Wnt3a/β-Catenin/CBP Activation in the Progression of Cervical Intraepithelial Neoplasia.

Piwil2 reprograms HPV-infected reserve cells in the cervix into tumor-initiated cells (TICs) and upregulates Wnt3a expression sequentially, which leads to cervical intraepithelial neoplasia (CIN) and ultimately squamous cell carcinoma (SCC). However, little is known regarding Wnt signaling in the maintenance of TIC stemness during the progression of cervical lesions. We herein investigated the expression of canonical Wnt3a signaling and related genes by microarray data set analysis and immunohistochemical (IHC) staining of samples obtained by biopsy of normal cervix, low- and high-grade CIN, and invasive SCC tissue. Array data analyzed by GEO2R showed higher expression levels of Wnt signaling and their target genes, significant upregulation of stemness-associated markers, and notably downregulated cell differentiation markers in CIN and SCC tissues compared with those in the normal cervix tissue. Further, Gene Set Enrichment Analysis (GSEA) revealed that Wnt pathway-related genes significantly enriched in SCC. IHC staining showed gradually increased immunoreactivity score of Wnt3a and CBP and notable translocation of β-catenin from the membrane to the cytoplasm and nucleus during the lesion progression. The intensity and proportion of P16, Ki67 and CK17 staining also increased with the progression of cervical lesions, whereas minimal to negative Involucrin expression was observed in CIN2/3 and SCC. Therefore, canonical Wnt signaling may contribute to the progression of CIN to SCC and may be a potential therapeutic target.

Feng D ，Lin J ，Wang W ，Yan K ，Liang H ，Liang J ，Yu H ，Ling B ... -  《-》

CBP-mediated Wnt3a/β-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 β-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 β-catenin/ CREB binding protein-mediated transcription activated by Piwil2 is essential for the maintenance of TICs, therefore contributing to the progression of cervical oncogenesis.

Feng D ，Yan K ，Liang H ，Liang J ，Wang W ，Yu H ，Zhou Y ，Zhao W ，Dong Z ，Ling B ... -  《NEOPLASIA》

nm23-H1 protein immunoreactivity in intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix.

Lee CS ，Gad J 《PATHOLOGY INTERNATIONAL》

Down-regulation of E-cadherin is closely associated with progression of cervical intraepithelial neoplasia (CIN), but not with high-risk human papillomavirus (HPV) or disease outcome in cervical cancer.

Branca M ，Giorgi C ，Ciotti M ，Santini D ，Di Bonito L ，Costa S ，Benedetto A ，Bonifacio D ，Di Bonito P ，Paba P ，Accardi L ，Mariani L ，Syrjänen S ，Favalli C ，Syrjänen K ，HPV-PathogenISS Study Group ... -  《EUROPEAN JOURNAL OF GYNAECOLOGICAL ONCOLOGY》

Coordinate expression of cytokeratin 8 and cytokeratin 17 immunohistochemical staining in cervical intraepithelial neoplasia and cervical squamous cell carcinoma: an immunohistochemical analysis and review of the literature.

Ikeda K ，Tate G ，Suzuki T ，Mitsuya T ... -  《-》