Metadherin contributes to the pathogenesis of chronic lymphocytic leukemia partially through Wnt/β-catenin pathway.

Abstract

Metadherin (MTDH) is involved in aberrant proliferation, migration, and chemoresistance of tumor cells. It has been demonstrated that it can promote tumor growth by modulation multiple oncogenic signaling pathways. However, MTDH expression, significance, and related mechanism in chronic lymphocytic leukemia (CLL) are still unclear. The objective of this study was to investigate the expression of MTDH in CLL and the involvement of Wnt/β-catenin signaling pathway in MTDH effects. Overexpression of MTDH mRNAs was seen in CLL samples. MTDH expression was associated with Rai stage classification of CLL, and altered levels of β2-MG and lactate dehydrogenase in serum samples from patients. Overexpression of MTDH protein was seen in 87% of CLL samples. Specific siRNAs inhibited MEC-1 cell growth and enhanced cell apoptosis (P<0.05). Inhibition of MTDH expression resulted in decreased expression levels of lymphoid enhancer-binding factor 1 (LEF-1), and its downstream target genes c-myc and cyclin D1. And there was a strong correlation between MTDH and LEF-1 protein expression in 14 patients with CLL. The results demonstrate that MTDH is specifically expressed in B cell of CLL and exert a preservative role through activation of Wnt signaling pathway. Our findings indicated that MTDH may be a potential therapeutic target of CLL.