Crosstalk between Hh and Wnt signaling promotes osteosarcoma progression.

Objective: Osteosarcoma (OS) is the most common primary malignant tumor of bone. Patients with localized osteosarcoma are routinely treated with chemotherapy and surgery. However, many patients eventually relapse after these treatments. Therefore, it is important and urgent to identify better therapeutic strategies. Hedgehog-GLI is responsible for the development of bone and tumorigenesis. Aberrant activation of GLI-2 is correlated with various malignancies including OS.

Methods: RT-QPCR and western blot were performed to detect the expression of GLI-2 among human osteosarcoma cell lines U2OS, SaOS and human osteoblast cells HOB-c. siRNA or overexpression method were used to knock down/overexpress GLI-2 or β-catenin and MTS formazan generation method were applied to study the function of GLI-2 and β-catenin in the proliferation of OS cells.

Results: We showed that GLI-2 is highly expressed in osteosarcoma cell lines. Knockdown of GLI-2 by siRNA decreases osteosarcoma cell proliferation. Further, we showed that knockdown of GLI-2 can decrease the protein level of β-catenin, and β-catenin depletion by siRNA could decrease the proliferation of OS cells. Interestingly, overexpression of β-catenin in GLI-2 knockdown cells partially increased proliferation.

Conclusion: These findings suggest Hh/GLI-2-Wnt/β-catenin crosstalk is required for osteosarcoma cell proliferation. GLI-2 may play a role in the regulation of the expression of β-catenin in OS cells and β-catenin may function as downstream effector of crosstalk between Hh and Wnt signaling. GLI-2 may be exploited as a therapeutic target for the treatment of osteosarcoma patients.