MAGE-A3: an immunogenic target used in clinical practice

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Date: July 2015
From: Immunotherapy(Vol. 7, Issue 6)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 10,776 words
Lexile Measure: 2090L

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Author(s): Ali Esfandiary aff1 , Soudeh Ghafouri-Fard [*] aff1

Keywords:

cancer-testis antigen; immunotherapy; MAGE-A3

Melanoma antigen family A, 3 (MAGE-A3) belongs to a gene family of more than 60 genes almost all located on X chromosome [1 ]. The first member of this family (MAGE-A1) has been identified in 1991 based on its in vitro recognition by cytolytic T lymphocytes (CTLs) derived from a melanoma patient. Consequently, its expression has been detected in melanoma cell lines as well as some tumor cells of other histological types but not in any normal adult tissue rather than the testis [2 ]. According to the pattern of expression, genes attributed to this family fall into two groups: type I (cancer and testis specific) and type II (ubiquitous) ones with MAGE-A3 belonging to the former [3 ]. All MAGE-A family members have a conserved MAGE homology domain (MHD) with no apparent function attributed to this domain [4 ]. Similar to other cancer-testis antigens (CTAs) its aberrant expression has been shown in a wide variety of cancers. The expression of MAGE-A genes has been shown to be regulated by both hypermethylation and histone deacetylation [5 ]. In addition, it has been shown that Helicobacter pylori , a known carcinogen, can induce its expression in Meth-A sarcoma cells [ 6 ]. The frequent and high expression of MAGE-A3 in a broad array of cancers has endowed it a special position among tumor associated antigens in a way that National Cancer Institute has placed it into the top category of the Project for the Prioritization of Cancer Antigens [7 ].

Function

It has been shown that MAGE-A3 is involved in the process of tumorigenesis by inhibition of apoptosis in tumor cells. The evidences for such involvement have come from at least three independent studies. Firstly, MAGE-A3 has been shown to bind to procaspase-12 to inhibit its activation to caspase-12 and consequently prevent the caspase-12-mediated drug-induced apoptosis [ 8 ]. Secondly, it has been shown that knock-down of MAGE-A3 along with another member of MAGE family results in the induction of apoptosis in the malignant plasma cells and improves the response of these malignant cells to conventional therapies [9 ]. Finally, another independent study has shown that MAGE-A3 is involved in inhibition of apoptosis via suppression of Bax and preservation of survivin [ 10 ]. Collectively, convincing evidences point to the capability of some MAGE-I proteins to control the p53 tumor suppressor and regulate essential pathways associated with cell proliferation [11 ]. Recent studies have proposed MAGE-A3 as a binding partner for really interesting new gene (RING) domain proteins. Such interaction may increase ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. In addition, MAGE-A3 might increase ubiquitin ligase activity of TRIM28 and induce p53/TP53 ubiquitination by TRIM28 [ 12 ]. This tumorigenesis related function for MAGE-A3 makes it an appropriate candidate for molecularly targeted therapies. Consequently, siRNA mediated silencing of this gene has been proposed as an effective treatment modality for MAGE-A3 expressing tumors [13 ].

Expression pattern in normal tissues

MAGE-A3 has...

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Gale Document Number: GALE|A422428327