AEG-1/MTDH/LYRIC: clinical significance

Abstract

"Gain-of-function" and "loss-of-function" studies in human cancer cells and analysis of a transgenic mouse model have convincingly established that AEG-1/MTDH/LYRIC performs a seminal role in regulating proliferation, invasion, angiogenesis, metastasis, and chemoresistance, the salient defining hallmarks of cancer. These observations are strongly buttressed by clinicopathologic correlations of AEG-1/MTDH/LYRIC expression in a diverse array of cancers distinguishing AEG-1/MTDH/LYRIC as an independent biomarker for highly aggressive metastatic disease with poor prognosis. AEG-1/MTDH/LYRIC has been shown to be a marker predicting response to chemotherapy, and serum anti-AEG-1/MTDH/LYRIC antibody titer also serves as a predictor of advanced stages of aggressive cancer. However, inconsistent findings have been reported regarding the localization of AEG-1/MTDH/LYRIC protein in the nucleus or cytoplasm of cancer cells and the utility of nuclear or cytoplasmic AEG-1/MTDH/LYRIC to predict the course and prognosis of disease. This chapter provides a comprehensive analysis of the existing literature to emphasize the common and conflicting findings relative to the clinical significance of AEG-1/MTDH/LYRIC in cancer.

Keywords: AEG-1/MTDH/LYRIC; Cancer; Clinicopathological correlation; Metastasis; Prognosis.

Figure 2.1

Molecular mechanism of AEG-1/MTDH/LYRIC overexpression in cancer. Genomic amplification (8q22 gain) leading to increased AEG-1/MTDH/LYRIC expression has been documented in breast and liver cancers. Activation of Ha-ras results in activation of PI3K/Akt and subsequent binding of c-Myc to AEG-1/MTDH/LYRIC promoter increasing transcription. Monoubiquitination of AEG-1/MTDH/LYRIC protein in cancer cells leads to increased stabilization and cytoplasmic accumulation. AEG-1/MTDH/LYRIC mRNA is posttranscriptionally regulated by several tumor suppressor mRNAs, such as miR-375, miR-136, and miR-26a, which are downregulated in multiple cancers. Cytoplasmic polyadenylation element-binding protein 1 (CEBP1) binds to the 3′-UTR of AEG-1/MTDH/LYRIC mRNA and promotes its translation in glioma cells.