MAGE-A inhibit apoptosis and promote proliferation in multiple myeloma through regulation of BIM and p21Cip1

Mei, Anna; Tung, Kaity; Han, Jessie; Perumal, Deepak; Laganà, Alessandro; Auclair, Daniel; Chari, Ajai; Jagannath, Sundar; Parekh, Samir; Cho, Hearn Jay

doi:10.18632/oncotarget.27488

Cited by 13 publications

(9 citation statements)

References 42 publications

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“…Further, MAGE-A2 can form a complex with estrogen receptor (ER)-α, either directly or via ER cofactors, and enhance its transcriptional activity [77]. MAGE-A-mediated suppression of p53 can suppress the expression of pro-apoptotic proteins such as BIM and p21 Cip1 in multiple myeloma [97]. Interestingly, MAGE-A3 can interact with long noncoding RNA (LINC01234) and microRNA (microRNA-31-5p) to facilitate proliferation and chemoresistance in hepatocellular carcinoma [98].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Melanoma-Associated Antigen-A (MAGE-A) Gene Expression in Various Human Cancers: A Systematic Review and Meta-analysis of 7428 Patients and 44 Studies

2020

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Background Members of the melanoma-associated antigen-A (MAGE-A) subfamily are overexpressed in many cancers and can drive cancer progression, metastasis, and therapeutic recurrence. Objective This study is the first comprehensive meta-analysis evaluating the prognostic utility of MAGE-A members in different cancers. Methods A systematic literature search was conducted in PubMed, Google Scholar, Science Direct, and Web of Science. The pooled hazard ratios with 95% confidence intervals were estimated to evaluate the prognostic significance of MAGE-A expression in various cancers. Results In total, 44 eligible studies consisting of 7428 patients from 11 countries were analysed. Univariate and multivariate analysis for overall survival, progression-free survival, and disease-free survival showed a significant association between high MAGE-A expression and various cancers (P < 0.00001). Additionally, subgroup analysis demonstrated that high MAGE-A expression was significantly associated with poor prognosis for lung, gastrointestinal, breast, and ovarian cancer in both univariate and multivariate analysis for overall survival. Conclusion Overexpression of MAGE-A subfamily members is linked to poor prognosis in multiple cancers. Therefore, it could serve as a potential prognostic marker of poor prognosis in cancers.

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Section: Discussionmentioning

confidence: 99%

Prognostic Value of Melanoma-Associated Antigen-A (MAGE-A) Gene Expression in Various Human Cancers: A Systematic Review and Meta-analysis of 7428 Patients and 44 Studies

2020

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“…We for the first time demonstrate that C19MC miRNA-520G promotes the expression of MAGEA-3, 6 and 12 in p53-defective cells and that C19MC miRNAs are overexpressed in p53 transcriptionally incompetent HCC tumors. Defects in p53 transcription can result in impaired apoptosis and enhanced cellular transformation 36 , 37 and MAGEAs are known to inhibit p53 and p21 (a p53 transcriptional target) -induced apoptosis 38 . Although p53 is known to have defects in Hep3B cells, the exact nature of p53 defect in Hep3B cells was not known.…”

Section: Discussionmentioning

confidence: 99%

Mutant p53s and chromosome 19 microRNA cluster overexpression regulate cancer testis antigen expression and cellular transformation in hepatocellular carcinoma

Jinesh

Napoli

Smallin

et al. 2021

Sci Rep

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A subset of hepatocellular carcinoma (HCC) overexpresses the chromosome 19 miRNA cluster (C19MC) and is associated with an undifferentiated phenotype marked by overexpression of cancer testis antigens (CTAs) including anti-apoptotic melanoma-A antigens (MAGEAs). However, the regulation of C19MC miRNA and MAGEA expression in HCCs are not understood. Here we show that, C19MC overexpression is tightly linked to a sub-set of HCCs with transcription-incompetent p53. Using next-generation and Sanger sequencing we found that, p53 in Hep3B cells is impaired by TP53-FXR2 fusion, and that overexpression of the C19MC miRNA-520G in Hep3B cells promotes the expression of MAGEA-3, 6 and 12 mRNAs. Furthermore, overexpression of p53-R175H and p53-R273H mutants promote miR-520G and MAGEA RNA expression and cellular transformation. Moreover, IFN-γ co-operates with miR-520G to promote MAGEA expression. On the other hand, metals such as nickel and zinc promote miR-526B but not miR-520G, to result in the suppression of MAGEA mRNA expression, and evoke cell death through mitochondrial membrane depolarization. Therefore our study demonstrates that a MAGEA-promoting network involving miR-520G, p53-defects and IFN-γ that govern cellular transformation and cell survival pathways, but MAGEA expression and survival are counteracted by nickel and zinc combination.

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“…In contrast, inhibitory effect of MAGEs on apoptosis has also been reported: MAGEA3 was shown to promote proliferation while suppressing apoptosis of cervical cancer cells [ 22 ]. Similarly, it was shown that MAGEA3 suppresses apoptosis of multiple myeloma cells [ 23 ], and MAGE-C suppresses apoptosis of melanoma and colon cancer cell lines [ 24 ]. These reports collectively indicate that each member of MAGEs may play a different role in apoptosis.…”

Section: Discussionmentioning

confidence: 99%

MAGEH1 interacts with GADD45G and induces renal tubular cell apoptosis

2021

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Background Melanoma-associated antigen H1 (MAGEH1) is a protein that belongs to melanoma-associated antigen (MAGE) superfamily. Growth arrest and DNA damage 45G (GADD45G) is a member of the DNA damage-inducible gene family which responds to environmental stresses. We have previously shown that GADD45G is a protein that promotes apoptosis of renal tubular cells in response to a nephrotoxic injury. In this study, we show evidence that MAGEH1 interacts with GADD45G and is involved in the induction of nephrotoxin-induced apoptosis of renal tubular cells. Methods Primary human renal tubular epithelial (HRE) cells and human kidney 2 (HK-2) cells were used in this study. To produce stable cell lines in which MAGEH1 expression was silenced, HRE cells were transduced with a lentiviral vector encoding a single guide RNA construct targeting the MAGEH1 gene. To knockdown GADD45G expression in HRE cells, a vector containing short hairpin RNA (shRNA) was used. We used short interfering RNAs (siRNA) to achieve transient silencing of genes in HK-2 cells. Recombinant adenoviruses were synthesized to overexpress MAGEH1 and GADD45G proteins. Human protein microarray was used to identify proteins that binds to GADD45G. Co-immunoprecipitation assays were then performed to confirm microarray results. Cell death was induced by cyclosporine A (CsA). Real-time quantitative PCR assay was used to evaluate gene expression levels. The degree of apoptosis and necrosis of cultured cells was evaluated by flow cytometry. Expression levels of caspases were examined using western blot analysis. Results We found that GADD45G bound to one protein spotted in the protein microarray, which was subsequently identified as MAGEH1. We confirmed the interaction between GADD45G and MAGEH1 protein using the co-immunoprecipitation assay. MAGEH1 gene expression was not altered by CsA-induced cytotoxic injury, whereas GADD45G gene expression was increased significantly upon CsA treatment. MAGEH1 expression was significantly downregulated in GADD45G knockdown HRE stable cells suggesting that MAGEH1 expression may be dependent on GADD45G expression. CsA-induced apoptosis was significantly reduced in MAGEH1 knockdown HRE stable cells which led to an increased survival of these cells. Similar results were observed in GADD45G knockdown HRE stable cells. Accordingly, CsA-induced apoptosis was significantly decreased in MAGEH1 siRNA and GADD45G siRNA transfected HK-2 cells. CsA-induced activation of caspase-7 and caspase-9 was inhibited in MAGEH1 knockdown HRE stable cells, and similarly in GADD45G knockdown HRE stable cells. Conclusions To the best of our knowledge, this is the first study to show that MAGEH1 interacts with GADD45G and that MAGEH1 is involved in caspase-dependent apoptosis of renal tubular cells induced by nephrotoxic drugs.

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MAGE-A inhibit apoptosis and promote proliferation in multiple myeloma through regulation of BIM and p21Cip1

Cited by 13 publications

References 42 publications

Prognostic Value of Melanoma-Associated Antigen-A (MAGE-A) Gene Expression in Various Human Cancers: A Systematic Review and Meta-analysis of 7428 Patients and 44 Studies

Prognostic Value of Melanoma-Associated Antigen-A (MAGE-A) Gene Expression in Various Human Cancers: A Systematic Review and Meta-analysis of 7428 Patients and 44 Studies

Mutant p53s and chromosome 19 microRNA cluster overexpression regulate cancer testis antigen expression and cellular transformation in hepatocellular carcinoma

MAGEH1 interacts with GADD45G and induces renal tubular cell apoptosis

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