Restoration of Wnt-7a Expression Reverses Non-small Cell Lung Cancer Cellular Transformation through Frizzled-9-mediated Growth Inhibition and Promotion of Cell Differentiation

Abstract

The Wnt signaling pathway is critical in normal development, and mutation of specific components is frequently observed in carcinomas of diverse origins. However, the potential involvement of this pathway in lung tumorigenesis has not been established. In this study, analysis of multiple Wnt mRNAs in non-small cell lung cancer (NSCLC) cell lines and primary lung tumors revealed markedly decreased Wnt-7a expression compared with normal short-term bronchial epithelial cell lines and normal uninvolved lung tissue. Wnt-7a transfection in NSCLC cell lines reversed cellular transformation, decreased anchorage-independent growth, and induced epithelial differentiation as demonstrated by soft agar and three-dimensional cell culture assays in a subset of the NSCLC cell lines. The action of Wnt-7a correlated with expression of the specific Wnt receptor Frizzled-9 (Fzd-9), and transfection of Fzd-9 into a Wnt-7a-insensitive NSCLC cell line established Wnt-7a sensitivity. Moreover, Wnt-7a was present in Fzd-9 immunoprecipitates, indicating a direct interaction of Wnt-7a and Fzd-9. In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not ␤-catenin/T cell factor activity. In addition, transfection of gain-of-function JNK strongly inhibited anchorage-independent growth. Thus, this study demonstrates that Wnt-7a and Fzd-9 signaling through activation of the JNK pathway induces cadherin proteins and the receptor tyrosine kinase inhibitor Sprouty-4 and represents a novel tumor suppressor pathway in lung cancer that is required for maintenance of epithelial differentiation and inhibition of transformed cell growth in a subset of human NSCLCs.

Secreted Frizzled-Related Protein 4 Regulates Two Wnt7a Signaling Pathways and Inhibits Proliferation in Endometrial Cancer Cells

“…Although Wnt7a has been recognized as a major ligand in the endometrium, no information is available about its cognate Fzd partners or underlying signaling mechanism in the adult. Wnt7a has been shown to activate both canonical and noncanonical pathways in other cellular environments (33)(34)(35)(36). Therefore, it could be expected that Wnt7a has multiple functions in the endometrium.…”

Stabilization of phenotypic plasticity through mesenchymal-specific DNA hypermethylation in cancer cells

“…Among Wnt pathway-related genes, WNT4A and WNT5A are known to contribute to EMT (Taki et al, 2003). WNT7A has been demonstrated to induce expression of E-cadherin through b-catenin and JNK signaling pathways in lung cancer cell lines (Ohira et al, 2003;Winn et al, 2005). In addition, the epigenetic inactivation of WNT7A and WNT10A was described in pancreatic cancer cell lines and primary tumors and in glioblastoma and astrocytoma cell lines, respectively (Sato et al, 2003;Ordway et al, 2006).…”

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

“…Direct binding of human FZD has been demonstrated for some Wnt proteins, including Wnt3A and Wnt7. A Wnt7A ligand activates the canonical Wnt signaling via FZD5-LRP6 receptor complex in PC12 cells [2] and the Jun-N-terminal kinase (JNK) pathway through FZD9 in non-small cell lung cancer [3]. Wnt7B activates canonical signaling in epithelial and vascular smooth muscle cells through interactions with FZD1 and FZD10 [4].…”