Association of the Plasma and Tissue Riboflavin Levels with C20orf54 Expression in Cervical Lesions and Its Relationship to HPV16 Infection

Aixingzi Aili,Batur Mamtimin,Halmurat Upur,Xia Guo,Alimujiang Kelimu,Ayshamgul Hasim,Abuliz Abudula,Shannon M Hawkins

doi:10.1371/journal.pone.0079937

Aixingzi Aili, Batur Mamtimin + Show 6 more

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https://doi.org/10.1371/journal.pone.0079937

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Abstract

Riboflavin deficiency can cause a variety of metabolic problems that lead to skin and mucosal disorders. Limited evidence suggests that high intake of riboflavin may reduce overall risks of cancer. However, association of this deficiency with cervical cancer and precancerous lesions are still not definitively known. In this study, we characterized the relationship between plasma and tissue riboflavin levels and C20orf54 protein expression in patients with cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (CSCC) as well as the relationship of these levels with human papillomavirus virus 16, 18 (HPV16/18) infections. High-performance liquid chromatography (HPLC) was used to measure blood riboflavin levels in patients with CIN and CSCC, and an enzyme-linked immunosorbent assay (ELISA) was used to determine tissue riboflavin levels in patients with CSCC and matched normal mucous epithelia. The expression of C20orf54 in fresh CSCC and matched tissues were detected by qRT-PCR and western blot, respectively. And it was further confirmed by immunohistochemistry (IHC) with formalin-fixed, paraffin-embedded CIN and CSCC. An HPV genotyping chip was used to analyze HPV infection and typing. The results showed that patients with CIN and CSCC had decreased plasma riboflavin levels as compared with normal controls. There was also significantly decreased riboflavin in tissues from CSCC patients, when compared with normal cervical epithelia. C20orf54 expression were significantly up-regulated in CSCC compared to matched control on both mRNA and protein level. Tissue riboflavin levels were significantly lower in HPV16/18 positive tissue compared with HPV16/18-negative tissue, and an inverse association was found between tissue riboflavin levels and C20orf54 mRNA and protein expression in CSCC. Additionally, C20orf54 was significantly correlated with tumor stages. In conclusion, C20orf54 tend to play a protective role in Uyghur cervical carcinogenesis of which modulating riboflavin absorption, and it is also related with HPV infection.

Highlights

Worldwide, cervical cancer has the second highest incidence of cancer in women
Human papillomavirus (HPV) infection plays a central role in the pathogenesis of cervical cancer and its precancerous lesions (CIN), with HPV infection considered a necessary, but not always sufficient, cause [1,2]
This study demonstrated that samples of recurrent Uyghur cervical squamous cell carcinoma (CSCC) and CIN exhibited significantly higher protein levels of C20orf54 than normal counterpart tissue

Summary

Introduction

Human papillomavirus (HPV) infection plays a central role in the pathogenesis of cervical cancer and its precancerous lesions (CIN), with HPV infection considered a necessary, but not always sufficient, cause [1,2]. Development of human cervical cancer without involvement of a specific HPV is exceptional, but it is widely accepted that in addition to HPV infection, other cofactors may have important roles in the development of cervical lesions [3,4]. HPV infection is usually transient, and only a small proportion of women who test positive for high risk HPV infection develop cervical cancer. HPV infection may be necessary but not sufficient to cause cervical cancer. Nutritional factors may affect the persistence of HPV infection and thereby influence the progression of early precancerous lesions to invasive cancer [5,6]

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