HIV gp120/Tat protein-induced epithelial–mesenchymal transition promotes the progression of cervical lesions

Abstract

Abstract Background Human immunodeficiency virus (HIV) infection is associated with an elevated incidence of cervical cancer, and accelerated disease progression, but the underlying mechanisms are not well understood. This study aimed to investigate the relationship between HIV infection and epithelial–mesenchymal transition (EMT) in cervical cancer. Methods Tissue samples from HIV-positive and negative patients with cervical intraepithelial neoplasia (CIN) and cervical cancer were analyzed for EMT-related proteins. Human cervical cancer SiHa cells were treated with HIV Tat and gp120 proteins to test their effects on EMT, migration, and invasion. Results HIV-positive patients had lower E-cadherin and cytokeratin, and higher N-cadherin and vimentin levels than HIV-negative patients. HIV Tat and gp120 proteins induced EMT, migration, and invasion in SiHa cells. Transcriptome sequencing analysis revealed that, compared to the control group, the protein-treated group showed upregulation of 22 genes and downregulation of 77 genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed the involvement of the Wnt signaling pathway in EMT. Further analysis of gene expression related to this pathway revealed upregulation of DVL1, TCF7, KRT17, and VMAC, while GSK3β, SFRP2, and CDH1 were downregulated. Immunofluorescence assay demonstrated that HIVgp120 and Tat proteins treatment induced elevated β-catenin expression with nuclear accumulation in SiHa cells. Conclusions The treatment of SiHa cells with HIV Tat and gp120 proteins induces EMT and activates the Wnt/β-catenin pathway, suggesting that the Wnt/β-catenin pathway may play a crucial role in promoting EMT progression in cervical lesion tissues of HIV-infected patients.

Keywords

• HIV infection
• gp120 protein
• Tat protein
• Epithelial–mesenchymal transition (EMT)
• Cervical cancer