Pleiotropic roles of AEG-1/MTDH/LYRIC in breast cancer
ABSTRACT Since the initial discovery of AEG-1/MTDH/LYRIC, our appreciation for this novel protein's involvement in cancer has increased dramatically over the past few years. AEG-1/MTDH/LYRIC is a key functional target of the 8q22 genomic gain that is frequently observed in poor-prognosis breast cancer, where it plays a dual role in promoting chemoresistance and metastasis. Beyond this, growing evidence from clinical research indicates a strong correlation between AEG-1/MTDH/LYRIC expression and the pathogenesis of a large spectrum of cancer types, and multiple studies employing in vitro cell culture systems and in vivo xenograft models have revealed multifaceted roles of AEG-1/MTDH/LYRIC in cancer biology, including tumor cell proliferation, apoptosis, angiogenesis, and autophagy. With increasing mechanistic understanding of AEG-1/MTDH/LYRIC, discovery of agents that can block AEG-1/MTDH/LYRIC and its regulated pathways will be beneficial to cancer patients with aberrant expression of AEG-1/MTDH/LYRIC.
- SourceAvailable from: Vitali Stanevich
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- "INTRODUCTION MTDH, also known as metadherin, is overexpressed in a large spectrum of cancer types, and its elevated levels are associated with poor prognosis in cancer patients (Sarkar and Fisher, 2013; Wan and Kang, 2013). Functionally, MTDH has been implicated in several cancer-related processes, including proliferation, cell death, invasion, and angiogenesis, and has been linked to multiple oncogenic pathways such as PI3K/AKT, Wnt/b-catenin, and NF-kB (Emdad et al., 2013; Wan and Kang, 2013). "
ABSTRACT: Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here, we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1's roles in breast cancer and for SND1 stability under stress. Our study reveals a unique mode of interaction with SN domains that dictates cancer-promoting activity and provides a structural basis for mechanistic understanding of MTDH-SND1-mediated signaling and for exploring therapeutic targeting of this complex.Cell Reports 09/2014; 8(6). DOI:10.1016/j.celrep.2014.08.033 · 7.21 Impact Factor
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ABSTRACT: Alb/MTDH: A transgenic mouse with hepatocyte-specific expression of AEG-1 by directing the expression of human AEG-1 under an upstream enhancer region fused to the 335-base-pair core region of mouse albumin promoter.
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ABSTRACT: Astrocyte elevated gene-1 (AEG-1) is involved in important biological processes including cell invasion, metastasis, and carcinogenesis. However, its clinical significance has remained largely unknown in hepatocellular carcinoma. Here, specimens from 144 patients with hepatocellular carcinomas in Beijing and Heilongjiang regions were investigated by immunohistochemical staining for AEG-1, vimentin, and E-cadherin expressions. A clinicopathological study revealed that AEG-1 expression level in tumor cells was significantly correlated with TNM stage (P = 0.001) and Edmonson grade (P < 0.0001). In addition, AEG-1, vimentin, and E-cadherin (epithelial-mesenchymal transition (EMT) biomarker) expressions were correlated with each other. These findings suggest that AEG-1 may be an epithelial-mesenchymal transition-associated biomarker in human hepatocellular carcinoma and play important roles in the progression of hepatocellular carcinoma. In addition, the AEG-1 gene is a potential target for elimination of hepatocellular carcinoma in the future.Tumor Biology 10/2013; 35(3). DOI:10.1007/s13277-013-1300-3 · 3.61 Impact Factor