Trugilo Kleber Paiva, Cebinelli Guilherme Cesar Martelossi, Castilha Eliza Pizarro, da Silva Mariane Ricciardi, Berti Fernanda Costa Brandão, de Oliveira Karen Brajão
Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
Hospital Israelita Albert Einstein, São Paulo, SP 05652-900, Brazil.
Cytokine Growth Factor Rev. 2024 Dec;80:12-23. doi: 10.1016/j.cytogfr.2024.10.006. Epub 2024 Oct 22.
Human papillomavirus (HPV) is involved in virtually all cases of cervical cancer. However, HPV alone is not sufficient to cause malignant development. The effects of chronic inflammation and the interaction of immune components with the microenvironment infected with the high-risk HPV type (HR) may contribute to cancer development. Transforming growth factor β (TGFB) appears to play an important role in cervical carcinogenesis. Protein and mRNA levels of this cytokine gradually increase as normal tissue develops into malignant tissue and are closely related to the severity of HPV infection. At the onset of infection, TGFB can inhibit the proliferation of infected cells and viral amplification by inhibiting cell growth and downregulating the transcriptional activity of the long control region (LCR) of HPV, thereby reducing the expression of early genes. When infected cells progress to a malignant phenotype, the response to the cell growth inhibitory effect of TGFB1 is lost and the suppression of E6 and E7 expression decreases. Subsequently, TGFB1 expression is upregulated by high levels of E6 and E7 oncoproteins, leading to an increase in TGFB1 in the tumor microenvironment, where this molecule promotes epithelial-to-mesenchymal transition (EMT), cell motility, angiogenesis, and immunosuppression. This interaction between HPV oncoproteins and TGFB1 is an important mechanism promoting the development and progression of cervical cancer.
人乳头瘤病毒（HPV）几乎与所有宫颈癌病例都有关联。然而，仅HPV本身不足以导致恶性发展。慢性炎症的影响以及免疫成分与感染高危型HPV（HR）的微环境之间的相互作用可能有助于癌症的发展。转化生长因子β（TGFB）似乎在宫颈癌发生过程中起重要作用。随着正常组织发展为恶性组织，这种细胞因子的蛋白质和mRNA水平逐渐升高，并且与HPV感染的严重程度密切相关。在感染开始时，TGFB可通过抑制细胞生长和下调HPV长控制区（LCR）的转录活性来抑制受感染细胞的增殖和病毒扩增，从而降低早期基因的表达。当受感染细胞发展为恶性表型时，对TGFB1的细胞生长抑制作用的反应丧失，对E6和E7表达的抑制作用减弱。随后，TGFB1的表达被高水平的E6和E7癌蛋白上调，导致肿瘤微环境中TGFB1增加，在该微环境中该分子促进上皮-间质转化（EMT）、细胞迁移、血管生成和免疫抑制。HPV癌蛋白与TGFB1之间的这种相互作用是促进宫颈癌发展和进展的重要机制。
