A15

Wnt signaling is involved in the normal development and tumorigenesis via epithelial-mesenchymal transition (EMT), initiated by down-regulation of E-cadherin by the transcription factor Snail. Wnt signaling inhibits Snail phosphorylation through Axin2-dependent pathway that sustains nuclear accumulation of Snail by driving GSK3β nucleocytoplasmic export, then consequently increases Snail protein levels and induces an EMT. However, the roles of Wnt and Axin expression and their functional implication on Snail dependent EMT program are not clear during the multistep carcinogenic process. We examined that canonical Wnt signaling engaging multistep carcinogenic process of uterine cervical cancer through Wnt-Axin2-Snail axis. In normal cervical mucosa, Wnt1, Wnt3a, and Axin2 mRNA expression were localized in basal cell layer suggesting that canonical Wnt is required for maintenance of self-renewal program of cervical epithelial cells. With progression to cervical intraepithelial neoplasia (CIN) and carcinoma, Wnt1, Wnt3a, Axin2, and Snail expression were gradually increased in patient samples suggesting that canonical Wnt pathway is involved in early step of carcinogenesis in uterine cervix. LRP6 and Axin2 transfected cells showed the highly increased nuclear Snail resulted from decreased level of nuclear GSK3β, indicating that LRP6-Axin2 serves to stabilize Snail protein levels and sustains its nuclear accumulation by driving GSK3β. RNA interference of Axin2 and Snail on SiHa cells relieved E-cadherin proximal promoter activity and block the in vivo chorioalantoic membrane invasion. These results suggest the canonical Wnt signaling regulating Axin2-GSK3β compartmentalization may important for stabilization of E-cadherin repressor Snail during the multistep carcinogenic process of uterine cervix. It may lead to not only tracing the proper biomarker of cancer progression, but also the development of new targets for therapeutic intervention in cancer.

First AACR Centennial Conference on Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

American Association for Cancer Research
2007