Klotho inhibits the capacity of cell migration and invasion in cervical cancer

Aberrant activation of the Wnt/β-catenin signaling pathway is common inhuman cervical cancers. However, the mechanisms of Wnt activation in cervicalcancer remain largely unknown. In the present study, we demonstrate that Klotho,a Wnt antagonist, is downregulated in invasive human cervical tumors and in acell line we analyzed. Our data demonstrated that in vivo Klotho expression wasnot observed in invasive cervical carcinoma. In vitro restoration of Klotho expressionin SiHa cells resulted in a decreased cell motility and invasiveness through upregulationof E-cadherin, downregulation of N-cadherin and reduced expression of MMP7 and-9. Ectopic expression of Klotho also reduced the expression of the epithelial-to-mesenchymaltransition (EMT) transcription factors Slug and Twist. Furthermore, Klotho causesa significant inhibition of the Wnt/β-catenin pathway in cervical cancer cells,as supported by the expression of Wnt/β-catenin transcriptional target genes suchas c-Myc and cyclin D1. Consequently, our findings demonstrate for the first timethat Klotho regulates tumor invasion through the EMT process and provide novelmechanistic insights into the role of Klotho in cervical cancer progression andcontribute to treatment for metastatic cervical cancer patients.