Decreased RARβ expression induces abundant inflammation and cervical precancerous lesions

• RARβ deficiency induces cervical squamous metaplasia and inflammatory infiltrate.
• RARβ deficiency leads to histological changes such as moderate dysplasia in the cervical tissue.
• The relationship between RARβ expression and p16ink4a was studied in vivo.
• RARβ is a tumor suppressor which is important in regulation of p16ink4a and cell differentiation.

It is well known that vitamin A and its receptors protect against cancer development and that Retinoid Acid Receptor β (RARβ) is epigenetically silenced during tumoral progression. Cervical Cancer (CC) has been causally linked to high risk human papillomavirus (HR-HPV) infection. However, host factors are important in determining the outcome of persistent HR-HPV infection as most cervical precancerous lesions containing HR-HPVs do not progress to invasive carcinomas. Increasing evidence suggests that low diet in vitamin A and their receptors participate in the development of CC. The aim of this study has been to investigate the effects of abated RARβ expression in the development of cervical premalignant lesions in 4 month-old conditional mice (RARβL−/L−). Results demonstrated the development of spontaneous squamous metaplasia, inflammatory infiltrate, enhanced mitotic activity, loss of cell differentiation, as well as decreased apoptosis and p16INK4a protein levels in RARβL−/L− mice cervix. All these changes are hallmarks of moderate dysplasia. Importantly, our results suggest that the low expression of RARβ, may induce the down regulation of p16INK4a, chronic inflammation and decreased apoptosis and may be involved in vulnerability to HR-HPV and early stage cervical carcinogenesis.