Switches of SOX17 and SOX2 expression in the development of squamous metaplasia and squamous intraepithelial lesions of the uterine cervix.

Kim A D Wouters,Manon Van Engeland,Jobran M Moshi,Frans C S Ramaekers,Mieke E R Henfling,Anton N H Hopman,Imke Demers,Monique Ummelen,Hans Stoop,Leendert H J Looijenga,Klaas J Hoogduin

doi:10.1002/cam4.3201

Abstract

AimsThe dynamics and topographical distribution of SOX17 and SOX2 expression was studied in the transformation zone (TZ) of the uterine cervix. This TZ is a dynamic area where switches from glandular into squamous epithelium can be recognized, new squamocolumnar junctions are formed, and premalignant lesions originate. SOX17 and SOX2 show mutually exclusive expression patterns in the normal uterine cervix, with SOX2 being exclusively found in squamous epithelium, while SOX17 is detected in endocervical columnar cells and reserve cells.Methods and ResultsNormal cervices and squamous intraepithelial lesions (SIL) were studied with immunohistochemistry, methylation of SOX17, human papilloma virus (HPV) genotyping, and in situ hybridization. In the TZ squamous metaplasia originating from these reserve cells can still show SOX17 expression, while also remnants of SOX17‐positive immature metaplasia can be recognized in the normal squamous epithelium. SOX17 expression is gradually lost during maturation, resulting in the exclusive expression of SOX2 in the majority of (SIL). This loss of SOX17 expression is independent of methylation of the CpG island in its promotor region. HPV can be detected in SOX17‐positive immature metaplastic regions in the immediate vicinity of SOX2‐positive SIL, suggesting that switches in SOX17 and 2 expression can occur upon HPV infection.ConclusionsThis switch in expression, and the strong association between the distribution of reserve cells and squamous areas within the columnar epithelium in the TZ, suggests that reserve cell proliferations, next to basal cells in the squamous epithelium, are potential targets for the formation of squamous lesions upon viral infection.

Highlights

The premalignant lesions of the uterine cervix originate in the transformation zone (TZ), an area where endocervical columnar cells are replaced by squamous epithelium
In contrast to what is seen in the squamous epithelium of the original squamocolumnar junction (SqCJ) (OSqCJ), these regions of immature squamous metaplasia can show a strong immunostaining for SOX17 (Figure 1H), but are generally negative for SOX2 (Figure 1G) or can occasionally show a weak cytoplasmic reactivity for this marker (Figure S1C,D)
The first, well described and accepted pathway suggests that high-grade squamous intraepithelial lesions (HSIL) develops via low-grade squamous intraepithelial lesions (LSIL) and that LSIL originates in the ectocervical epithelium by high risk human papilloma virus infection of the basal cell compartment in the squamous epithelium.[24,41,47,48]

Summary

| INTRODUCTION

The premalignant lesions of the uterine cervix originate in the transformation zone (TZ), an area where endocervical columnar cells are replaced by squamous epithelium These two epithelial tissue types merge at the squamocolumnar junction (SqCJ). We could show an unexpected downregulation of SOX17 in a fraction of AIS lesions, which could be explained by the methylation status of its gene promotor region Triggered by these earlier, more static findings we wanted to study the dynamics of SOX2 and SOX17 expression in the carcinogenesis of the uterine cervix, with a focus on the origin of the very early stages of squamous preneoplasia and the role of the reserve cells in this process. We provide new insights into the involvement of reserve cells and the metaplastic epithelium in the formation of preneoplastic squamous lesions in the TZ of the uterine cervix

| MATERIALS AND METHODS

| RESULTS

| DISCUSSION

Findings

| CONCLUSION

CONFLICT OF INTEREST