MLLT3 promotes proliferation of osteosarcoma cells by regulating JNK signaling.

Osteosarcoma was the most common malignant tumor derived from bone/soft tissues and afflicted mainly the adolescents. Surgical removing assisted with chemotherapy/radiotherapy was the major therapeutics regardless of high mortality. MLLT3 was one of the most common partners fused with mixed lineage leukemia gene and caused leukemia. But its role in osteosarcoma was not previously reported. In this study, we found that MLLT3 was expressed abundantly in osteosarcoma tissues and cell lines including U-2OS, MG-63, Saos-2 and HOS. And by Kaplan-Meier analysis, MLLT3 expression was shown to be clinically correlated with survival of osteosarcoma patients. The 5-year survival rate was 64.3% for patients with low MLLT3 expression (n=14) while it was 36.4% for patients with high MLLT3 expression (n=11). The difference was significant (p=0.026). When MLLT3 was knocked-down, the proliferation ability decreased about 38% in HOS cells and 46% in MG-63 cells. But the migration as well as the invasive ability was not affected. In addition, the expression level of β-catenin was comparable in HOS cells with/without knockdown of MLLT3. The specific inhibitor LGK-974 against Wnt/β-catenin signaling showed little additive effect with MLLT3 knockdown on growth ability of HOS cells. But the level of c-Jun, BCL-2, Akt and c-Myc was significantly decreased in HOS cells with MLLT3 knockdown, which indicated that MLLT3 may at least partially regulate JNK signaling in HOS cells. In conclusion, we proved MLLT3 as an oncogene in osteosarcoma through partially regulating the JNK signaling pathway. And MLLT3 may be a promising target for treatment of patients with osteosarcoma.