ALDH2 gene polymorphism in different types of cancers and its clinical significance Rui Li, Zihan Zhao, Mingyang Sun, Jiachi Luo, Yechen Xiao PII: DOI: Reference:
S0024-3205(16)30028-5 doi: 10.1016/j.lfs.2016.01.028 LFS 14665
To appear in:
Life Sciences
Received date: Revised date: Accepted date:
22 October 2015 8 January 2016 15 January 2016
Please cite this article as: Li Rui, Zhao Zihan, Sun Mingyang, Luo Jiachi, Xiao Yechen, ALDH2 gene polymorphism in different types of cancers and its clinical significance, Life Sciences (2016), doi: 10.1016/j.lfs.2016.01.028
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
ALDH2 gene polymorphism in different types of cancers
a
SC R
IP
Rui Li a,b, Zihan Zhao c, Mingyang Sun c, Jiachi Luo d, Yechen Xiao a*
T
and its clinical significance
Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, China
Department of Radiology, School of Public Health, Jilin University, Changchun, China
c
School of Clinical Medicine, Jilin University, Changchun, China
d
College of Letters and Science, University of California Berkeley, Berkeley,CA,USA
MA
NU
b
D
*Correspondence to: Yechen Xiao, Department of Biochemistry and Molecular Biology, College
TE
of Basic Medical Science, Jilin University,126 Xinmin Street, Changchun 130021, China Tel.: +86-431-85619474; fax: +86-431-85619303.
CE P
E-mail addresses: [email protected] (Yechen Xiao).
ABSTRACT
Aldehyde dehydrogenase 2 (ALDH2), an important mitochondrial enzyme governing
AC
ethanol metabolism, displays polymorphism in human. Recent evidence suggested that genetic polymorphism in ALDH2 gene may be significantly correlated with the susceptibility to cancer, such as colorectal cancer, esophageal cancer, liver cancer, etc. To investigate the correlation between ALDH2 mutant gene and the risk of a certain cancer, many studies have been done by testing the ALDH2 genotype in patients with cancers. Here, we summarized 84 ALDH2 gene single nucleotide polymorphism (SNP) sites in human cancer, which focus primarily on the rs671 SNP site. As a novel biological marker, ALDH2 displays a very attractive prospect in the screening, diagnosis and evaluation of the prognosis of many diseases. Moreover, much attention has been attracted to the studies of the biological functions and potential value of
1
ACCEPTED MANUSCRIPT ALDH2 in the human cancer treatment. This review will provide an overview about the clinical prospects of ALDH2 based on the available information.
IP
T
Keywords: ALDH2; single nucleotide polymorphism; clinical application; cancer;
SC R
Introduction
Aldehyde dehydrogenase 2 (ALDH2), a member of the acetaldehyde dehydrogenase superfamily, is a 56 kDa tetrameric protein and highly polymorphic enzyme with
NU
identical subunits. Each of the four polymers’ subunits contains the structure of the three main domains: catalytic domain, coenzyme- or NAD+-binding domain, and
MA
oligomerization domain (Cai et al. 2015; Gross et al. 2015; Xu et al. 2014). Human ALDH2, consisting of 517 amino acids, is encoded by a nuclear gene which located at chromosome 12q24. This protein is transported to the mitochondrial matrix, which
D
depends on the amino-terminal 17 amino acids, and thus forms the mature 500-amino
TE
acid protein that has many biological functions (Chen et al. 2014; Gross et al. 2015;
CE P
Xu et al. 2014). The gene-encoding ALDH2 spans approximately 44 kb and contains 13 exons, and it is ubiquitously expressed in all tissues but is richer in the liver and many other organs which require high mitochondrial oxidative phosphorylation, like
AC
the lung, heart and brain (Chen et al. 2014). ALDH2 is closely related with biological oxidation. It has the lowest Km for acetaldehyde (~0.2 μM), which suggests that ALDH2 plays an essential role in aldehyde metabolism (Gross et al. 2015; Song et al. 2011). Meanwhile, ALDH2 can also prevent acetaldehyde on membrane lipid peroxidation, reducing reactive oxygen metabolites caused by acetaldehyde accumulation, lessening cellular damage. ALDH2, consisting of two alleles, generates three genotypes, including the wild type called GG allele (ALDH2*1/*1) with normal activity, the heterozygous mutation type called AG (ALDH2*1 /*2) with approximately 10%-45% of the normal ALDH2 activity, and the homozygous mutation type called AA (ALDH2*2/*2) with only 1-5% of the normal enzymatic activity (Gross et al. 2015). The structure of ALDH2* 2/*2 apoenzyme was showed in the Fig.1. The Glu487Lys mutation in the ALDH2*2 2
ACCEPTED MANUSCRIPT apoenzyme disturbs the stabilization of hydrogen bonds and magically leads to disorder in the αG helix and the loop that consists of Arg-475. The loss of these interactions apparently impairs the structure of the NAD+-binding site and repositions
T
as well as several catalytically important residues. The presence of Lys at 487 site in
IP
the ALDH2*2 also results in a 200-fold increase in the Km for NAD+ and a 10-fold
SC R
reduced Kcat when compared with the wild-type ALDH2 enzyme, so that the mutants are unable to efficiently combine with NAD+ or coenzymes to exert enzymatic activity (Larson et al. 2007).
NU
To our knowledge, there are clear differences in the frequencies of the ALDH2 mutant gene in differing geographical, ethnic, and racial types. The ALDH2*2
MA
mutation exits primarily in East Asians, with an occurrence rate of 30%-50%, which is more than 8% of the world population (Brooks and Zakhari 2014; Chen et al. 2014;
D
Gross et al. 2015; Xu et al. 2014). It was discovered that 84 single nucleotide
TE
polymorphism (SNP) sites of ALDH2 gene are present in human tumors, and amongst them, the rs671 polymorphism in exon 12 which leads to the amino acid sequence on
CE P
the 487th glutamic acid mutation for lysine (Glu487Lys) has been most reported. A base mutation occurs at nucleotide 1459, where an adenine (A) is substituted for a guanine (G), causing a codon change from GAA to AAA. It is also referred to as
AC
Glu487Lys, Glu504Lys, or rs671 (Singh et al. 2015). Current studies focus primarily on the rs671 SNP site, which acts a coenzyme binding site. Its mutation may cause the ALDH2 enzyme to be unable to combine with coenzymes, thus leading to the reduction of enzymatic activity. Based on the studies of ALDH2 polymorphism in different diseases caused by abnormal alcohol metabolism, we summarized four SNP loci of ALDH2 gene (rs671, rs886205, rs2238151 and rs16941667) that are very important in the treatment of hepatic cirrhosis, cardiovascular diseases, and cancers.
Molecular mechanisms of ALDH2 As an important oxidative stress molecule, ALDH2 can reduce the generation of reactive oxygen species (ROS), and thus prevent the apoptosis and cellular damage 3
ACCEPTED MANUSCRIPT caused by hyperoxia or acetaldehyde (Chen et al. 2008; Chen et al. 2014; Churchill et al. 2009; Guo et al. 2015; Xu et al. 2006). In particular, acetaldehyde metabolism can be dramatically decreased when the ALDH2 gene mutation occurs in vivo. The
IP
T
non-oxidized acetaldehyde will enter the bloodstream, and combine with xanthine oxidase, then translate into superoxide, causing membrane peroxidation as well as
SC R
producing a large number of end products, such as 4-hydroxy-2-nonenal (4-HNE) and malonaldehyde (MDA). These aldehydes may interact with the macromolecular material in vivo, such as DNA and protein, forming a large number of DNA adduct
NU
products and inactivating proteins, and then activate the apoptosis pathways and drive the oxidative stress-induced cell apoptosis (Brooks and Zakhari 2014; Chen et al.
MA
2014; Gross et al. 2015; Song et al. 2011). Previous studies have shown that many organs, such as the liver, heart, and lung, require the protective role of ALDH2 in
D
attenuating the hyperoxia-induced mitochondrial damage in the process of alcohol
TE
metabolism. However, the protective effects will be reduced when the ALDH2 gene mutation occurs in vivo, thus causing the sharp increase of 4-HNE. In the liver,
CE P
4-HNE can induce the release of cytokines, which may lead to liver damage by disrupting the cell membrane. And in the myocardium, 4-HNE is also able to cause an accumulation of damaged proteins and further destroy the generative abilities of
AC
mitochondrial ATP and the opening of mitochondrial membrane’s permeability transition pore (MPTP), which may promote the myocardial cells to go through apoptosis, thus inducing arrhythmia and heart failure (Zhang and Shah 2007). Recent studies have reported that ALDH2 may be directly or indirectly involved in multiple signaling pathways (Fig.2.), which may give us an explanation of the phenomenon above from the molecular level.
Signaling transduction pathways of ALDH2 ALDH2 and protein kinase C (PKC) The protection of ALDH2 to myocardial cells is closely linked with PKC activation. PKC increases the activity of ALDH2 by phosphorylating ALDH2. Chen et al. (Chen et al. 2008) found that alcohol-preconditioning and the use of PKC 4
ACCEPTED MANUSCRIPT activators increase the activity of ALDH2 and enhance the protective effects of preconditioning on myocardial cells in the myocardial ischemia-reperfusion injury model of rats. In contrast, PKC inhibitors can alleviate the activation of ALDH2,
IP
T
further block the myocardial protection effects of preconditioning. Utilizing similar methods, Churchill et al. (Churchill et al. 2009) demonstrated that the ethanol
SC R
pretreatment activates ALDH2 and strengthens its protective effects of myocardial cell injury through inducing the translocation of PKC to cardiac mitochondria coupling with the phosphorylation of ALDH2. Churchill found that both cardiac
NU
isoforms of JNK1/2 and ERK1/2 were hyper-phosphorylated after the ligation of the left anterior descending coronary artery (LAD) in rats, but the levels of isoforms of
MA
JNK1/2, ERK1/2 decreased significantly after the intraperitoneal injection of ethanol. The results showed that cardio protective effects of ethanol may proceed through
D
PKC-mediated activation of ALDH2, which reduced 4-HNE production in the blood
JNK1/2 and ERK1/2.
TE
and blocked the apoptosis signal pathways by inhibiting the phosphorylation of
CE P
ALDH2 and other apoptotic pathways ALDH2 was
reported
involved in
the regulation of ERK1/2,
P38
mitogen-activated kinase (MAPK), Pl3K-Akt, and other signaling molecules,
AC
including mTOR, STAT3, Notch1, PP2A, and PP2C (Xu et al. 2006). High expression of ALDH2 reduces reactive oxygen species (ROS) generation, and further inhibits the hyperoxia- or acetaldehyde-induced apoptosis in human lung epithelial cells (Chen et al. 2014; Xu et al. 2006). In addition, Li et al. (Li et al. 2004) transfected the transgene-encoding human aldehyde dehydrogenase-2 (ALDH2) into human umbilical
vein
endothelial
cells
(HUVECs),
thus
suppressing
the
acetaldehyde-induced ROS generation and the activation of p38-MAPK, ERK1/2. Additionally, nitroglycerin preconditioning may also inhibit cell damage and apoptosis via the regulation of the ERK1 /2，SAPK/JNK and p38-MAPK signaling pathways (Iliodromitis et al. 2006). Collectively, it was revealed that ALDH2 overexpression may prevent acetaldehyde-induced cell injury and the activation of oxidative stress signals, but the detailed molecular mechanisms of these protective 5
ACCEPTED MANUSCRIPT effects of ALDH2 remain unclear, pending further study. Additionally, Chen et al. (Chen et al. 2014) indicates that the ALDH2 gene mutation increases the myocardial cell injury which was produced by regulating the levels of the phosphorylation of
IP
T
glycogen synthase kinase (GSK-3β), Akt and forkhead transcription factor of the O subtype (FOXO3a).
SC R
Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide) is a potent activator of ALDH2, which can itself activate the ALDH2 enzyme in both human and mice. Guo’s study (Guo et al. 2015) indicated that ALda-1 decreased significantly the
NU
phosphorylation level of AMPK and increased the expression of P-FOXO3a. Moreover, high expression of ALDH2 by ALda-1 treatment can reduce the release of
MA
cytosolic Bax, cytochrome C, thereby inhibiting the activation of caspase-9 and
D
caspase-3.
TE
ALDH2 gene polymorphism in different types of cancers and its clinical significance
CE P
As far as we know, many types of cancers are induced by abnormal alcoholic metabolism, and most of them are associated with ALDH2 gene mutation (Table 1), such as hepatocellular carcinoma, gastric cancer, and colon cancer, etc. There may be
AC
a close connection between the single nucleotide polymorphism (SNP) of ALDH2 rs671 and these cancers. From a clinical point of view, the detection of mutant gene will play a pivotal role in the diagnosis, treatment, and prognosis of these diseases.
ALDH2 and Oral squamous cell carcinoma (OSCC) OSCC is a common malignant tumor, and is most prevalent amongst young females, accounting for roughly 3% of the total malignant tumors in humans, and those people with the tumor have a survival rate of less than 40% (Zhang et al. 2014a). The occurrence rate of OSCC increases sharply as daily alcohol intake levels. Current studies suggest that the ALDH2 mutants may determine an individual’s susceptibility to developing OSCC. Zhang et al. (Zhang et al. 2014a) analyzed peripheral blood leukocytes obtained from 750 OSCC patients and 750 healthy individuals through the 6
ACCEPTED MANUSCRIPT use of the polymerase chain reaction’s fragment polymorphism, and found that ALDH2 G1510A polymorphism causes mutation of the amino acid sequence on the 487th glutamic acid for lysine (Glu487Lys) to significantly decrease its catalytic
IP
T
ability to acetaldehyde metabolism, leading to the risk of OSCC being significantly increased (OR=2.85, P
S0024-3205(16)30028-5 doi: 10.1016/j.lfs.2016.01.028 LFS 14665
To appear in:
Life Sciences
Received date: Revised date: Accepted date:
22 October 2015 8 January 2016 15 January 2016
Please cite this article as: Li Rui, Zhao Zihan, Sun Mingyang, Luo Jiachi, Xiao Yechen, ALDH2 gene polymorphism in different types of cancers and its clinical significance, Life Sciences (2016), doi: 10.1016/j.lfs.2016.01.028
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
ALDH2 gene polymorphism in different types of cancers
a
SC R
IP
Rui Li a,b, Zihan Zhao c, Mingyang Sun c, Jiachi Luo d, Yechen Xiao a*
T
and its clinical significance
Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, China
Department of Radiology, School of Public Health, Jilin University, Changchun, China
c
School of Clinical Medicine, Jilin University, Changchun, China
d
College of Letters and Science, University of California Berkeley, Berkeley,CA,USA
MA
NU
b
D
*Correspondence to: Yechen Xiao, Department of Biochemistry and Molecular Biology, College
TE
of Basic Medical Science, Jilin University,126 Xinmin Street, Changchun 130021, China Tel.: +86-431-85619474; fax: +86-431-85619303.
CE P
E-mail addresses: [email protected] (Yechen Xiao).
ABSTRACT
Aldehyde dehydrogenase 2 (ALDH2), an important mitochondrial enzyme governing
AC
ethanol metabolism, displays polymorphism in human. Recent evidence suggested that genetic polymorphism in ALDH2 gene may be significantly correlated with the susceptibility to cancer, such as colorectal cancer, esophageal cancer, liver cancer, etc. To investigate the correlation between ALDH2 mutant gene and the risk of a certain cancer, many studies have been done by testing the ALDH2 genotype in patients with cancers. Here, we summarized 84 ALDH2 gene single nucleotide polymorphism (SNP) sites in human cancer, which focus primarily on the rs671 SNP site. As a novel biological marker, ALDH2 displays a very attractive prospect in the screening, diagnosis and evaluation of the prognosis of many diseases. Moreover, much attention has been attracted to the studies of the biological functions and potential value of
1
ACCEPTED MANUSCRIPT ALDH2 in the human cancer treatment. This review will provide an overview about the clinical prospects of ALDH2 based on the available information.
IP
T
Keywords: ALDH2; single nucleotide polymorphism; clinical application; cancer;
SC R
Introduction
Aldehyde dehydrogenase 2 (ALDH2), a member of the acetaldehyde dehydrogenase superfamily, is a 56 kDa tetrameric protein and highly polymorphic enzyme with
NU
identical subunits. Each of the four polymers’ subunits contains the structure of the three main domains: catalytic domain, coenzyme- or NAD+-binding domain, and
MA
oligomerization domain (Cai et al. 2015; Gross et al. 2015; Xu et al. 2014). Human ALDH2, consisting of 517 amino acids, is encoded by a nuclear gene which located at chromosome 12q24. This protein is transported to the mitochondrial matrix, which
D
depends on the amino-terminal 17 amino acids, and thus forms the mature 500-amino
TE
acid protein that has many biological functions (Chen et al. 2014; Gross et al. 2015;
CE P
Xu et al. 2014). The gene-encoding ALDH2 spans approximately 44 kb and contains 13 exons, and it is ubiquitously expressed in all tissues but is richer in the liver and many other organs which require high mitochondrial oxidative phosphorylation, like
AC
the lung, heart and brain (Chen et al. 2014). ALDH2 is closely related with biological oxidation. It has the lowest Km for acetaldehyde (~0.2 μM), which suggests that ALDH2 plays an essential role in aldehyde metabolism (Gross et al. 2015; Song et al. 2011). Meanwhile, ALDH2 can also prevent acetaldehyde on membrane lipid peroxidation, reducing reactive oxygen metabolites caused by acetaldehyde accumulation, lessening cellular damage. ALDH2, consisting of two alleles, generates three genotypes, including the wild type called GG allele (ALDH2*1/*1) with normal activity, the heterozygous mutation type called AG (ALDH2*1 /*2) with approximately 10%-45% of the normal ALDH2 activity, and the homozygous mutation type called AA (ALDH2*2/*2) with only 1-5% of the normal enzymatic activity (Gross et al. 2015). The structure of ALDH2* 2/*2 apoenzyme was showed in the Fig.1. The Glu487Lys mutation in the ALDH2*2 2
ACCEPTED MANUSCRIPT apoenzyme disturbs the stabilization of hydrogen bonds and magically leads to disorder in the αG helix and the loop that consists of Arg-475. The loss of these interactions apparently impairs the structure of the NAD+-binding site and repositions
T
as well as several catalytically important residues. The presence of Lys at 487 site in
IP
the ALDH2*2 also results in a 200-fold increase in the Km for NAD+ and a 10-fold
SC R
reduced Kcat when compared with the wild-type ALDH2 enzyme, so that the mutants are unable to efficiently combine with NAD+ or coenzymes to exert enzymatic activity (Larson et al. 2007).
NU
To our knowledge, there are clear differences in the frequencies of the ALDH2 mutant gene in differing geographical, ethnic, and racial types. The ALDH2*2
MA
mutation exits primarily in East Asians, with an occurrence rate of 30%-50%, which is more than 8% of the world population (Brooks and Zakhari 2014; Chen et al. 2014;
D
Gross et al. 2015; Xu et al. 2014). It was discovered that 84 single nucleotide
TE
polymorphism (SNP) sites of ALDH2 gene are present in human tumors, and amongst them, the rs671 polymorphism in exon 12 which leads to the amino acid sequence on
CE P
the 487th glutamic acid mutation for lysine (Glu487Lys) has been most reported. A base mutation occurs at nucleotide 1459, where an adenine (A) is substituted for a guanine (G), causing a codon change from GAA to AAA. It is also referred to as
AC
Glu487Lys, Glu504Lys, or rs671 (Singh et al. 2015). Current studies focus primarily on the rs671 SNP site, which acts a coenzyme binding site. Its mutation may cause the ALDH2 enzyme to be unable to combine with coenzymes, thus leading to the reduction of enzymatic activity. Based on the studies of ALDH2 polymorphism in different diseases caused by abnormal alcohol metabolism, we summarized four SNP loci of ALDH2 gene (rs671, rs886205, rs2238151 and rs16941667) that are very important in the treatment of hepatic cirrhosis, cardiovascular diseases, and cancers.
Molecular mechanisms of ALDH2 As an important oxidative stress molecule, ALDH2 can reduce the generation of reactive oxygen species (ROS), and thus prevent the apoptosis and cellular damage 3
ACCEPTED MANUSCRIPT caused by hyperoxia or acetaldehyde (Chen et al. 2008; Chen et al. 2014; Churchill et al. 2009; Guo et al. 2015; Xu et al. 2006). In particular, acetaldehyde metabolism can be dramatically decreased when the ALDH2 gene mutation occurs in vivo. The
IP
T
non-oxidized acetaldehyde will enter the bloodstream, and combine with xanthine oxidase, then translate into superoxide, causing membrane peroxidation as well as
SC R
producing a large number of end products, such as 4-hydroxy-2-nonenal (4-HNE) and malonaldehyde (MDA). These aldehydes may interact with the macromolecular material in vivo, such as DNA and protein, forming a large number of DNA adduct
NU
products and inactivating proteins, and then activate the apoptosis pathways and drive the oxidative stress-induced cell apoptosis (Brooks and Zakhari 2014; Chen et al.
MA
2014; Gross et al. 2015; Song et al. 2011). Previous studies have shown that many organs, such as the liver, heart, and lung, require the protective role of ALDH2 in
D
attenuating the hyperoxia-induced mitochondrial damage in the process of alcohol
TE
metabolism. However, the protective effects will be reduced when the ALDH2 gene mutation occurs in vivo, thus causing the sharp increase of 4-HNE. In the liver,
CE P
4-HNE can induce the release of cytokines, which may lead to liver damage by disrupting the cell membrane. And in the myocardium, 4-HNE is also able to cause an accumulation of damaged proteins and further destroy the generative abilities of
AC
mitochondrial ATP and the opening of mitochondrial membrane’s permeability transition pore (MPTP), which may promote the myocardial cells to go through apoptosis, thus inducing arrhythmia and heart failure (Zhang and Shah 2007). Recent studies have reported that ALDH2 may be directly or indirectly involved in multiple signaling pathways (Fig.2.), which may give us an explanation of the phenomenon above from the molecular level.
Signaling transduction pathways of ALDH2 ALDH2 and protein kinase C (PKC) The protection of ALDH2 to myocardial cells is closely linked with PKC activation. PKC increases the activity of ALDH2 by phosphorylating ALDH2. Chen et al. (Chen et al. 2008) found that alcohol-preconditioning and the use of PKC 4
ACCEPTED MANUSCRIPT activators increase the activity of ALDH2 and enhance the protective effects of preconditioning on myocardial cells in the myocardial ischemia-reperfusion injury model of rats. In contrast, PKC inhibitors can alleviate the activation of ALDH2,
IP
T
further block the myocardial protection effects of preconditioning. Utilizing similar methods, Churchill et al. (Churchill et al. 2009) demonstrated that the ethanol
SC R
pretreatment activates ALDH2 and strengthens its protective effects of myocardial cell injury through inducing the translocation of PKC to cardiac mitochondria coupling with the phosphorylation of ALDH2. Churchill found that both cardiac
NU
isoforms of JNK1/2 and ERK1/2 were hyper-phosphorylated after the ligation of the left anterior descending coronary artery (LAD) in rats, but the levels of isoforms of
MA
JNK1/2, ERK1/2 decreased significantly after the intraperitoneal injection of ethanol. The results showed that cardio protective effects of ethanol may proceed through
D
PKC-mediated activation of ALDH2, which reduced 4-HNE production in the blood
JNK1/2 and ERK1/2.
TE
and blocked the apoptosis signal pathways by inhibiting the phosphorylation of
CE P
ALDH2 and other apoptotic pathways ALDH2 was
reported
involved in
the regulation of ERK1/2,
P38
mitogen-activated kinase (MAPK), Pl3K-Akt, and other signaling molecules,
AC
including mTOR, STAT3, Notch1, PP2A, and PP2C (Xu et al. 2006). High expression of ALDH2 reduces reactive oxygen species (ROS) generation, and further inhibits the hyperoxia- or acetaldehyde-induced apoptosis in human lung epithelial cells (Chen et al. 2014; Xu et al. 2006). In addition, Li et al. (Li et al. 2004) transfected the transgene-encoding human aldehyde dehydrogenase-2 (ALDH2) into human umbilical
vein
endothelial
cells
(HUVECs),
thus
suppressing
the
acetaldehyde-induced ROS generation and the activation of p38-MAPK, ERK1/2. Additionally, nitroglycerin preconditioning may also inhibit cell damage and apoptosis via the regulation of the ERK1 /2，SAPK/JNK and p38-MAPK signaling pathways (Iliodromitis et al. 2006). Collectively, it was revealed that ALDH2 overexpression may prevent acetaldehyde-induced cell injury and the activation of oxidative stress signals, but the detailed molecular mechanisms of these protective 5
ACCEPTED MANUSCRIPT effects of ALDH2 remain unclear, pending further study. Additionally, Chen et al. (Chen et al. 2014) indicates that the ALDH2 gene mutation increases the myocardial cell injury which was produced by regulating the levels of the phosphorylation of
IP
T
glycogen synthase kinase (GSK-3β), Akt and forkhead transcription factor of the O subtype (FOXO3a).
SC R
Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide) is a potent activator of ALDH2, which can itself activate the ALDH2 enzyme in both human and mice. Guo’s study (Guo et al. 2015) indicated that ALda-1 decreased significantly the
NU
phosphorylation level of AMPK and increased the expression of P-FOXO3a. Moreover, high expression of ALDH2 by ALda-1 treatment can reduce the release of
MA
cytosolic Bax, cytochrome C, thereby inhibiting the activation of caspase-9 and
D
caspase-3.
TE
ALDH2 gene polymorphism in different types of cancers and its clinical significance
CE P
As far as we know, many types of cancers are induced by abnormal alcoholic metabolism, and most of them are associated with ALDH2 gene mutation (Table 1), such as hepatocellular carcinoma, gastric cancer, and colon cancer, etc. There may be
AC
a close connection between the single nucleotide polymorphism (SNP) of ALDH2 rs671 and these cancers. From a clinical point of view, the detection of mutant gene will play a pivotal role in the diagnosis, treatment, and prognosis of these diseases.
ALDH2 and Oral squamous cell carcinoma (OSCC) OSCC is a common malignant tumor, and is most prevalent amongst young females, accounting for roughly 3% of the total malignant tumors in humans, and those people with the tumor have a survival rate of less than 40% (Zhang et al. 2014a). The occurrence rate of OSCC increases sharply as daily alcohol intake levels. Current studies suggest that the ALDH2 mutants may determine an individual’s susceptibility to developing OSCC. Zhang et al. (Zhang et al. 2014a) analyzed peripheral blood leukocytes obtained from 750 OSCC patients and 750 healthy individuals through the 6
ACCEPTED MANUSCRIPT use of the polymerase chain reaction’s fragment polymorphism, and found that ALDH2 G1510A polymorphism causes mutation of the amino acid sequence on the 487th glutamic acid for lysine (Glu487Lys) to significantly decrease its catalytic
IP
T
ability to acetaldehyde metabolism, leading to the risk of OSCC being significantly increased (OR=2.85, P
