Trp53 and Rb1 in chondrocytes cooperate to constrain chondrosarcoma progression through YAP signaling



Yang Li

Li, Yang, Yang, Shuying
University of Pennsylvania School of Dental Medicine, Department of Basic and Translational Sciences

Introduction

Chondrosarcoma is a rare type of primary bone cartilage malignancies. Due to its poor response to chemotherapy and radiotherapy, surgical resection currently is the primary clinical treatment for chondrosarcoma. However, the therapeutic effect remains unsatisfactory with high local recurrence and low 5-year survival rates. Thus, management of this disease remains an ongoing challenge, and the development of new treatment options is urgently needed.

Methods

Real time PCR, western blot and immunohistochemistry were used to identify the expression and function of Trp53, Rb1 and YAP in both human chondrosarcoma samples and chondrosarcoma mouse model Col2-Cre;Trp53f/f/Rb1f/f. Cell migration and invasion assays were performed by using transwell chambers. Docking calculations were performed using PyMOL and AutoDock. The SPSS19 software was used for statistical analysis.

Results

Here, we found deletion of both Trp53 and Rb1 in chondrocyte lineage can cause chondrasarcoma and lung metastasis, but single deletion of Trp53 or Rb1 in Col2-expressing cells couldn’t cause chondrosarcoma. By performing bioinformatic analysis of human chondrosarcoma database, we found that Trp53 and Rb1 genes have higher mutation in chondrosarcoma compared to normal groups, reaching up to 33.5% and 8.7%, respectively. Chondrosarcoma data in human and mice also suggested Hippo-YAP pathway plays an important role in the chondrosarcoma initiation, development and metastasis progression. Moreover, we found a novel YAP inhibitor metformin, which significantly decreased YAP expression and activation. Additionally, we also found that metformin predictably binds to the activity area of YAP protein (6GE3 from PDB), and inhibits chondrosarcoma cell proliferation, migration and invasion, and lung metastasis.

Conclusion

Loss of Trp53 and Rb1 in chondrocytes causes chondrosarcoma formation through activating YAP signaling.