Runx2-smad signaling impacts the progression of tumor-induced bone disease
| Autor: | Gary S. Stein, John J. Wixted, Jane B. Lian, Gillian Browne, Janet L. Stein, Xuhui Zhang, Stacey Russell, Jacqueline Akech |
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| Rok vydání: | 2014 |
| Předmět: |
musculoskeletal diseases
Cancer Research Pathology medicine.medical_specialty Bone disease biology business.industry musculoskeletal neural and ocular physiology Cancer SMAD musculoskeletal system medicine.disease Metastasis Prostate cancer medicine.anatomical_structure stomatognathic system Oncology Prostate embryonic structures medicine biology.protein Osteopontin Signal transduction business |
| Zdroj: | International Journal of Cancer. 136:1321-1332 |
| ISSN: | 0020-7136 |
| DOI: | 10.1002/ijc.29094 |
| Popis: | Runx2, a master regulator of osteogenesis, is abnormally expressed in advanced prostate cancer. Here we addressed Runx2 contribution to formation of prostate cancer-related osteolytic and osteoblastic bone lesions by mediating TGFβ/BMP signaling through direct interaction with Smads. Further, we examined involvement of the Runx2-Smad complex in mediating tumor growth and distal metastasis. To identify Runx2-Smad specific mechanisms of prostate tumor activity in bone, we generated PC3 prostate cancer cell lines expressing Runx2-WT or one of two mutant proteins (Runx2-HTY and Runx2-ΔC) that each disrupt the Runx2-Smad interaction, either directly through a point mutation or by deletion of the functional C-terminus, respectively. Intratibial tumors generated from these cells revealed that Runx2-WT expressing cells resulted in predominantly osteolytic disease, while cells expressing mutant proteins exhibited tumors with mixed osteolytic/osteoblastic lesions. Extent of bone loss and of woven bone formation was assessed by radiography and micro-computed tomography. Bioluminescent imaging showed the presence of labeled prostate cancer cells in the lung at the latest time point examined, with Runx2-WT group exhibiting increased incidence of tumor cells in lung. Notably, disruption of the Runx2-Smad interaction significantly reduced incidence and size of lung tumors. Altered expression of Runx2 target genes involved in invasion, growth, adhesion and metastasis supported our findings. Thus, our studies demonstrate that Runx2 in prostate cancer cells plays a significant role in intratibial prostate cancer-related tumor growth and bone loss through mechanisms mediated by the Runx2-Smad signaling pathway. This work expands upon the potential importance of Runx2 as a therapeutic target in cancer. |
| Databáze: | OpenAIRE |
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