The MTDH gene, which encodes the Metadherin protein, acts as an oncogene and its altered expression has been associated with carcinogenesis of the liver, brain, skin and breast as well as metastasis in the lung and bone. Metadherin is able to carry out its oncogenic action through several pathways. As a transcription coactivator, it modulates the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis and senescence. It thus positively regulates angiogenesis and autophagy while inhibiting apoptosis.
Specific pathways regulated by MTDH include lipopolysaccharide-mediated signaling, protein kinase B signaling and I-kappaB kinase/NF-kappaB signaling. MTDH positively regulates NF-kappaB transcription factor activity and by activating the NF-kappaB signaling pathway, it is believed to play a role in the chronic inflammatory changes seen prior to hepatocellular carcinoma. Metadherin also interacts with PLZF, a protein that regulates the expression of genes involved in cell growth and apoptosis. By reducing PLZF binding to promoters, MTDH is able to reduce PLZF-mediated repression, thus evading apoptosis and increasing cell growth.