Astrocyte elevated gene-1: Recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration
Introduction
Cancer arises from a stepwise accumulation of genetic alterations that drive the progressive transformation of normal human cells ultimately culminating in highly malignant derivatives. This multistep process results in alterations in cellular physiology that underlie malignant cell growth, such as self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion from apoptosis, unlimited replicative potential, and aberrant angiogenesis, as well as tissue invasion and metastasis (Fidler and Ellis, 1994, Hahn and Weinberg, 2002). The initiation and progression of solid tumors is in part dependent on a variety of signaling pathways, and also are the processes that allow for invasion and metastasis. Cellular motility and extracellular matrix degradation are 2 major determinants of cancer cell invasion. Invasion through basement membrane from solid tumors to blood vessels and then to the secondary sites involves secretion of chemokines that help in tumor cell motility in a defined direction and proteolytic enzymes involved in extracellular matrix degradation by the host as well as tumor cells (Liotta & Kohn, 2001).
Metastases arise following the spread of cancer cells from a primary site with the formation of new tumors in a distant organ. On the molecular level, the metastatic phenotype is orchestrated by the expression of homing receptors with associated signaling molecules, their ligands, and extracellular matrix-degrading proteases (Kurschat & Mauch, 2000). Metastasis consists of a series of sequential steps that include shedding of cells from a primary tumor into the circulation, survival of the cells in the circulation, arrest in a new organ, extravasations into the surrounding tissue, initiation and maintenance of growth and vascularization of the metastatic tumor (Fig. 1). This process involves coordination of diverse signal-transduction pathways that allow cancer cells to proliferate, remodel their surrounding environment, invade to a distant site and reestablish the tumor. The precise molecular events leading to acquisition of the metastatic phenotype remain largely ambiguous.
We recently reported the cloning and functional characterization of an human immunodeficiency virus (HIV)-inducible gene, astrocyte elevated gene (AEG)-1, which is induced in primary human fetal astrocytes (PHFA) infected with HIV-1 or treated with recombinant HIV-1 envelope glycoprotein (gp120) or tumor necrosis factor-α (TNF-α) (Su et al., 2002, Su et al., 2003a, Kang et al., 2005). AEG-1 is a downstream target molecule of Ha-ras and c-myc mediating their tumor-promoting effects (Lee et al., 2006). Intriguingly, AEG-1 induces increased anchorage-independent growth and invasiveness of tumor cells and increased expression of adhesion molecules by activating the nuclear factor kappa B (NF-κB) pathway and can physically interact with the p65 subunit of NF-κB and modulate its function in the nucleus (Emdad et al., 2006). Moreover, AEG-1 expression is elevated in diverse neoplastic conditions; it cooperates with Ha-ras to promote transformation; and its overexpression augments invasion of transformed cells demonstrating its functional involvement in Ha-ras-mediated tumorigenesis (Kang et al., 2005, Emdad et al., 2006, Lee et al., 2006). This review explores the multiple functions of AEG-1 including effects on oncogenic signaling pathways that are linked to an invasive, metastatic phenotype as well as neurodegeneration associated with brain tumor development and progression and HIV-1 infection.
Section snippets
Cloning of Astrocyte Elevated Gene-1
HIV-1 infection can impact on central nervous system (CNS) functions resulting in neurodegeneration and HIV-1-associated dementia (HAD) (Lipton & Gendelman, 1995). The pathogenic events triggered by HIV-1 in the brain ultimately result in neuronal loss and CNS dysfunction. Neurons are rarely infected with HIV-1 in vivo and most evidence suggests that macrophages and microglial cells are the primary target cells for productive HIV-1 infection in the CNS (Lipton & Gendelman, 1995). Astrocytes
Structure and localization of Astrocyte Elevated Gene-1
The full-length AEG-1 cDNA consists of 3611 bp, excluding the poly-A tail (Kang et al., 2005). The open reading frame (ORF) from 220 to 1968 nts encodes a putative 582-amino acid protein with a calculated molecular mass of 64 kDa with a pI of 9.33. Genomic blast search demonstrated that the AEG-1 gene consists of 12 exons/11 introns and is located at 8q22 where cytogenetic analysis of human gliomas indicated recurrent amplifications. Protein motif analysis, such as SMART, predicted a
Astrocyte Elevated Gene-1 in tumor progression and metastasis
The accumulation of mutations during carcinogenesis results in 6 essential alterations in cell physiology that collectively dictate malignant growth: self sufficiency in cell growth, insensitivity to growth-inhibitory signals, evasion of cell death, limitless replicative proliferation, sustained angiogenesis, and tissue invasion and metastasis (Hanahan & Weinberg, 2000). Most of these alterations affect cell signaling pathways, and the majority of oncogenes are integral components of cellular
Conclusion and future perspectives
An enhanced understanding of the regulators of common signaling pathways involved in tumor progression and metastasis will pave the way for the development of more potent and selective inhibitors of neoplasia. This should be a useful adjunct to conventional therapies, potentially permitting interference with tumor progression at several nodal points in this process. This review highlights recent studies on AEG-1, which strongly support a central role of AEG-1 in tumor progression and metastasis
Acknowledgments
The present studies were supported in part by National Institutes of Health grants P01 NS31492 (DJV, PBF) and R01 CA35675 (PBF), the Samuel Waxman Cancer Research Foundation (PBF), the Chernow Endowment (PBF), a Joelle Syverson Fellowship from the American Brain Tumor Association (LE), and a grant from the Goldhirsh Foundation (DS).
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2021, Advances in Cancer ResearchSignificance of BRCA1 expression in breast and ovarian cancer patients with brain metastasis – A multicentre study
2019, Advances in Medical SciencesCitation Excerpt :In all cases of breast cancer (100%) we detected the expression of BRMS1, a metastases-inhibiting gene protein, but in 96.6% of cases we detected the expression of AEG1. The protein of the gene is responsible for the development of metastases through several mechanisms, including the anchorage of metastatic cells, activity of matrix metalloproteinases as well as function of protein kinase C. Thus, the process of metastatic development is extremely complex [27,32,33]. Brain metastases in the course of ovarian cancer are rare, which has also been confirmed by the European MITO analysis [34].
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2018, Biomedicine and PharmacotherapyCitation Excerpt :The role of AEG-1 in tumorigenesis of gliomas has been widely studied. Emdad et al. reported that AEG-1 is overexpressed in >90% of human malignant glioma tissues and overexpression of AEG-1 promoted the migration and invasion of glioma cells [52]. Moreover, the knockdown of AEG-1 suppressed the cell viability, cloning efficiency and invasive ability of glioma cells associated with inhibiting the expression of matrix metalloproteases 2/9 [31].