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A novel sLRP6E1E2 inhibits canonical Wnt signaling, epithelial-to-mesenchymal transition, and induces mitochondria-dependent apoptosis in lung cancer.

ABSTRACT: Aberrant activation of the Wnt pathway contributes to human cancer progression. Antagonists that interfere with Wnt ligand/receptor interactions can be useful in cancer treatments. In this study, we evaluated the therapeutic potential of a soluble Wnt receptor decoy in cancer gene therapy. We designed a Wnt antagonist sLRP6E1E2, and generated a replication-incompetent adenovirus (Ad), dE1-k35/sLRP6E1E2, and a replication-competent oncolytic Ad, RdB-k35/sLRP6E1E2, both expressing sLRP6E1E2. sLRP6E1E2 prevented Wnt-mediated stabilization of cytoplasmic ?-catenin, decreased Wnt/?-catenin signaling and cell proliferation via the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways. sLRP6E1E2 induced apoptosis, cytochrome c release, and increased cleavage of PARP and caspase-3. sLRP6E1E2 suppressed growth of the human lung tumor xenograft, and reduced motility and invasion of cancer cells. In addition, sLRP6E1E2 upregulated expression of epithelial marker genes, while sLRP6E1E2 downregulated mesenchymal marker genes. Taken together, sLRP6E1E2, by inhibiting interaction between Wnt and its receptor, suppressed Wnt-induced cell proliferation and epithelial-to-mesenchymal transition.

SUBMITTER: Lee JS

PROVIDER: S-EPMC3351461 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A novel sLRP6E1E2 inhibits canonical Wnt signaling, epithelial-to-mesenchymal transition, and induces mitochondria-dependent apoptosis in lung cancer.

Lee Jung-Sun JS Hur Man-Wook MW Lee Seong Kyung SK Choi Won-Il WI Kwon Young-Guen YG Yun Chae-Ok CO

PloS one 20120514 5

Aberrant activation of the Wnt pathway contributes to human cancer progression. Antagonists that interfere with Wnt ligand/receptor interactions can be useful in cancer treatments. In this study, we evaluated the therapeutic potential of a soluble Wnt receptor decoy in cancer gene therapy. We designed a Wnt antagonist sLRP6E1E2, and generated a replication-incompetent adenovirus (Ad), dE1-k35/sLRP6E1E2, and a replication-competent oncolytic Ad, RdB-k35/sLRP6E1E2, both expressing sLRP6E1E2. sLRP6 ...[more]

PMID: 22606268

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Project description:Lung cancer is a malignant tumor responsible for the highest mortality rate in humans. The identification of novel functional genes is of great importance in the treatment of lung cancer. The reported roles of replication factor C subunit 3 (RFC3) in tumorigenesis are contradictory. The present study aimed to explore the role and mechanism of RFC3 in lung cancer cells. An immunohistochemical study of 165 lung cancer and adjacent tissues was conducted (123 lung adenocarcinoma tissues and 42 lung squamous cell carcinoma tissues). Kaplan‑Meier analysis and Cox multivariate analysis were employed to explore the relationship between RFC3 and patient prognosis. In addition, the proliferation, cell cycle distribution and apoptosis of A549 and H1299 cells were determined by MTT assay and flow cytometry, respectively, following cell transfection to induce overexpression and knockdown of RFC3. A Boyden chamber assay and wound‑healing assay were conducted to determine the invasive and migratory abilities of A549 and H1299 cells. Western blotting was used to analyze the effects of RFC3 overexpression and RFC3 small interfering RNA‑induced knockdown, and to explore the potential mechanism and pathway underlying the effects of RFC3. Positive expression of RFC3 was detected in lung adenocarcinoma, and overexpression of RFC3 shortened the survival time of patients with lung adenocarcinoma. Furthermore, overexpression of RFC3 increased the invasion and migration of A549 cells, whereas knockdown of RFC3 significantly reduced the invasion and migration of H1299 cells. Ectopic expression of RFC3 induced epithelial‑mesenchymal transition (EMT), as determined by downregulation of E‑cadherin, and upregulation of N‑cadherin, vimentin and Wnt signaling target genes, including c‑MYC, Wnt1 and β‑catenin, and the ratio of phosphorylated‑glycogen synthase kinase 3 (GSK3)‑β (Ser9)/GSK3‑β. In conclusion, RFC3 may be considered a coactivator that promotes the Wnt/β‑catenin signaling pathway, and induces EMT and metastasis in lung adenocarcinoma.

Dataset Information

A novel sLRP6E1E2 inhibits canonical Wnt signaling, epithelial-to-mesenchymal transition, and induces mitochondria-dependent apoptosis in lung cancer.

Publications

A novel sLRP6E1E2 inhibits canonical Wnt signaling, epithelial-to-mesenchymal transition, and induces mitochondria-dependent apoptosis in lung cancer.

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