Frizzled-8 receptor is activated by the Wnt-2 ligand in non-small cell lung cancer

BMC Cancer

Dawn T Bravo¹  Yi-Lin Yang¹  Kristopher Kuchenbecker¹  Ming-Szu Hung¹  Zhidong Xu¹  David M Jablons¹  Liang You¹ 

[1] Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, 2340 Sutter Street, N-221, San Francisco, CA 94115, USA

关键词: Wnt Signaling;    Lung Cancer;    dnhWnt-2 Construct;    Wnt-2;    Frizzled-8;   

Others  :  1079674
DOI  :  10.1186/1471-2407-13-316

 received in 2013-03-07, accepted in 2013-06-20,  发布年份 2013

【 摘 要 】

Background

Wnt-2 plays an oncogenic role in cancer, but which Frizzled receptor(s) mediates the Wnt-2 signaling pathway in lung cancer remains unclear. We sought to (1) identify and evaluate the activation of Wnt-2 signaling through Frizzled-8 in non-small cell lung cancer, and (2) test whether a novel expression construct dominant negative Wnt-2 (dnhWnt-2) reduces tumor growth in a colony formation assay and in a xenograft mouse model.

Methods

Semi-quantitative RT-PCR was used to identify the expression of Wnt-2 and Frizzled-8 in 50 lung cancer tissues from patients. The TCF reporter assay (TOP/FOP) was used to detect the activation of the Wnt canonical pathway in vitro. A novel dnhWnt-2 construct was designed and used to inhibit activation of Wnt-2 signaling through Frizzled-8 in 293T, 293, A549 and A427 cells and in a xenograft mouse model. Statistical comparisons were made using Student’s t-test.

Results

Among the 50 lung cancer samples, we identified a 91% correlation between the transcriptional increase of Wnt-2 and Frizzled-8 (p<0.05). The Wnt canonical pathway was activated when both Wnt-2 and Frizzled-8 were co-expressed in 293T, 293, A549 and A427 cells. The dnhWnt-2 construct we used inhibited the activation of Wnt-2 signaling in 293T, 293, A549 and A427 cells, and reduced the colony formation of NSCLC cells when β-catenin was present (p<0.05). Inhibition of Wnt-2 activation by the dnhWnt-2 construct further reduced the size and mass of tumors in the xenograft mouse model (p<0.05). The inhibition also decreased the expression of target genes of Wnt signaling in these tumors.

Conclusions

We demonstrated an activation of Wnt-2 signaling via the Frizzled-8 receptor in NSCLC cells. A novel dnhWnt-2 construct significantly inhibits Wnt-2 signaling, reduces colony formation of NSCLC cells in vitro and tumor growth in a xenograft mouse model. The dnhWnt-2 construct may provide a new therapeutic avenue for targeting the Wnt pathway in lung cancer.

【 授权许可】

   
2013 Bravo et al.; licensee BioMed Central Ltd.

【 图 表 】

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