Estudo dos componentes do sistema ativina-inibina-folistatina na progressão do carcinoma cervical escamoso

Abstract

Cervical cancer (CC) associated with human papillomavirus (HPV) infection is the fourth most common type of cancer in women. The activin-inhibin-follistatin system regulates several cellular processes including proliferation, differentiation and tumorigenesis. We hypothesized that βA-activin/inhibin subunit and follistatin immunostaining vary in a cell type-dependent manner in pre-neoplastic and neoplastic cervical lesions. Therefore, we evaluated the immunolocalization of the βA- activin/inhibin subunit and follistatin in tissues corresponding to different stages of cervical neoplasia, and associated the resulting immunolabeling data with HPV infection. In this retrospective study, cervical paraffin-embedded tissues from 162 patients sorted in control (n=15), cervical intraepithelial neoplasia (CIN) grade 1 (n=38), CIN2 (n=37), CIN3 (n=39) and Squamous cell carcinoma (SCC; n=33) groups were examined for βA-activin/inhibin subunit and follistatin immunolocalization. A semiquantitative immunoreactive score (IRS) was employed to compare the stained area among groups. HPV detection and genotyping were performed by PCR. Fifty- nine % (n=88) of all cervical specimens were HPV+. The most detected high-risk (HR)- HPV type was HPV16 (54%; n=44) followed by HPV18 (21%; n=17.4). Patient age and HPV16 genotyping were higher in SCC vs Control. βA-activin/inhibin subunit and follistatin were localized in the nucleus and cytoplasm of all sample tissues. Cytoplasmatic IRS of βA-activin/inhibin subunit and follistatin was higher than nuclear IRS in all cervical epithelium layers of CIN1, CIN2, CIN3 and SCC groups. A significant decrease (P<0.05) in cytoplasmic and nuclear IRS of βA-activin/inhibin subunit was detected in all cervical epithelial layers from Control to CIN1, CIN2, CIN3 and SCC groups. Only nuclear follistatin IRS exhibited significant reduction (P<0.05) in specific epithelial layers of cervical tissues from CIN1, CIN2, CIN3 and SCC, in comparison to tissues from Control group. Decreased βA-activin/inhibin subunit and follistatin IRS in cervical epithelium layers at specific stages of CIN progression suggests that the activin-inhibin-follistatin system participates in the loss of differentiation and proliferative control of pre-neoplastic and neoplastic cervical cells. Importantly, this decrease may be related to the persistence of HR-HPV infection during the progression from cervical pre-neoplastic lesions to SCC.