Uncoupling Protein 2 and Signal Transducer and Activator of Transcription 1 Are Targets of Human Papillomavirus Oncoproteins and May Be Prognostic Markers for Cervical Cancer Development

Mariana Carmezim Beldi¹Fabiane Cristina Colunna¹Noely Paula Lorenzi¹Jordy Alexander Lasso Larco¹Laura Sichero²Edmund Baracat¹Vanesca de Souza Lino¹Enrique Boccardo¹Giana Mota¹Luisa Lina Villa¹Maricy Tacla¹Márcia Kamilos³Maria Luiza Nogueira Dias Genta²Ana Paula Lepique^1*

• ¹Universidade de Sao Paulo, São Paulo, Brazil
• ²Universidade de Sao Paulo Instituto do Cancer do Estado de Sao Paulo, São Paulo, Brazil
• ³Hospital Heliopolis, São Paulo, Brazil

Cervical cancer, almost always caused by persistent high-risk Human Papillomavirus infection, remains a major public health concern in developing countries. Prognostic markers that aid in managing patients with precursor lesions could enhance healthcare. We compared gene expression between low-and high-grade cervical intraepithelial lesions, focusing on inflammation-and oxidative stress-related genes. Among the differentially expressed genes, we identified STAT1 (Signal Transducer and Activator of Transcription 1) and UCP2 (Uncoupling Protein 2), which we chose for validation because of their known roles in other cancer types. Using immunodetection in monolayer and organotypic cultures, we examined whether HPV oncoproteins could regulate these proteins' expression. We then evaluated their expression through immunohistochemistry in two groups: one with patients having precursor lesions and cancer, and another with only cervical cancer patients. In culture, HaCaT cells transduced with E6/E7 HPV oncogenes altered the expression of both proteins, mainly in organotypic cultures. In patients, UCP2 and STAT1 levels increased with the grade of cervical precursor lesions, and a strong correlation between their expressions was observed. Although very few cancer samples showed nuclear STAT1 expression, an indication of protein activation, these were linked to poor prognosis. Conversely, positive UCP2 expression was associated with better survival and lower recurrence. Our results indicate that HPV oncoproteins influence UCP2 and STAT1 expression, and these proteins could serve as prognostic markers for patients with precursor lesions and, in the case of UCP2, cervical cancer.