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

Abstract

Aims The 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 Results Normal 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. Conclusions This 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.

Squamous Metaplasia of the Stomach Associated with Lymphoma Infiltration

“…In contrast to the infrequent observations of squamous Intern Med Advance Publication DOI: 10.2169/internalmedicine.6271-20 metaplasia in the stomach, transition of the epithelium to squamous cells is more commonly seen in the uterine cervix, bladder, and airways (5). Such squamous metaplasia is considered to develop as a consequence of mechanical irritation and/or chronic inflammation.…”

Co-expression of SOX2 and HR-HPV RISH predicts poor prognosis in small cell neuroendocrine carcinoma of the uterine cervix

“…Recent studies have shown that SOX2 was related to HPV infection. Interestingly, HPV infection drives switches in SOX2 expression in the transformation zone in the uterine cervix [ 15 ], and SOX2 locus amplification was related with HPV mRNA positivity in vulvar carcinoma [ 14 ]. Furthermore, SOX2 was reported to be regulator of HPV16 at the transcriptional level in cervical squamous cell carcinoma [ 42 ].…”

“…The small infiltrating cancer nests surrounding CIN 3 margins or the CIN 3-like SCC with deep invasion generally display a decreased SOX2 level locally, and this indicates reduced SOX2 expression during invasive growth [ 13 ]. SOX2 has been reported to be related to HPV infection in previous studies [ 14 , 15 ]. However, its expression, clinical significance and the association between SOX2 and HPV status in SCNEC have not been evaluated.…”

SOX2 as a prognostic marker and a potential molecular target in cervical cancer: A meta-analysis

“…Based on the inclusion criteria, 17 articles with 1906 participants (1172 cervical cancer patients and 734 control samples) were published between 2010 and 2020. 8,[11][12][13][14][15][20][21][22][23][24][25][26][27][28][29][30] These studies were conducted in China (n = 13), Korea (n = 1), Australia (n = 2), and The Netherlands (n = 1). Of these studies, seven studies evaluated the difference of SOX2 expression between cancer and CIN.…”

“…7 Recently, some studies have reported the association between SOX2 expression and cervical cancer. [11][12][13] However, the clinical and prognostic significance of SOX2 in cervical cancer remains largely unknown.…”