Expert Review of Anticancer Therapy
ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20
ADAR1: a promising new biomarker for esophageal squamous cell carcinoma? Jun-Jing Qiao, Tim Hon Man Chan, Yan-Ru Qin & Leilei Chen To cite this article: Jun-Jing Qiao, Tim Hon Man Chan, Yan-Ru Qin & Leilei Chen (2014) ADAR1: a promising new biomarker for esophageal squamous cell carcinoma?, Expert Review of Anticancer Therapy, 14:8, 865-868 To link to this article: http://dx.doi.org/10.1586/14737140.2014.928595
Published online: 13 Jun 2014.
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Date: 06 November 2015, At: 03:51
Editorial
ADAR1: a promising new biomarker for esophageal squamous cell carcinoma? Expert Rev. Anticancer Ther. 14(8), 865–868 (2014)
Downloaded by [70.91.158.137] at 03:51 06 November 2015
Jun-Jing Qiao Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China and Cancer Science Institute of Singapore, National University of Singapore, Singapore
Tim Hon Man Chan Cancer Science Institute of Singapore, National University of Singapore, Singapore
Yan-Ru Qin Author for correspondence: Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China Tel.: +86 371 6629 5542 [email protected]
Leilei Chen Author for correspondence: Cancer Science Institute of Singapore, National University of Singapore, Singapore and Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Tel.: +65 6516 8435 Fax: +65 6516 1873 [email protected]
Esophageal Squamous Cell Carcinoma (ESCC) is a heterogeneous tumor with enormous genetic and epigenetic changes. RNA editing is an epigenetic mechanism that serves as an additional layer of ‘RNA mutations’ in parallel to DNA mutations. The most frequent type of RNA editing, A-to-I (adenosine-to-inosine) editing catalyzed by Adenosine DeAminase that act on RNA (ADARs), modulates RNA transcripts with profound impact on cellular functions. RNA editing dysregulation has been found to be associated with cancers. Our recent study demonstrated that among all the three RNA editing enzymes, only ADAR1 was overexpressed in primary ESCCs compared with matched non-tumor specimens. In this review, we will discuss current views on the involvement of abnormal A-to-I editing in cancer development, more specifically on the ADAR1-mediated editing in ESCC. Although much is not yet learned about the role of ADAR1 in ESCC, ADAR1 may present an attractive option as a new biomarker for ESCC and as a new molecular therapeutic target.
Esophageal squamous cell carcinoma (ESCC), accounting for more than 90% of all esophageal cancer, is the leading cause of cancer death worldwide and is associated with a poor prognosis [1,2]. Recent advances have proved largely ineffective in treatment, thus studying the molecular pathogenesis of ESCC is the current trend that might potentially lead to the identification of biological markers for early diagnosis and targeted therapies. Up to now, most cancer scientists have focused on studying DNA mutations that convey irreversible changes in the genome. However, discoveries in last decade completely changed our views on RNA and the enormous diversity that can be generated at the RNA level. RNA editing may lead to tumor-specific ‘RNA mutation’, exceeding the number of genomic mutations. In humans, the most frequent type of editing is the conversion of adenosine to inosine (A-to-I), which is catalyzed by the dsRNA-specific Adenosine DeAminase that act on RNA (ADAR) family of protein [3]. The imbalance of ADARs expression/activity is found to be associated with a variety of human diseases, such as amyotrophic
lateral sclerosis [4], systemic lupus erythematosus [5,6], neurological disorders [7,8] and cancer [9]. Recently, we have provided the first analyses of expression profiles of ADARs in human ESCC and demonstrated that among all three RNA editing enzymes ADAR1, ADAR2 and ADAR3 [10], only ADAR1 was significantly overexpressed in ESCC tumors, which has great prognostic value and diagnostic potential for ESCC; ADAR1 functions as an oncogene in the development of ESCC; the tight link between the differential expression of ADAR1 and an altered gene-specific editing pattern was investigated to illustrate how the A-to-I RNA editing balance is deregulated in ESCC; and a new functional recurrent RNA editing event, resulting in an amino acid substitution of the AZIN1 gene (antizyme inhibitor 1), was specifically regulated by ADAR1 and found to confer more aggressive tumorigenic behaviors [11]. In this article, we discuss recent studies connecting the differentially expressed ADAR genes with RNA editing alteration in human cancers, with a specific focus on ADAR1mediated RNA editing in carcinogenesis.
KEYWORDS: ADAR1 • biomarker • esophageal squamous cell carcinoma • RNA editing
informahealthcare.com
10.1586/14737140.2014.928595
2014 Informa UK Ltd
ISSN 1473-7140
865
Editorial
Qiao, Chan, Qin & Chen
Downloaded by [70.91.158.137] at 03:51 06 November 2015
ADAR1 expression & localization
The developmental and cell type-specific modulation of A-to-I RNA editing is tightly linked to ADAR expression and localization. ADAR1 and ADAR2, ubiquitously expressed in many tissues, catalyze all currently known A-to-I editing sites. In contrast, the brain-specifically expressed ADAR3 protein has no documented deaminase activity. ADAR1 protein is the largest of the three family members and its transcripts generate two major ADAR1 isoforms, a full-length interferon-inducible ADAR1 p150 and a shorter and constitutive N-terminally truncated ADAR1 p110. It has been recently reported that both ADAR1 p150 and ADAR1 p110 shuttle between the nucleus and cytoplasm [12]. The nuclear ADAR1 p110 is considered to catalyze A-to-I editing of double-stranded primary RNA transcripts mainly in the nucleus. ADAR1 p150 is detected mainly in the cytoplasma, possibly targeting a different class of dsRNA substrates, such as endoribonuclease-prepared siRNAs [13] and viral RNAs [3,14]. It has been reported that interferons induce the upregulation of ADAR1 [15], therefore raising the possibility that ADAR1 serves as an antiviral defense mechanism against viral infection and inflammation. The expression of ADAR1 is also downregulated by miRNA-1 (miR-1) [16,17], and the tight regulation of ADAR1 by miR-1 is likely to be critical for heart development [18,19]. In ESCC, we found that ADAR1 gene, which is mapped to chromosome 1q21, was amplified in approximately 70% of ESCC tumors using fluorescent in situ hybridization, and there was a positive correlation between overexpression of ADAR1 and the genomic amplification of ADAR1 gene in ESCC specimens [11], suggesting another mechanism of ADAR1 overexpression in tumors. ADAR1-regulated RNA editing in cancer
The imbalance in expression of ADARs enzymes is highly correlated with cancer development and progression [9,20]. Despite the fact that more than 85% of RNAs are found to be edited in noncoding and/or coding sequences [21], the edited mammalian transcripts have been only well studied in central nervous system and include transcripts encoding the subunits GluR-B, GluR-C, and GluR-D of the a-amino-3-hydroxy-5-methyl4-isoxazolepropionate receptor, the subunits GluR-6 and GluR-5 of the kainite receptor, and the serotonin receptor (5-HT2C) [21,22]. However, investigating link between the altered RNA editing activity and cancer progression is only the initial step. In brain tumors, all of three editing enzymes were found to be downregulated in brain tumors [23], and ADAR1 was frequently reduced in metastatic melanomas [16]. As a common editing target by ADAR1 and ADAR2, the decreased editing frequency of glioma-associated oncogene 1 was observed in basal cell carcinoma tumor samples when compared to normal skin, and RNA editing of glioma-associated oncogene 1 transcription factor are involved in Hedgehog signaling [24]. In contrast, ADAR1 was found to be upregulated in tumor tissues, such as hepatocellular carcinoma (HCC) [25], ESCC [11] and breast cancer [26]. It has been reported that homodimer formation may be necessary for ADAR1 and ADAR2 to act as 866
active deaminases [27]. In pediatric glioblastoma multiforme, the overexpression of ADAR1 p110 may cause the formation of an inactive ADAR1/ADAR2 heterodimer or the sequestration of ADAR2 from editing substrates, leading to the altered ADAR2 editing activity and the subsequent decreased editing frequencies [28]. In prostate cancer (CaP), high expression of both enzymes ADAR1 and ADAR2 in androgen-independent CaP cells (DU145 and PC3) resulted in the higher number of RNA editing mutation when compared with androgen-dependent CaP cells (LNCaP and 22Rv1) [29]. Due to the interferonresponsive ADAR1 activity, ADAR1 p150 was upregulated in chronic myeloid leukemia patient samples, which was correlated with BCR/ABL (oncogenic gene fusion protein) amplification and the increased A-to-I editing level [30]. Similarly, ADAR1 was also found to be required for the survival of leukemia cells [31]. Among different types of pediatric acute leukemias, only the B-cell acute lymphoblastic leukemia subgroup exhibited a significant overexpression of ADAR1 p110, with a dramatic decrease in its level in patients achieving complete remission [32]. ADAR1, a prognosis marker in ESCC
Our recent studies have reported that the differential expression of ADAR1 and/or ADAR2 was observed in HCC and ESCC tumors, leading to a gene-specific hyper or hypo-editing phenotype [11,25,33]. In ESCC, ADAR1 and ADAR2 were abundantly expressed, whereas ADAR3 was undetectable. Among all three RNA editing enzymes, ADAR1 was the only RNA editing enzyme found to be significantly upregulated in primary ESCC tumors [11]. The overexpression of ADAR1 in two ESCC cell lines, KYSE180 and EC109 cells, demonstrated more aggressive tumor behavior than control cells, as manifested by the accelerated growth rate, higher frequencies of focus formation and colony formation in soft agar, and the increased migrative and invasive capabilities. As reported previously, ADAR1 could catalyze the deaminase reaction of target genes AZIN1 and FLNB (filament B, b) in HCC cells [23]. The wild-type AZIN1 protein is a short-lived protein and shares high homology with ornithine decarboxylase (ODC). Antizyme binds to ODC and AZIN1, but AZIN1 possesses higher binding affinity to antizyme than ODC [34]. AZIN1 can reduce antizyme-mediated ODC degradation by sequestering antizyme from ODC. Compared with wild-type AZIN1 protein, the edited form binds to antizyme with a higher affinity, and the resultant higher protein stability could promote cell proliferation via neutralizing the antizymemediated degradation of ODC and other oncoproteins [25]. Due to the overexpression of ADAR1 in ESCC tumors, the editing frequencies of AZIN1 and FLNB were significantly higher than those in non-tumor specimens. Moreover, the edited form of AZIN1 conferred a ‘gain-of-function’ phenotype associated with aggressive tumor behavior, suggesting that AZIN1 is likely to be one of the downstream editing targets that are responsible for the ADAR1-induced tumorigenicity during ESCC progression. Expert Rev. Anticancer Ther. 14(8), (2014)
ADAR1, new biomarker for ESCC?
RNA editing enzyme levels could be used as prognostic markers for identifying ESCC patients at an early stage, selecting treatment modalities for individual patients, and determining post-therapeutic outcomes. Elevated level of ADAR1 was found to be associated with shorter overall survival time of ESCC patients [19]. Moreover, the tumoral overexpression of ADAR1 was shown to be the independent prognostic factor for the overall survival [19]. Overall, ADAR1 is of great clinical value as a new diagnostic, therapeutic indicator and prognostic prediction based on the molecular mechanism underlying esophageal carcinogenesis.
Downloaded by [70.91.158.137] at 03:51 06 November 2015
Conclusions
We speculate that monitoring expression level of ADAR1 represents a useful new biomarker for the detection of disorders in cancer before clinical symptoms become apparent. Better understanding the ADAR1 expression of ESCC may lead to more effective management of ESCC by precise prognostic References 1.
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Shahbaz Sarwar CM, Luketich JD, Landreneau RJ, Abbas G. Esophageal cancer: an update. Int J Surg 2010;8(6): 417-22
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Bass BL. RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 2002;71:817-46
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Laxminarayana D, O’Rourke KS, Maas S, Olorenshaw I. Altered editing in RNA editing adenosine deaminase ADAR2 gene transcripts of systemic lupus erythematosus T lymphocytes. Immunology 2007;121(3):359-69 Orlowski RJ, O’Rourke KS, Olorenshaw I, et al. Altered editing in cyclic nucleotide phosphodiesterase 8A1 gene transcripts of systemic lupus erythematosus T lymphocytes. Immunology 2008;125(3): 408-19 Peng PL, Zhong X, Tu W, et al. ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 2006;49(5):719-33 Schulte JH, Marschall T, Martin M, et al. Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma. Nucleic Acids Res 2010;38(17):5919-28
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indicators and effective personalized therapy. RNA editing dysregulation can be rectified by restoring ADAR balance by overexpressing or silencing ADARs by shRNAs (small hairpin RNAs) or clustered regularly interspaced short palindromic repeats [35]. However, due to the widespread activity of RNA editing enzymes, reinstating a specific hyper-edited or hypoedited transcript by introducing a specific RNA-binding peptide [36] or locked nucleotide acids [37] would be more effective. Financial & competing interests disclosure:
This research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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Dominissini D, Moshitch-Moshkovitz S, Amariglio N, Rechavi G. Adenosine-to-inosine RNA editing meets cancer. Carcinogenesis 2011;32(11):1569-77
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Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009; 59(4):225-49
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Qin YR, Qiao JJ, Chan TH, et al. Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma. Cancer Res 2014;74(3):840-51
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Fritz J, Strehblow A, Taschner A, et al. RNA-regulated interaction of transportin-1 and exportin-5 with the double-stranded RNA-binding domain regulates nucleocytoplasmic shuttling of ADAR1. Mol Cell Biol 2009;29(6):1487-97
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Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev 2001;14(4):778-809. table of contents
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Patterson JB, Samuel CE. Expression and regulation by interferon of a doublestranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol Cell Biol 1995; 15(10):5376-88
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Nemlich Y, Greenberg E, Ortenberg R, et al. MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. J Clin Invest 2013;123(6): 2703-18
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Wang Q, Miyakoda M, Yang W, et al. Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem 2004;279(6): 4952-61
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progenitor cell survival via RNA editing. Proc Natl Acad Sci U S A 2009;106(42): 17763-8
tumour profiled at single nucleotide resolution. Nature 2009;461(7265):809-13 27.
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Cho DS, Yang W, Lee JT, et al. Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. J Biol Chem 2003;278(19):17093-102 Cenci C, Barzotti R, Galeano F, et al. Down-regulation of RNA editing in pediatric astrocytomas: ADAR2 editing activity inhibits cell migration and proliferation. J Biol Chem 2008;283(11): 7251-60
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Expert Rev. Anticancer Ther. 14(8), (2014)
ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20
ADAR1: a promising new biomarker for esophageal squamous cell carcinoma? Jun-Jing Qiao, Tim Hon Man Chan, Yan-Ru Qin & Leilei Chen To cite this article: Jun-Jing Qiao, Tim Hon Man Chan, Yan-Ru Qin & Leilei Chen (2014) ADAR1: a promising new biomarker for esophageal squamous cell carcinoma?, Expert Review of Anticancer Therapy, 14:8, 865-868 To link to this article: http://dx.doi.org/10.1586/14737140.2014.928595
Published online: 13 Jun 2014.
Submit your article to this journal
Article views: 343
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iery20 Download by: [70.91.158.137]
Date: 06 November 2015, At: 03:51
Editorial
ADAR1: a promising new biomarker for esophageal squamous cell carcinoma? Expert Rev. Anticancer Ther. 14(8), 865–868 (2014)
Downloaded by [70.91.158.137] at 03:51 06 November 2015
Jun-Jing Qiao Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China and Cancer Science Institute of Singapore, National University of Singapore, Singapore
Tim Hon Man Chan Cancer Science Institute of Singapore, National University of Singapore, Singapore
Yan-Ru Qin Author for correspondence: Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China Tel.: +86 371 6629 5542 [email protected]
Leilei Chen Author for correspondence: Cancer Science Institute of Singapore, National University of Singapore, Singapore and Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Tel.: +65 6516 8435 Fax: +65 6516 1873 [email protected]
Esophageal Squamous Cell Carcinoma (ESCC) is a heterogeneous tumor with enormous genetic and epigenetic changes. RNA editing is an epigenetic mechanism that serves as an additional layer of ‘RNA mutations’ in parallel to DNA mutations. The most frequent type of RNA editing, A-to-I (adenosine-to-inosine) editing catalyzed by Adenosine DeAminase that act on RNA (ADARs), modulates RNA transcripts with profound impact on cellular functions. RNA editing dysregulation has been found to be associated with cancers. Our recent study demonstrated that among all the three RNA editing enzymes, only ADAR1 was overexpressed in primary ESCCs compared with matched non-tumor specimens. In this review, we will discuss current views on the involvement of abnormal A-to-I editing in cancer development, more specifically on the ADAR1-mediated editing in ESCC. Although much is not yet learned about the role of ADAR1 in ESCC, ADAR1 may present an attractive option as a new biomarker for ESCC and as a new molecular therapeutic target.
Esophageal squamous cell carcinoma (ESCC), accounting for more than 90% of all esophageal cancer, is the leading cause of cancer death worldwide and is associated with a poor prognosis [1,2]. Recent advances have proved largely ineffective in treatment, thus studying the molecular pathogenesis of ESCC is the current trend that might potentially lead to the identification of biological markers for early diagnosis and targeted therapies. Up to now, most cancer scientists have focused on studying DNA mutations that convey irreversible changes in the genome. However, discoveries in last decade completely changed our views on RNA and the enormous diversity that can be generated at the RNA level. RNA editing may lead to tumor-specific ‘RNA mutation’, exceeding the number of genomic mutations. In humans, the most frequent type of editing is the conversion of adenosine to inosine (A-to-I), which is catalyzed by the dsRNA-specific Adenosine DeAminase that act on RNA (ADAR) family of protein [3]. The imbalance of ADARs expression/activity is found to be associated with a variety of human diseases, such as amyotrophic
lateral sclerosis [4], systemic lupus erythematosus [5,6], neurological disorders [7,8] and cancer [9]. Recently, we have provided the first analyses of expression profiles of ADARs in human ESCC and demonstrated that among all three RNA editing enzymes ADAR1, ADAR2 and ADAR3 [10], only ADAR1 was significantly overexpressed in ESCC tumors, which has great prognostic value and diagnostic potential for ESCC; ADAR1 functions as an oncogene in the development of ESCC; the tight link between the differential expression of ADAR1 and an altered gene-specific editing pattern was investigated to illustrate how the A-to-I RNA editing balance is deregulated in ESCC; and a new functional recurrent RNA editing event, resulting in an amino acid substitution of the AZIN1 gene (antizyme inhibitor 1), was specifically regulated by ADAR1 and found to confer more aggressive tumorigenic behaviors [11]. In this article, we discuss recent studies connecting the differentially expressed ADAR genes with RNA editing alteration in human cancers, with a specific focus on ADAR1mediated RNA editing in carcinogenesis.
KEYWORDS: ADAR1 • biomarker • esophageal squamous cell carcinoma • RNA editing
informahealthcare.com
10.1586/14737140.2014.928595
2014 Informa UK Ltd
ISSN 1473-7140
865
Editorial
Qiao, Chan, Qin & Chen
Downloaded by [70.91.158.137] at 03:51 06 November 2015
ADAR1 expression & localization
The developmental and cell type-specific modulation of A-to-I RNA editing is tightly linked to ADAR expression and localization. ADAR1 and ADAR2, ubiquitously expressed in many tissues, catalyze all currently known A-to-I editing sites. In contrast, the brain-specifically expressed ADAR3 protein has no documented deaminase activity. ADAR1 protein is the largest of the three family members and its transcripts generate two major ADAR1 isoforms, a full-length interferon-inducible ADAR1 p150 and a shorter and constitutive N-terminally truncated ADAR1 p110. It has been recently reported that both ADAR1 p150 and ADAR1 p110 shuttle between the nucleus and cytoplasm [12]. The nuclear ADAR1 p110 is considered to catalyze A-to-I editing of double-stranded primary RNA transcripts mainly in the nucleus. ADAR1 p150 is detected mainly in the cytoplasma, possibly targeting a different class of dsRNA substrates, such as endoribonuclease-prepared siRNAs [13] and viral RNAs [3,14]. It has been reported that interferons induce the upregulation of ADAR1 [15], therefore raising the possibility that ADAR1 serves as an antiviral defense mechanism against viral infection and inflammation. The expression of ADAR1 is also downregulated by miRNA-1 (miR-1) [16,17], and the tight regulation of ADAR1 by miR-1 is likely to be critical for heart development [18,19]. In ESCC, we found that ADAR1 gene, which is mapped to chromosome 1q21, was amplified in approximately 70% of ESCC tumors using fluorescent in situ hybridization, and there was a positive correlation between overexpression of ADAR1 and the genomic amplification of ADAR1 gene in ESCC specimens [11], suggesting another mechanism of ADAR1 overexpression in tumors. ADAR1-regulated RNA editing in cancer
The imbalance in expression of ADARs enzymes is highly correlated with cancer development and progression [9,20]. Despite the fact that more than 85% of RNAs are found to be edited in noncoding and/or coding sequences [21], the edited mammalian transcripts have been only well studied in central nervous system and include transcripts encoding the subunits GluR-B, GluR-C, and GluR-D of the a-amino-3-hydroxy-5-methyl4-isoxazolepropionate receptor, the subunits GluR-6 and GluR-5 of the kainite receptor, and the serotonin receptor (5-HT2C) [21,22]. However, investigating link between the altered RNA editing activity and cancer progression is only the initial step. In brain tumors, all of three editing enzymes were found to be downregulated in brain tumors [23], and ADAR1 was frequently reduced in metastatic melanomas [16]. As a common editing target by ADAR1 and ADAR2, the decreased editing frequency of glioma-associated oncogene 1 was observed in basal cell carcinoma tumor samples when compared to normal skin, and RNA editing of glioma-associated oncogene 1 transcription factor are involved in Hedgehog signaling [24]. In contrast, ADAR1 was found to be upregulated in tumor tissues, such as hepatocellular carcinoma (HCC) [25], ESCC [11] and breast cancer [26]. It has been reported that homodimer formation may be necessary for ADAR1 and ADAR2 to act as 866
active deaminases [27]. In pediatric glioblastoma multiforme, the overexpression of ADAR1 p110 may cause the formation of an inactive ADAR1/ADAR2 heterodimer or the sequestration of ADAR2 from editing substrates, leading to the altered ADAR2 editing activity and the subsequent decreased editing frequencies [28]. In prostate cancer (CaP), high expression of both enzymes ADAR1 and ADAR2 in androgen-independent CaP cells (DU145 and PC3) resulted in the higher number of RNA editing mutation when compared with androgen-dependent CaP cells (LNCaP and 22Rv1) [29]. Due to the interferonresponsive ADAR1 activity, ADAR1 p150 was upregulated in chronic myeloid leukemia patient samples, which was correlated with BCR/ABL (oncogenic gene fusion protein) amplification and the increased A-to-I editing level [30]. Similarly, ADAR1 was also found to be required for the survival of leukemia cells [31]. Among different types of pediatric acute leukemias, only the B-cell acute lymphoblastic leukemia subgroup exhibited a significant overexpression of ADAR1 p110, with a dramatic decrease in its level in patients achieving complete remission [32]. ADAR1, a prognosis marker in ESCC
Our recent studies have reported that the differential expression of ADAR1 and/or ADAR2 was observed in HCC and ESCC tumors, leading to a gene-specific hyper or hypo-editing phenotype [11,25,33]. In ESCC, ADAR1 and ADAR2 were abundantly expressed, whereas ADAR3 was undetectable. Among all three RNA editing enzymes, ADAR1 was the only RNA editing enzyme found to be significantly upregulated in primary ESCC tumors [11]. The overexpression of ADAR1 in two ESCC cell lines, KYSE180 and EC109 cells, demonstrated more aggressive tumor behavior than control cells, as manifested by the accelerated growth rate, higher frequencies of focus formation and colony formation in soft agar, and the increased migrative and invasive capabilities. As reported previously, ADAR1 could catalyze the deaminase reaction of target genes AZIN1 and FLNB (filament B, b) in HCC cells [23]. The wild-type AZIN1 protein is a short-lived protein and shares high homology with ornithine decarboxylase (ODC). Antizyme binds to ODC and AZIN1, but AZIN1 possesses higher binding affinity to antizyme than ODC [34]. AZIN1 can reduce antizyme-mediated ODC degradation by sequestering antizyme from ODC. Compared with wild-type AZIN1 protein, the edited form binds to antizyme with a higher affinity, and the resultant higher protein stability could promote cell proliferation via neutralizing the antizymemediated degradation of ODC and other oncoproteins [25]. Due to the overexpression of ADAR1 in ESCC tumors, the editing frequencies of AZIN1 and FLNB were significantly higher than those in non-tumor specimens. Moreover, the edited form of AZIN1 conferred a ‘gain-of-function’ phenotype associated with aggressive tumor behavior, suggesting that AZIN1 is likely to be one of the downstream editing targets that are responsible for the ADAR1-induced tumorigenicity during ESCC progression. Expert Rev. Anticancer Ther. 14(8), (2014)
ADAR1, new biomarker for ESCC?
RNA editing enzyme levels could be used as prognostic markers for identifying ESCC patients at an early stage, selecting treatment modalities for individual patients, and determining post-therapeutic outcomes. Elevated level of ADAR1 was found to be associated with shorter overall survival time of ESCC patients [19]. Moreover, the tumoral overexpression of ADAR1 was shown to be the independent prognostic factor for the overall survival [19]. Overall, ADAR1 is of great clinical value as a new diagnostic, therapeutic indicator and prognostic prediction based on the molecular mechanism underlying esophageal carcinogenesis.
Downloaded by [70.91.158.137] at 03:51 06 November 2015
Conclusions
We speculate that monitoring expression level of ADAR1 represents a useful new biomarker for the detection of disorders in cancer before clinical symptoms become apparent. Better understanding the ADAR1 expression of ESCC may lead to more effective management of ESCC by precise prognostic References 1.
2.
Shahbaz Sarwar CM, Luketich JD, Landreneau RJ, Abbas G. Esophageal cancer: an update. Int J Surg 2010;8(6): 417-22
3.
Bass BL. RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 2002;71:817-46
4.
Kuner R, Groom AJ, Bresink I, et al. Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit. Proc Natl Acad Sci U S A 2005; 102(16):5826-31
5.
6.
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indicators and effective personalized therapy. RNA editing dysregulation can be rectified by restoring ADAR balance by overexpressing or silencing ADARs by shRNAs (small hairpin RNAs) or clustered regularly interspaced short palindromic repeats [35]. However, due to the widespread activity of RNA editing enzymes, reinstating a specific hyper-edited or hypoedited transcript by introducing a specific RNA-binding peptide [36] or locked nucleotide acids [37] would be more effective. Financial & competing interests disclosure:
This research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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Expert Rev. Anticancer Ther. 14(8), (2014)
