control of malignancy, the mRNA cap-binding protein, EIF4E, as a central regulator of tumor formation, growth, invasion and metastasis.  Anticancer     Res 2000; 20:1343-1351.
10.Franklin S, Pho T, Abreo FW, Nassar R, De Benedetti A, Stucker FJ, et al. Detection of the proto-oncogene EIF4E in larynx and hypopharynx cancers. Arch Otolaryngol Head Neck Surg 1999; 125:177-182.
11.Nathan CA, Sander K, Abreo FW, Nassar R, Glass J. Correlation of p53 and the proto-oncogene EIF4E in larynx cancers, prognostic implications . Cancer Res 2000; 60:3599-3604.
12. Pavelic Z, Pavelic K, Carter C, Pavelic L. Heterogeneity of c-myc expression in histologically similar infiltrating ductal carcinoma of the breast . J Cancer Res Clin Oncol 1992; 118:16-22.
13.Van Trappen PO, Ryan A, Carroll M, Lecoeur C, Goff L, Gyselman VG, et al. A model for co-expression pattern analysis of genes implicated in angiogenesis and tumour cell invasion in cervical cancer. Br J Cancer 2002; 2002: 537-544.
14. Lee  JW,  Choi  JJ,  Lee  KM,  Choi  CH, Kim  TJ, Lee  JH, et  al.  EIF4E expression is associated with histopathologic grades in cervical neoplasia. Hum Pathol 2005; 2005:1197-1203.
15. Wang S, Pang T, Gao M, Kang H, Ding W, Sun X, et al. HPV E6 induces eIF4E transcription to promote the proliferation and migration of cervical cancer. FEBS Lett 2013; 587: 690-697.
16. Li G, He L, Zhang E, Shi J, Zhang Q, Le AD, et al. Overexpression of human papillomavirus (HPV) type 16 oncoproteins promotes angiogenesis via enhancing HIF-1α and VEGF expression in non-small cell lung cancer cells. Cancer lett 2011; 311:160-170.
17. Shin MK, Sage J, Lambert PF. Inactivating All Three Rb Family Pocket Proteins Is Insufficient to Initiate Cervical Cancer. Cancer Res 2012; 72:5418-5427.
18. Buitrago-Pérez A, Hachimi MA. Humanized mouse model of HPV-associated pathology driven by E7 expression. PLoS One 2012; 7:e41743.
19. Boyer SN, Wazer DE, Band V. E7 protein of human papilloma virus-16 induces degradation of      retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res 1996; 56:4620-4624.
20. Gonzalez SL, Stremlau M, He X, Basile JR, Munger K. Degradation of the retinoblastoma tumor suppressor by the human papillomavirus type 16 E7 oncoprotein is important for functional inactivation and is separable from proteasomal degradation of E7. J Virol 2001; 75:7583-7591.
21. Lin CJ, Cencic R, Mills JR, Robert F, Pelletier J. c-Myc and eIF4F are components of a feedforward loop that links transcription and translation. Cancer Res 2008; 68:5326-5334.
22. Sushma M, Vamsikrishna B, Babu M, Mohanraj R. A review on role of Human papilommavirus (HPV) in cervical cancer. Pharma Tutor 2014; 2:21-30.
23. Bin H, Ruifang W, Ruizhen L, Yiheng L, Zhihong L. Juan L, et al. Detention of HPV L1 capsid protein and hTERC gene in screening of cervical cancer. Iran J Basic Med Sci 2013; 16:797.
24. Sadaoui NC, Armaiz-Pena GN, Nagaraja AS, Rupaimoole R., Previs RA, Dalton HJ, et al. Sustained adrenergic signaling promotes cervical cancer progression. Cancer Res 2014; 74:3511-3511.
25. Stacey SN, Jordan D, Williamson AJ, Brown M, Coote JH, Arrand JR. Leaky scanning is the predominant mechanism for translation of human papillomavirus type 16 E7 oncoprotein from E6/E7 bicistronic mRNA. J Virol 2000; 74:7284-7297.
26. Stacey SN, Jordan D, Snijders PJ, Mackett M, Walboomers J M, Arrand JR. Translation of the human papillomavirus type 16 E7 oncoprotein from bicistronic mRNA is independent of splicing events within the E6 open reading frame. J Viral 1995; 69:7023-7031.