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

Abstract

Abstract. Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers. However, the mechanisms of Wnt activation in cervical cancer remain largely unknown. In the present study, we demonstrate that Klotho, a Wnt antagonist, is downregulated in invasive human cervical tumors and in a cell line we analyzed. Our data demonstrated that in vivo Klotho expression was not observed in invasive cervical carcinoma. In vitro restoration of Klotho expression in SiHa cells resulted in a decreased cell motility and invasiveness through upregulation of 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-mesenchymal transition (EMT) transcription factors Slug and Twist. Furthermore, Klotho causes a significant inhibition of the Wnt/β-catenin pathway in cervical cancer cells, as supported by the expression of Wnt/β-catenin transcriptional target genes such as c-Myc and cyclin D1. Consequently, our findings demonstrate for the first time that Klotho regulates tumor invasion through the EMT process and provide novel mechanistic insights into the role of Klotho in cervical cancer progression and contribute to treatment for metastatic cervical cancer patients. IntroductionCervical carcinoma is one of the most common cancers and the second-leading cause of cancer deaths in women worldwide (1). Substantial research has been performed to identify the causative agents for development of cervical cancer and now it is generally accepted that human papilloma virus (HPV) is the principal etiological agent of cervical cancer (2). Although the virus infecting these tumors can immortalize human cells, it does not result in transformation. Therefore, HPV infection is likely to be necessary, but insufficient for developing cervical cancers. It might mean there are factors epigenetic, genetic, cellular, and environmental that can influence carcinogenesis (3). Although the precise molecular mechanisms are still unclear, the most possible signaling pathways that is considered as the second hit in the multistep process of cervical carcinogenesis caused by HPV is the Wingless-type (Wnt)/β-catenin pathway (4,5).The Wnt pathway is an important regulator in the control of several biological processes such as proliferation and differentiation in embryogenesis, regulation of the cell cycle, tissue homeostasis in adult tissue and tumor progression (6). Wnt ligands binding to its receptor complex comprised of Frizzled/ low-density lipoprotein receptor-related protein (Fz/LRP) trigger a canonical pathway. In this pathway, β-catenin was stabilized by inhibition of its phosphorylation and subsequent proteosomal degradation. Stabilized β-catenin translocates to the nucleus and forms a complex with T-cell factor/lymphoid enhancer factor (TCF/LEF) to activate target genes (7). In contrast, Wnt inhibition caused by its antagonists leads to decreased accumulation of cytosolic and nuclear β-catenin with consequent downregulatio...

Klotho expression is correlated to molecules associated with epithelial‑mesenchymal transition in lung squamous cell carcinoma

“…Some reports have shown a reduction in the expression of Klotho in invasive breast cancers or cervical cancers, compared with normal lesions (19,20). Moreover, the expression of Klotho has been observed in carcinoma in situ, but not in invasive carcinoma (20,21). As shown in Figs.…”

Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers

“…Several studies have established a strong link between high levels of EMT transcription factors and increased cancer cell metastasis (26,27). SNAI2 is overexpressed in numerous cancers and also promotes invasion in lung adenocarcinoma, glioma, ovarian, cervical, and pancreatic cancers and is a prognostic marker in some cancers (7,28,29). A recent study found overexpression of SNAI2 in aggressive thyroid cancer (30).…”

MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro

“…KL has also been implicated as a tumor-suppressor protein in numerous cancers (Camilli 2010;Chang et al 2012;Chen 2010;Lee 2010;Wang 2011;Wolf 2008) where decreased expression promotes tumorigenesis.…”