MTDH

Official Full Name

metadherin

Organism

Homo sapiens

GeneID

92140

Background

Enables NF-kappaB binding activity; double-stranded RNA binding activity; and transcription coactivator activity. Involved in several processes, including lipopolysaccharide-mediated signaling pathway; positive regulation of intracellular signal transduction; and regulation of DNA-templated transcription. Located in endoplasmic reticulum; nuclear lumen; and perinuclear region of cytoplasm. Implicated in hepatocellular carcinoma. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

3D3; AEG1; AEG-1; LYRIC; LYRIC/3D3;

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Detailed Information

Metaadherin (MTDH), also known as AEG-1, LYRIC or 3D3, is an oncogene discovered in recent years. The MTDH gene plays an important role in tumor progression, including promoting tumor cell proliferation, invasion and metastasis, avoiding apoptosis, and promoting tumor cell resistance to chemotherapeutic drugs. MTDH promotes tumorigenesis by activating NF-κB, PI3K/AKT, MAPK and wnt/β-catenin signaling pathways.

Figure 1. MTDH and its signal pathway. (Emdad, L., et al. 2016)

MTDH Gene and Signaling Pathway

The PI3K/AK T pathway also plays an important role in regulating MTDH expression, and MTDH is a downstream target gene of Ha-ras. Haras induces transcription of MTDH by modulating the PI3K/AKT pathway, which causes the transcription factor c-myc to be ligated into the E-BOX box of the MTDH promoter region. MTDH in turn activates the PI3K/AKT signaling pathway, which in turn can counteract and protect normal cells under certain stress conditions. C-myc can induce MTDH transcription, and MTDH can also induce c-myc expression, which can induce an increase in N-myc expression in neuroblastoma, further enhancing tumorigenic effects. By activating AKT, MTDH down-regulates the pro-apoptotic proteins BAD and p21, and up-regulates MDM2, which disables p53 function and exerts anti-apoptotic effects. Inhibition of MTDH expression in prostate cancer cells can induce apoptosis by down-regulating AKT to upregulate (foxo)3a and p27.

MTDH also activates the MAP kinase pathway, particularly the MEK/ERK and p38 MAPK pathways, and inhibition of either of the above two pathways will inhibit the expression of MTDH, which in turn reduces the invasiveness of liver cancer cells. In prostate cancer cells, MTDH activates the MEK/ERK pathway by activating activator protein-1 (AP-1). In liver cancer cells, MTDH activates ERK42/44, which leads to nuclear translocation of β-catenin and up-regulates lympho-enhancement factor (LEF-1/TCF-1) to activate the wnt/β-catenin signaling pathway.

Progress, Invasion and Metastasis of MTDH Gene and Tumor

MTDH not only promotes the development of neurodegeneration, but also promotes tumor progression and metastasis, including abnormal proliferation, increased adhesion of tumor cells, invasiveness and anti-apoptosis under certain stress conditions. Over-expressed MTDH can increase the proliferative capacity of liver cancer, esophageal cancer, glioblastoma, neuroblastoma and melanocytes. In contrast, knockdown of the MTDH gene not only inhibits the proliferative capacity of prostate cancer, neuroblastoma, melanoma, and glioblastoma cells, but also induces the death of prostate cancer and melanocytes. Overexpression of MTDH increases the ability of clonal formation of immortalized cells and astrocytes. MTDH is overexpressed in many normal human cell lines, protecting cells from apoptosis induced by stress such as serum, indicating that MTDH can be used as an anti-apoptotic protein. MTDH can synergize with Ha-ras gene to promote the transformation of normal immortal melanin cells and human embryonic primary astrocytes, further supporting their tumorigenic function.

Over-expressed MTDH enhances angiogenic ability of umbilical vein endothelial cells. The use of RNAi to inhibit the expression of MTDH blocks vascular endothelial cell growth factor-induced vascularization in umbilical cord endothelial cells. Studies have shown that breast cancer MTDH gene amplification can promote lung metastasis of breast cancer cells and shorten the survival time of mice. The overexpressed MTDH gene promotes the adhesion of breast cancer cells to the endothelium and promotes the metastasis of breast cancer cells to the lungs, while inhibiting the expression of MTDH results in the opposite.

References:

Emdad, L. , Das, S. K. , Hu, B. , Kegelman, T. , Kang, D. C. , & Lee, S. G. , et al. (2016). Chapter four – aeg-1/mtdh/lyric : a promiscuous protein partner critical in cancer, obesity, and cns diseases. Advances in Cancer Research, 131, 97.
Tong, L. , Chu, M. , Yan, B. , Zhao, W. , Liu, S. , & Wei, W. , et al. (2017). Mtdh promotes glioma invasion through regulating mir-130b-cernas. Oncotarget, 8(11).
Zili, C. , Yifei, M. , Yaozhen, P. , Haitao, Z. , Chao, Y. , & Chengyi, S. . (2018). Mir-1297 suppresses pancreatic cancer cell proliferation and metastasis by targeting, mtdh. Molecular and Cellular Probes, S0890850818300264-.

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