CBP-mediated Wnt3a/?-catenin signaling promotes cervical oncogenesis initiated by Piwil2.
Our previous work demonstrated that Piwil2 reactivated by the human papillomavirus oncoproteins E6 and E7 may reprogram somatic cells into tumor-initiating cells (TICs), which contribute to cervical neoplasia lesions. Maintaining the stemness of TICs is critical for the progression of cervical lesions. Here, we determined that canonical Wnt signaling was ... aberrantly activated in HaCaT cells transfected with lentivirus expressing Piwil2 and in cervical lesion specimens of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, and invasive carcinoma. Blocking the ?-catenin and CREB binding protein interaction with ICG-001 significantly downregulated the reprogramming factors c-Myc, Nanog, Oct4, Sox2, and Klf4, thus leading to cell differentiation and preventing tumorigenicity in Piwil2-overexpressing HaCaT cells. Similarly, Piwil2 also critically regulated the canonical Wnt signaling pathway in cervical cancer. We further demonstrated that ICG-001 increased cisplatin sensitivity and significantly suppressed tumor growth of cervical cancer alone or in combination with cisplatin both in vitro and in vivo. The ?-catenin/ CREB binding protein-mediated transcription activated by Piwil2 is essential for the maintenance of TICs, therefore contributing to the progression of cervical oncogenesis.
Mesh Terms:
Animals, Antineoplastic Agents, Argonaute Proteins, Biomarkers, Tumor, CREB-Binding Protein, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Disease Models, Animal, Disease Susceptibility, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Kruppel-Like Factor 4, Mice, Models, Biological, Neoplastic Stem Cells, Uterine Cervical Neoplasms, Wnt Signaling Pathway, Xenograft Model Antitumor Assays
Animals, Antineoplastic Agents, Argonaute Proteins, Biomarkers, Tumor, CREB-Binding Protein, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Disease Models, Animal, Disease Susceptibility, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Kruppel-Like Factor 4, Mice, Models, Biological, Neoplastic Stem Cells, Uterine Cervical Neoplasms, Wnt Signaling Pathway, Xenograft Model Antitumor Assays
Neoplasia
Date: Dec. 01, 2020
PubMed ID: 33190089
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