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Kondo Y, Ohashi S, Katada C, Nakai Y, Yamamoto Y, Tamaoki M, Kikuchi O, Yamada A, Hirohashi K, Mitani Y, Kataoka S, Saito T, Vu THN, Kondo T, Uneno Y, Sunami T, Yokoyama A, Matsubara J, Matsuda T, Naganuma S, Oryu K, Flashner S, Shimonosono M, Nakagawa H, Muto M. Aldh2 and the tumor suppressor Trp53 play important roles in alcohol-induced squamous field cancerization. J Gastroenterol 2025; 60:546-560. [PMID: 39909947 PMCID: PMC12014750 DOI: 10.1007/s00535-024-02210-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/30/2024] [Indexed: 02/07/2025]
Abstract
BACKGROUND Field cancerization defined by multiple development of squamous cell carcinomas (SCCs) in upper aerodigestive tract was explained by excessive alcohol intake. A dysfunctional mitochondrial aldehyde dehydrogenase 2 (Aldh2) delays the clearance of acetaldehyde, a genotoxic alcohol metabolite, and increases SCC risks. TP53 plays key roles in squamous carcinogenesis. However, the mechanism of alcohol-mediated squamous field cancerization has not been clearly elucidated. METHODS We developed a novel genetically engineered mouse strain KTPA-/- (Krt5CreERT2; Trp53loxp/loxp; Aldh2-/-) featuring Aldh2-loss concurrent with epithelial-specific Trp53 deletion. These mice were given 10%-EtOH, and we evaluated the development of squamous cell carcinogenesis histologically and genetically. RESULTS Widespread multifocal rete ridges (RRs), characterized by downward growth of proliferative preneoplastic cells, were found only in Aldh2+/- and Aldh2-/- mice with keratin5-specific Trp53 deletion (KTPA+/- and KTPA-/- mice, respectively), and alcohol drinking apparently increased RR formation rate. SCC occurred only in KTPA-/- (Aldh2 loss/TP53 loss) mice with alcohol drinking (15/18: 83%). Total alcohol consumption volume was significantly higher in KTPA-/- (Aldh2 loss/TP53 loss) mice with SCCs than those without SCCs. Further, target sequence revealed the occurrence of genetic abnormalities including Trp53 mutations in the esophageal epithelium of Aldh2-/- mice with alcohol drinking, suggesting direct mutagenic effects of alcohol drinking to the esophageal epithelium. CONCLUSION This study provides for the first time the evidence that alcohol drinking, Aldh2 dysfunction and Trp53 loss cooperate in squamous field cancerization. Alcohol consumption volume affects the SCCs development, even in the same genotype.
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Affiliation(s)
- Yuki Kondo
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Shinya Ohashi
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan.
- Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital, Kyoto, Japan.
| | - Chikatoshi Katada
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Yukie Nakai
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Yoshihiro Yamamoto
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Masashi Tamaoki
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Osamu Kikuchi
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Atsushi Yamada
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Kenshiro Hirohashi
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Yosuke Mitani
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Shigeki Kataoka
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Tomoki Saito
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Trang H Nguyen Vu
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Tomohiro Kondo
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Yu Uneno
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Tomohiko Sunami
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Akira Yokoyama
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Junichi Matsubara
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Tomonari Matsuda
- Environment Health Division, Kyoto University Graduate School of Engineering, Kyoto, Japan
| | - Seiji Naganuma
- Faculty of Health Sciences, Department of Medical Laboratory Science, Kochi Gakuen University, Kochi, Japan
| | - Kohei Oryu
- Faculty of Health Sciences, Department of Nutrition, Kochi Gakuen University, Kochi, Japan
| | - Samuel Flashner
- Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, USA
| | - Masataka Shimonosono
- Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, USA
| | - Hiroshi Nakagawa
- Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, USA
| | - Manabu Muto
- Department of Medical Oncology, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
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Ishida N, Osawa S, Sugiura K, Takebe T, Takahashi K, Asai Y, Tamura S, Matsuura T, Yamade M, Iwaizumi M, Hamaya Y, Yamada T, Sugimoto K. Characteristics of Esophageal Squamous Cell Carcinomas Based on Circumferential Localization. JGH Open 2024; 8:e70063. [PMID: 39649069 PMCID: PMC11624006 DOI: 10.1002/jgh3.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 11/02/2024] [Accepted: 11/11/2024] [Indexed: 12/10/2024]
Abstract
BACKGROUND AND AIM In terms of their longitudinal positioning, esophageal squamous cell carcinoma (ESCC) commonly arises in the middle segment of the esophagus. However, limited attention has been given to the circumferential aspect. This study aimed to investigate the prevalence and characteristics of ESCC lesions resected via endoscopic submucosal dissection (ESD), taking into consideration both longitudinal and circumferential positions. METHODS We retrospectively evaluated 193 ESD-resected ESCC lesions and compared the occurrence rate of ESCC development and the degree of histopathological invasion across various circumferential and longitudinal positions. We scrutinized lesion characteristics by location, with a particular focus on the proportion of early-stage small lesions in each site. RESULTS Regarding lesion location, 27 were situated on the anterior wall, 62 on the left, 66 on the posterior, and 38 on the right. Among the four circumferential positions, the anterior wall group had the smallest median tumor size. Additionally, the anterior wall group had the highest proportions of lesions with invasion depths limited to the epithelial layer and sizes < 10 mm, at 44.4% and 25.9%, respectively. Furthermore, a significant difference was noted among the four circumferential positions with respect to the proportion of ESCC lesions satisfying both criteria, with the highest proportion observed in the anterior wall group (p = 0.049). CONCLUSIONS Our findings suggest that while ESCC occurrence on the anterior wall is less frequent, these lesions may present as small lesions with superficial invasion depths.
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Affiliation(s)
- Natsuki Ishida
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Kiichi Sugiura
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Tomohiro Takebe
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Kenichi Takahashi
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Yusuke Asai
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Satoshi Tamura
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Tomoharu Matsuura
- Department of Laboratory MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Mihoko Yamade
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Moriya Iwaizumi
- Department of Laboratory MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Yasushi Hamaya
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Takanori Yamada
- Department of Endoscopic and Photodynamic MedicineHamamatsu University School of MedicineHamamatsuJapan
| | - Ken Sugimoto
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
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Nasalingkhan C, Sirinonthanawech N, Sato BK, Wilhelm JE, Noree C. Localization and regulation of yeast aldehyde dehydrogenase Ald4p structures. Heliyon 2024; 10:e39048. [PMID: 39640825 PMCID: PMC11620093 DOI: 10.1016/j.heliyon.2024.e39048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 10/01/2024] [Accepted: 10/07/2024] [Indexed: 12/07/2024] Open
Abstract
Previously, we identified yeast strains, namely SWORD, showing more robust Ald4p-GFP filament formation than the typical ALD4::GFP strains. Here, we report that Ald4p-GFP in SWORD strains favorably polymerize into gigantic structures in the cytoplasm, despite the enzyme being established as a mitochondrial resident. In addition, we have found that nocodazole, a microtubule destabilizer, has no effect on Ald4p high-order assembly, suggesting no direct association between microtubule dynamics and Ald4p structure formation. Ald4p assembly cannot be induced by sodium azide treatment, indicating that ATP is not a primary effector of Ald4p polymerization. Interestingly, addition of exogenous acetaldehyde, a substrate of the enzyme, can significantly enhance the structure formation of Ald4p, implying that structure formation may be related to enzymatic activity.
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Affiliation(s)
- Channarong Nasalingkhan
- Institute of Molecular Biosciences, Mahidol University 25/25 Phuttamonthon 4 Road, Salaya, Phuttamonthon, Nakhon Pathom, 73170, Thailand
| | - Naraporn Sirinonthanawech
- Institute of Molecular Biosciences, Mahidol University 25/25 Phuttamonthon 4 Road, Salaya, Phuttamonthon, Nakhon Pathom, 73170, Thailand
| | - Brian K. Sato
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, 2238 McGaugh Hall, Irvine, CA, 92697, USA
| | - James E. Wilhelm
- Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive (MC0347), La Jolla, CA, 92093-0347, USA
| | - Chalongrat Noree
- Institute of Molecular Biosciences, Mahidol University 25/25 Phuttamonthon 4 Road, Salaya, Phuttamonthon, Nakhon Pathom, 73170, Thailand
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Kang B, Kim C, Shin SH, Shin H, Cho Y. Impact of Alcohol-Induced Facial Flushing Phenotype on Alcohol Consumption Among Korean Adults: 2-Year Cross-Sectional Study. JMIR Public Health Surveill 2024; 10:e49826. [PMID: 38796304 PMCID: PMC11325126 DOI: 10.2196/49826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 04/29/2024] [Accepted: 05/23/2024] [Indexed: 05/28/2024] Open
Abstract
BACKGROUND The alcohol-induced facial flushing phenotype (flushing) is common among East Asians. Despite a small intake of alcohol, they experience heightened levels of acetaldehyde, a group-1 carcinogen, which, in turn, causes unpleasant symptoms such as redness, acting as a robust protective mechanism against consuming alcohol. However, some individuals with this genetic trait exhibit weakened alcohol restraint, which increases the risk of developing alcohol-related cancers, such as esophageal and head or neck cancer, by several times. Although this flushing phenomenon is crucial for public health, there is a paucity of studies that have comprehensively investigated the effect of flushing or its genotype on alcohol consumption in a large group of East Asians while controlling for various sociodemographic and health-related variables at a country level. OBJECTIVE This 2-year cross-sectional study aims to explore the effect of flushing on drinking behavior in Koreans and to examine whether the effect varies across sociodemographic and health-related factors. METHODS We used data from the Korea National Health and Nutrition Examination Survey (KNHANES) for 2019 and 2020 conducted by the Korea Disease Control and Prevention Agency. Our sample comprised 10,660 Korean adults. The study investigated the association of 26 variables, including flushing, with drinking frequency and amount. The effect of flushing was examined with and without adjusting for the other 25 variables using multinomial logistic regression analysis. In addition, we tested the interaction effect with flushing and conducted a simple effect analysis. We used complex sample design elements, including strata, clusters, and weights, to obtain unbiased results for the Rao-Scott χ2 test, 2-tailed t test, and multinomial logistic regression analysis. RESULTS The suppressive effect of flushing was significant (P<.001) across all pronounced categories of alcohol consumption in 2019. The ranges of standardized regression slopes and odds ratios (ORs) were -6.70≥β≥-11.25 and 0.78≥OR≥0.50 for frequency and -5.37≥β≥-17.64 and 0.73≥OR≥0.36 for amount, respectively. The effect became somewhat stronger when adjusted for confounders. The effect also exhibited an overall stronger trend as the severity of alcohol consumption increased. The β values and ORs were consistently smaller in 2020 compared to the previous year. A simple effect analysis revealed a diminished alcohol-suppressive effect of flushing on alcohol consumption for specific groups (eg, those with low levels of education, limited family support, physical labor, or health-related issues). CONCLUSIONS Our findings suggest that flushing suppresses drinking in Koreans overall but has little or no effect in certain susceptible populations. Therefore, health authorities should conduct targeted epidemiological studies to assess drinking patterns and disease profiles, particularly regarding alcohol-related cancers, and establish effective preventive measures tailored to this population.
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Affiliation(s)
- Bossng Kang
- Department of Emergency Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Changsun Kim
- Department of Emergency Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Seon-Hi Shin
- Biostatistical Consulting and Research Lab, Medical Research Collaborating Center, Hanyang University, Seoul, Republic of Korea
| | - Hyungoo Shin
- Department of Emergency Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Yongil Cho
- Department of Emergency Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
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Woo AYH, Jia L. ALDH2 mutations and defense against genotoxic aldehydes in cancer and inherited bone marrow failure syndromes. Mutat Res 2024; 829:111870. [PMID: 38944932 DOI: 10.1016/j.mrfmmm.2024.111870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 07/02/2024]
Abstract
Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion called interstrand crosslink (ICL). Aldehyde-metabolizing enzymes such as aldehyde dehydrogenases (ALDHs) and the Fanconi anemia (FA) pathway constitute the main defense lines against aldehyde-induced genotoxicity. Biallelic mutations of genes in any one of the FA complementation groups can impair the ICL repair mechanism and cause FA, a heterogeneous disorder manifested by bone marrow failure (BMF), congenital abnormality and a strong predisposition to cancer. The defective ALDH2 polymorphism rs671 (ALDH2*2) is a known risk and prognostic factor for alcohol drinking-associated cancers. Recent studies suggest that it also promotes BMF and cancer development in FA, and its combination with alcohol dehydrogenase 5 (ADH5) mutations causes aldehyde degradation deficiency syndrome (ADDS), also known by its symptoms as aplastic anemia, mental retardation, and dwarfism syndrome. ALDH2*2 and another pathogenic variant in the alcohol-metabolizing pathway, ADH1B1*1, is prevalent among East Asians. Also, other ALDH2 genotypes with disease-modifying potentials have lately been identified in different populations. Therefore, it would be appropriate to summarize current knowledge of genotoxic aldehydes and defense mechanisms against them to shed new light on the pathogenic effects of ALDH2 variants together with other genetic and environmental modifiers on cancer and inherited BMF syndromes. Lastly, we also presented potential treatment strategies for FA, ADDS and cancer based on the manipulation of aldehyde-induced genotoxicity.
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Affiliation(s)
- Anthony Yiu-Ho Woo
- School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
| | - Lina Jia
- School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
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Imani MM, Moradi MM, Rezaei F, Mozaffari HR, Sharifi R, Safaei M, Azizi F, Basamtabar M, Sohrabi Z, Shalchi M, Sadeghi M. Association between alcohol dehydrogenase polymorphisms (rs1229984, rs1573496, rs1154460, and rs284787) and susceptibility to head and neck cancers: A systematic review and meta-analysis. Arch Oral Biol 2024; 160:105898. [PMID: 38278126 DOI: 10.1016/j.archoralbio.2024.105898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/25/2023] [Accepted: 01/19/2024] [Indexed: 01/28/2024]
Abstract
OBJECTIVE Head and neck cancer (HNC) is a prevalent and complex group of malignancies with increasing incidence globally. Alcohol dehydrogenases (ADHs) play a crucial role in alcohol metabolism, and their polymorphisms have been linked to HNC risk. This systematic review and meta-analysis aims to evaluate the association between ADH polymorphisms and susceptibility to HNCs, incorporating additional analyses and adding more studies to increase power and accuracy of the results. DESIGN Subgroup analysis, meta-regression analysis, and sensitivity analyses were conducted to explore potential differences within the data and assess the stability of pooled odds ratios (ORs). To mitigate the risk of false conclusions from meta-analyses, a trial sequential analysis was performed. RESULTS For ADH1B rs1229984, the pooled OR (95 % confidence interval (CI)) was 0.73 (0.65, 0.82), 0.42 (0.35, 0.50), 0.57 (0.44, 0.73), 0.56 (0.50, 0.62), and 0.80 (0.73, 0.88), as well as for ADH7 rs1573496, the pooled OR was 0.72 (0.62, 0.85), 0.36 (0.17, 0.74), 0.76 (0.64, 0.91), 0.80 (0.71, 0.91), and 0.38 (0.18, 0.78) with a p < 0.05 in all allelic, homozygous, heterozygous, recessive, and dominant models, respectively. However, no significant association was found between the ADH7 rs1154460 and rs284787 polymorphisms and the risk of HNC with pooled ORs of 1.11 (p = 0.19) and 1.09 (p = 0.24) for the recessive model, respectively. The ethnicities, tumor subsites, control sources, sample sizes, quality scores, and Hardy-Weinberg equilibrium statuses were confounding factors. CONCLUSION The ADH1B rs1229984 and ADH7 rs1573496 polymorphisms are significantly associated with a reduced risk of HNC.
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Affiliation(s)
- Mohammad Moslem Imani
- Department of Orthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohamad Mehdi Moradi
- Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farzad Rezaei
- Department of Oral and Maxillofacial Surgery, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hamid Reza Mozaffari
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Roohollah Sharifi
- Department of Endodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohsen Safaei
- Advanced Dental Sciences Research Center, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Azizi
- Department of Orthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoumeh Basamtabar
- Department of Orthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zahra Sohrabi
- Department of periodontology, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Majid Shalchi
- Orthodontic Department, Guilan University of Medical Sciences, School of Dentistry, Rasht, Iran
| | - Masoud Sadeghi
- Medical Biology Research Centre, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Flashner S, Shimonosono M, Tomita Y, Matsuura N, Ohashi S, Muto M, Klein-Szanto AJ, Alan Diehl J, Chen CH, Mochly-Rosen D, Weinberg KI, Nakagawa H. ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment. Carcinogenesis 2024; 45:95-106. [PMID: 37978873 PMCID: PMC10859731 DOI: 10.1093/carcin/bgad085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 11/19/2023] Open
Abstract
The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent among East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three-dimensional organoids and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.
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Affiliation(s)
- Samuel Flashner
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
| | - Masataka Shimonosono
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
| | - Yasuto Tomita
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
| | - Norihiro Matsuura
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
| | - Shinya Ohashi
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Kyoto 606-8507, Japan
| | - Manabu Muto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Kyoto 606-8507, Japan
| | | | - J Alan Diehl
- Case Comprehensive Cancer Center, Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Che-Hong Chen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Kenneth I Weinberg
- Division of Stem Cell Biology and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hiroshi Nakagawa
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
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Cui Y, Ren W, Du X, Yang L, Tan B. Research Progress of Multiple Primary Malignancies Associated With Esophageal Cancer. Cancer Control 2023; 30:10732748231176641. [PMID: 37212379 PMCID: PMC10214099 DOI: 10.1177/10732748231176641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 04/07/2023] [Accepted: 04/28/2023] [Indexed: 05/23/2023] Open
Abstract
With the improvement in survival of patients with tumors, and continuous advancement of diagnostic technology and treatment modalities, instances of multiple primary malignancies (MPMs) are becoming an increasingly common phenomenon. The occurrence of esophageal-relevant MPMs increases the difficulty of diagnosis and treatment, and the overall prognosis is poor. Esophageal cancer related-MPMs tend to occur in areas such as the head, neck, stomach, and lungs. "Field cancerization" is one theoretical basis for the disease, and chemoradiotherapy, environmental life factors, and gene polymorphism are etiological factors. However, the influence of new therapeutic methods on MPM is still unclear, and the relationship between gene polymorphism and MPMs related to esophageal cancer needs further elucidation. Additionally, there is a lack of unified standards for diagnosis and treatment. Therefore, this study aimed to review the causes, clinical features, and prognostic factors of MPMs related to esophageal cancer.
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Affiliation(s)
- Yu Cui
- Department of Oncology, Affiliated Hospital of North Sichuan
Medical College, Nanchong City, Sichuan Province, China
| | - Wenxia Ren
- Department of Oncology, Affiliated Hospital of North Sichuan
Medical College, Nanchong City, Sichuan Province, China
| | - Xue Du
- Department of Oncology, Affiliated Hospital of North Sichuan
Medical College, Nanchong City, Sichuan Province, China
| | - Lu Yang
- Department of Oncology, Affiliated Hospital of North Sichuan
Medical College, Nanchong City, Sichuan Province, China
| | - Bangxian Tan
- Department of Oncology, Affiliated Hospital of North Sichuan
Medical College, Nanchong City, Sichuan Province, China
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Isothiocyanates (ITCs) 1-(Isothiocyanatomethyl)-4-phenylbenzene and 1-Isothiocyanato-3,5-bis(trifluoromethyl)benzene—Aldehyde Dehydrogenase (ALDH) Inhibitors, Decreases Cisplatin Tolerance and Migratory Ability of NSCLC. Int J Mol Sci 2022; 23:ijms23158644. [PMID: 35955773 PMCID: PMC9369118 DOI: 10.3390/ijms23158644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 01/27/2023] Open
Abstract
One of the main treatment modalities for non-small-cell lung cancer (NSCLC) is cisplatin-based chemotherapy. However, the acquisition of cisplatin resistance remains a major problem. Existing chemotherapy regimens are often ineffective against cancer cells expressing aldehyde dehydrogenase (ALDH). As such, there is an urgent need for therapies targeting ALDH-positive cancer cells. The present study compares the anticancer properties of 36 structurally diverse isothiocyanates (ITCs) against NSCLC cells with the ALDH inhibitor disulfiram (DSF). Their potential affinity to ALDH isoforms and ABC proteins was assessed using AutoDockTools, allowing for selection of three compounds presenting the strongest affinity to all tested proteins. The selected ITCs had no impact on NSCLC cell viability (at tested concentrations), but significantly decreased the cisplatin tolerance of cisplatin-resistant variant of A549 (A549CisR) and advanced (stage 4) NSCLC cell line H1581. Furthermore, long-term supplementation with ITC 1-(isothiocyanatomethyl)-4-phenylbenzene reverses the EMT phenotype and migratory potential of A549CisR to the level presented by parental A549 cells, increasing E-Cadherin expression, followed by decreased expression of ABCC1 and ALDH3A1. Our data indicates that the ALDH inhibitors DSF and ITCs are potential adjuvants of cisplatin chemotherapy.
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10
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Inoue M, Shimizu Y, Taniguchi M, Kimura Y, Furuhashi H, Dobashi A, Ikeya T, Goda K, Kato M, Kato M, Sakamoto N, Watanabe A. Evaluation of the risk of metachronous multiple squamous cell carcinoma of the head and neck after transoral surgery based on the genetic polymorphisms of alcohol dehydrogenase 1B and aldehyde dehydrogenase 2. Carcinogenesis 2021; 42:1232-1238. [PMID: 34546328 DOI: 10.1093/carcin/bgab085] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 09/08/2021] [Accepted: 09/20/2021] [Indexed: 01/01/2023] Open
Abstract
Patients with superficial head and neck squamous cell carcinoma (HNSCC) can be completely treated by techniques of transoral surgery (TOS). The aim of this study was to evaluate the risk of metachronous multiple HNSCC arising after TOS based on alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2). We registered patients who underwent TOS for superficial HNSCC. Buccal cell samples were obtained by using a cotton swab to examine two single nucleotide polymorphisms in ADH1B and ALDH2 genotyping. We used Cox proportional hazards models to examine the risk of metachronous HNSCC. A total of 198 patients who underwent TOS for HNSCC were evaluated. In multivariate analysis, risks for second HNSCC were ADH1B*1/*1 [hazard ratio (HR), 1.88; 95% confidence interval (CI), 1.11-3.19; P = 0.02], ALDH2*1/*2 (HR, 2.11; 95% CI, 1.00-5.16; P = 0.048) and alcohol consumption before TOS (HR, 1.17; 95% CI, 1.06-1.27; P = 0.01). The 5-year incidence rates of second primary HNSCC in the temperance group and the non-temperance group were 20.8 and 46.5%, respectively (HR, 0.54; 95% CI, 0.31-0.92; P = 0.02). Cumulative development rates of third HNSCC in the temperance group and non-temperance group at 10 years were 11.3 and 36.1%, respectively (HR, 0.19; 95% CI, 0.03-0.65; P = 0.006). ADH1B*1/*1, ALDH2*1/*2 and moderate or heavy alcohol consumption before treatment are independent risk factors of metachronous HNSCC. Since it was shown that temperance decreased the incidences of second and third metachronous HNSCC, advice to discontinue alcohol drinking is necessary.
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Affiliation(s)
- Masaki Inoue
- Department of Gastroenterology and Hepatology, Graduate School of Medicine and Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yuichi Shimizu
- Division of Endoscopy, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Masanobu Taniguchi
- Department of Otolaryngology Head and Neck Surgery, Keiyukai Sapporo Hospital, Sapporo, Hokkaido, Japan
| | - Yuki Kimura
- Department of Otolaryngology Head and Neck Surgery, Keiyukai Sapporo Hospital, Sapporo, Hokkaido, Japan
| | - Hiroto Furuhashi
- Department of Endoscopy, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Akira Dobashi
- Department of Endoscopy, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Takashi Ikeya
- Department of Gastroenterology, St. Luke's International Hospital, Chuo-ku, Tokyo, Japan
| | - Kenichi Goda
- Department of Gastroenterology, Dokkyo Medical University, Shimotsuga, Tochigi, Japan
| | - Masayuki Kato
- Department of Endoscopy, The Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
| | - Mototsugu Kato
- Department of Gastroenterology, National Hospital Organization Hakodate National Hospital, Hakodate, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine and Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Akihito Watanabe
- Department of Otolaryngology Head and Neck Surgery, Keiyukai Sapporo Hospital, Sapporo, Hokkaido, Japan
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11
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Acetaldehyde Enhances Alcohol Sensitivity and Protects against Alcoholism: Evidence from Alcohol Metabolism in Subjects with Variant ALDH2*2 Gene Allele. Biomolecules 2021; 11:biom11081183. [PMID: 34439848 PMCID: PMC8391449 DOI: 10.3390/biom11081183] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/29/2021] [Accepted: 08/07/2021] [Indexed: 01/03/2023] Open
Abstract
Alcoholism is a complex behavior trait influenced by multiple genes as well as by sociocultural factors. Alcohol metabolism is one of the biological determinants that can significantly influence drinking behaviors. Alcohol sensitivity is thought to be a behavioral trait marker for susceptibility to develop alcoholism. The subjective perceptions would be an indicator for the alcohol preference. To investigate alcohol sensitivity for the variants ADH1B*2 and ALDH2*2, sixty healthy young males with different combinatory ADH1B and ALDH2 genotypes, ADH1B*2/*2–ALDH2*1/*1 (n = 23), ADH1B*2/*2–ALDH2*1/*2 (n = 27), and ADH1B*1/*1–ALDH2*1/*1 (n = 10), participated in the study. The subjective perceptions were assessed by a structured scale, and blood ethanol and acetaldehyde were determined by GC and HPLC after an alcohol challenge in two dose sessions (0.3 g/kg or 0.5 g/kg ethanol). The principal findings are (1) dose-dependent increase of blood ethanol concentration, unaffected by ADH1B or ALDH2; (2) significant build-up of blood acetaldehyde, strikingly influenced by the ALDH2*2 gene allele and correlated with the dose of ingested alcohol; (3) the increased heart rate and subjective sensations caused by acetaldehyde accumulation in the ALDH2*2 heterozygotes; (4) no significant effect of ADH1B polymorphism in alcohol metabolism or producing the psychological responses. The study findings provide the evidence of acetaldehyde potentiating the alcohol sensitivity and feedback to self-control the drinking amount. The results indicate that ALDH2*2 plays a major role for acetaldehyde-related physiological negative responses and prove the genetic protection against development of alcoholism in East Asians.
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Zhu LP, Yin WL, Peng L, Zhou XH, Zhou P, Xuan SX, Luo Y, Chen C, Cheng B, Lin JD, Liu YM, Tan FJ, Yin WG. Association of Aldehyde Dehydrogenase 2 Gene Polymorphism with Myocardial Infarction. J Inflamm Res 2021; 14:3039-3047. [PMID: 34262327 PMCID: PMC8274824 DOI: 10.2147/jir.s311885] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/22/2021] [Indexed: 01/15/2023] Open
Abstract
Objective This study explored the correlation between myocardial infarction (MI) and the Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene in the Qingyuan area. Methods The Glu504Lys polymorphism of the ALDH2 gene was analyzed using the polymerase chain reaction and deoxyribonucleic acid microarray analysis for 468 patients diagnosed with MI for the first time and 132 healthy subjects. Results There was a significant difference in the distribution of the ALDH2 genotype between the MI group and the control group (P = 0.0492), but there was no significant difference in allele frequency between the two groups (P = 0.1363). The clinical data showed that there were statistically significant differences (P < 0.05) in the two groups’ gender and age distributions, rates of diabetes and hypertension, levels of alcohol and tobacco use, serological levels of heart markers, blood lipids and glucose. The subgroup analysis of ALDH2 genotypes found that alcohol consumption, high levels of myoglobin, and low levels of high-density lipoprotein cholesterol were significantly associated with a higher incidence of MI (P < 0.05). After adjusting for gender, hypertension, diabetes, and other related influencing factors, logistic regression analysis showed that the ALDH2 genotype GA/AA was an independent risk factor for MI (P < 0.05, OR = 1.479, 95% CI = 1.003–2.179). Conclusion The presence of risk alleles with the genetic effect (ALDH2 genotype GA/AA) is an independent risk factor for MI.
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Affiliation(s)
- Li-Ping Zhu
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Wei-Lan Yin
- Department of Physiology & Institute of Neuroscience, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Lei Peng
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Xiao-Hong Zhou
- Kingmed Diagnostic Center for Clinical Laboratory, Guangzhou, 510330, Guangdong, People's Republic of China
| | - Peng Zhou
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Shu-Xia Xuan
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Ying Luo
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Chen Chen
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Bin Cheng
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Jin-Duan Lin
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Yan-Mei Liu
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Feng-Jun Tan
- Department of Otorhinolaryngology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
| | - Wei-Guo Yin
- Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, People's Republic of China
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Li X, Fan K, Liu Y, Liu Y, Liu PF. Administration of a recombinant ALDH7A1 (rA7) indicates potential regulation of the metabolite and immunology pathways in Atlantic salmon infected with Aeromonas salmonicida. JOURNAL OF FISH DISEASES 2021; 44:961-977. [PMID: 33645734 DOI: 10.1111/jfd.13355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/30/2021] [Accepted: 02/01/2021] [Indexed: 06/12/2023]
Abstract
The bacterium Aeromonas salmonicida is the pathogen responsible for furunculosis, which is a serious disease of salmonids. This disease has a significant economic impact on the economic benefits of the global salmon farming industry. However, the pathogenesis of this disease in fish is still unknown. Members of the aldehyde dehydrogenase gene (ALDH) superfamily play a key role in the enzyme detoxification of endogenous and exogenous aldehydes. In this study, we obtained a recombinant aldehyde dehydrogenase 7A1 (ALDH7A1) protein to find its functions on Atlantic salmon infected by A. salmonicida. The transcriptional response in the liver of Atlantic salmon (Salmo salar) with differing levels of A. salmonicida infection was analysed and compared in order to reveal mechanisms by which ALDH7A1 may confer infection resistance. With the addition of ALDH7A1 protein, it was found that a total of 13,369 genes were annotated with one or more KEGG and localized to 360 KEGG pathways in the high concentration infection group. The differential expression genes were more enriched in immune signalling pathways such as the Toll-like receptor signalling pathway, NF-kappa B signalling pathway and TNF signalling pathway. On the other hand, at low concentrations of infection, KEGG enriched a smaller number of differential expression genes. However, these differential genes were more concentrated in immune signalling pathways such as the PI3K-Akt signalling pathway, JAK-STAT signalling pathway and complement and coagulation cascades. In addition, several known immune-related genes including HSP90α, HSP70, DNA damage-inducible transcript 4, integrin alpha 5 and microtubule-associated protein 2 were among the differentially expressed transcripts. These data provide the first insights into the host-ALDH7A1 vaccine interactome. The results of this study contribute to identifying the potential resistance mechanisms of Atlantic salmon to A. salmonicida infection and determining future treatment strategies.
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Affiliation(s)
- Xiaohao Li
- College of Marine Technology and Environment, Dalian Ocean University, Dalian, China
- Key Laboratory of Environment Controlled Aquaculture, Ministry of Education, Dalian, China
| | - Kunpeng Fan
- Key Laboratory of Environment Controlled Aquaculture, Ministry of Education, Dalian, China
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, China
| | - Yafang Liu
- College of Marine Technology and Environment, Dalian Ocean University, Dalian, China
- Key Laboratory of Environment Controlled Aquaculture, Ministry of Education, Dalian, China
| | - Ying Liu
- College of Marine Technology and Environment, Dalian Ocean University, Dalian, China
- Key Laboratory of Environment Controlled Aquaculture, Ministry of Education, Dalian, China
| | - Peng-Fei Liu
- College of Marine Technology and Environment, Dalian Ocean University, Dalian, China
- Key Laboratory of Environment Controlled Aquaculture, Ministry of Education, Dalian, China
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14
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Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption. Sci Rep 2021; 11:13690. [PMID: 34211048 PMCID: PMC8249592 DOI: 10.1038/s41598-021-93086-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 06/18/2021] [Indexed: 12/19/2022] Open
Abstract
Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14+ monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms.
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15
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The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment. Acta Pharm Sin B 2021; 11:1400-1411. [PMID: 34221859 PMCID: PMC8245805 DOI: 10.1016/j.apsb.2021.02.008] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/29/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022] Open
Abstract
A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2 (ALDH2). The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported. Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types. Furthermore, the ALDH2∗2 polymorphism (rs671) is the most common single nucleotide polymorphism (SNP) in Asia. Epidemiological studies associate ALDH2∗2 with tumorigenesis and progression. This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence, progression, and treatment of tumors in various types of cancer. Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.
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Key Words
- 4-HNE, 4-hydroxy-2-nonenal
- ALD, alcoholic liver disease
- ALDH2
- ALDH2, aldehyde dehydrogenase 2
- AMPK, AMP-activated protein kinase
- Acetaldehyde
- BCa, bladder cancer
- COUP-TF, chicken ovalbumin upstream promoter-transcription factor
- CRC, colorectal cancer
- CSCs, cancer stem cells
- Cancer
- Cancer therapy
- DFS, disease-free survival
- EC, esophageal cancer
- FA, Fanconi anemia
- FANCD2, Fanconi anemia protein
- GCA, gastric cancer
- HCC, hepatocellular carcinoma
- HDACs, histone deacetylases
- HNC, head and neck cancer
- HNF-4, hepatocyte nuclear factor 4
- HR, homologous recombination
- LCSCs, liver cancer stem cells
- MDA, malondialdehyde
- MDR, multi-drug resistance
- MN, micronuclei
- Metastasis
- NAD, nicotinamide adenine dinucleotide
- NCEs, normochromic erythrocytes
- NER, nucleotide excision repair pathway
- NF-κB, nuclear factor-κB
- NHEJ, non-homologous end-joining
- NRF2, nuclear factor erythroid 2 (NF-E2)-related factor 2
- NRRE, nuclear receptor response element
- NSCLC, non-small-cell lung
- NeG, 1,N2-etheno-dGuo
- OPC, oropharyngeal cancer
- OS, overall survival
- OvCa, ovarian cancer
- PBMC, peripheral blood mononuclear cell
- PC, pancreatic cancer
- PdG, N2-propano-2′-deoxyguanosine
- Polymorphism
- Progression
- REV1, Y-family DNA polymerase
- SCC, squamous cell carcinoma
- TGF-β, transforming growth factor β
- Tumorigenesis
- VHL, von Hippel-Lindau
- ccRCC, clear-cell renal cell carcinomas
- εPKC, epsilon protein kinase C
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Dingler FA, Wang M, Mu A, Millington CL, Oberbeck N, Watcham S, Pontel LB, Kamimae-Lanning AN, Langevin F, Nadler C, Cordell RL, Monks PS, Yu R, Wilson NK, Hira A, Yoshida K, Mori M, Okamoto Y, Okuno Y, Muramatsu H, Shiraishi Y, Kobayashi M, Moriguchi T, Osumi T, Kato M, Miyano S, Ito E, Kojima S, Yabe H, Yabe M, Matsuo K, Ogawa S, Göttgens B, Hodskinson MRG, Takata M, Patel KJ. Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans. Mol Cell 2020; 80:996-1012.e9. [PMID: 33147438 PMCID: PMC7758861 DOI: 10.1016/j.molcel.2020.10.012] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/20/2020] [Accepted: 10/08/2020] [Indexed: 01/04/2023]
Abstract
Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.
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Affiliation(s)
- Felix A Dingler
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Meng Wang
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Haematology, University of Cambridge, Cambridge, UK
| | - Anfeng Mu
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan; Department of Genome Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | | | - Nina Oberbeck
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Sam Watcham
- Department of Haematology, University of Cambridge, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Lucas B Pontel
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET, Polo Científico Tecnológico, Godoy Cruz 2390, C1425FQD Buenos Aires, Argentina
| | | | - Frederic Langevin
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Camille Nadler
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Rebecca L Cordell
- Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK
| | - Paul S Monks
- Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK
| | - Rui Yu
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Nicola K Wilson
- Department of Haematology, University of Cambridge, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Asuka Hira
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan; Department of Genome Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Kenichi Yoshida
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Minako Mori
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan; Department of Genome Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Okamoto
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan; Department of Genome Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Okuno
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Muramatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichi Shiraishi
- Section of Genome Analysis Platform, Center for Cancer Genomic and Advanced Therapeutics, National Cancer Center, Tokyo, Japan
| | - Masayuki Kobayashi
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Hematology, Kyoto Katsura Hospital, Kyoto, Japan
| | | | - Tomoo Osumi
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Motohiro Kato
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Satoru Miyano
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo Japan
| | - Etsuro Ito
- Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Seiji Kojima
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiromasa Yabe
- Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Japan
| | - Miharu Yabe
- Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan; Division of Analytical Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Sweden; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
| | - Berthold Göttgens
- Department of Haematology, University of Cambridge, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | | | - Minoru Takata
- Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan; Department of Genome Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
| | - Ketan J Patel
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK; MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
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17
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Yokoyama A, Omori T, Yokoyama T. Risk factors for esophageal iodine-unstained lesions and changing trends among Japanese alcohol-dependent men (2003-2018). Cancer Sci 2020; 112:734-743. [PMID: 33249700 PMCID: PMC7894006 DOI: 10.1111/cas.14753] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/25/2020] [Accepted: 11/25/2020] [Indexed: 12/16/2022] Open
Abstract
Globally, a decreasing incidence of male esophageal squamous cell carcinoma (ESCC) has been observed in recent decades. We evaluated the determinants of esophageal distinct iodine-unstained lesions (DIULs), high-cancer-risk lesions and ESCC, among 3858 Japanese alcohol-dependent men (40-79 years) who underwent chromoendoscopic screening between 2003 and 2018. The initial screening detected DIULs ≥ 5 mm in 541 patients (dysplasia in 319 and SCC in 129) and multiple DIULs in 640. The detection rates for DIULs and chronic atrophic gastritis (CAG), pack-years, and the mean corpuscular volume (MCV) decreased over the course of the study period, while the detection of hiatal hernia and/or columnar-lined esophagus (HH/CLE) and the carriers of inactive heterozygous aldehyde dehydrogenase-2 (ALDH2, rs671) increased. Multiple logistic regression analyses showed that an older age, larger number of pack-years, smaller body mass index, larger MCV, presence of a slow-metabolizing alcohol dehydrogenase-1B genotype (rs1229984), presence of an inactive heterozygous ALDH2 genotype, and more advanced degree of CAG increased the odds ratios (ORs) for DIULs, while the 2008-2013 and 2014-2018 screening periods had lower ORs for DIULs than the 2003-2007 screening period. The presence of HH/CLE decreased the OR for multiple DIULs and was associated with a more proximal location of ESCC. In conclusion, the detection of DIULs in an alcohol-dependent population decreased between 2003 and 2018. In addition to reported determinants of ESCC, CAG and HH/CLE were associated with the risk of DIULs. Enigmatically, however, the decline in the detection of DIULs was not adequately explained by these factors and warrants further research.
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Affiliation(s)
- Akira Yokoyama
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai Omori
- Endoscopy Center, Kawasaki Municipal Ida Hospital, Kanagawa, Japan
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Saitama, Japan
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Joo Kang S, Shin CM, Sung J, Kim N. Association Between ALDH2 Polymorphism and Gastric Cancer Risk in Terms of Alcohol Consumption: A Meta-Analysis. Alcohol Clin Exp Res 2020; 45:6-14. [PMID: 33170513 DOI: 10.1111/acer.14508] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 11/02/2020] [Indexed: 01/19/2023]
Abstract
BACKGROUND Alcohol may increase gastric cancer risk. Alcohol can be more carcinogenic in persons who possess inactive ALDH2. The aim of this meta-analysis was to evaluate whether ALDH2 polymorphism can affect alcohol-induced gastric carcinogenesis. METHODS We searched the PubMed, EMBASE, and Cochrane databases to identify relevant articles published between January 2000 and September 2019. Eligible articles were selected according to inclusion and exclusion criteria. The data were analyzed using Review Manager 5.3. RESULTS A total of 7 case-control studies on ALDH2 rs671 polymorphism consisting of 3,251 gastric cancer cases and 4,943 controls were included in the analysis. Inactive ALDH2 genotypes (G/A or A/A) were associated with an increased risk of gastric cancer (odds ratio [OR] = 1.26, 95% confidence interval [CI]: 1.04 to 1.52, p = 0.02, I2 = 64%), compared with active ALDH2 (G/G genotype). Subgroup analysis by alcohol consumption showed that inactive ALDH2 increased risk for gastric cancer in moderate to heavy drinkers (OR = 1.85, 95% CI: 1.52 to 2.25, p < 0.01, I2 = 6%) more than in nondrinkers or mild drinkers (OR = 1.19; 95% CI: 1.05 to 1.36, p < 0.01, I2 = 6%). Moderate/heavy alcohol consumption increased gastric cancer risk in individuals with inactive ALDH2 (OR = 2.23, 95% CI: 1.63 to 3.05, p < 0.01, I2 = 30%) more than those with active ALDH2 (OR = 1.40, 95% CI: 0.98 to 2.01, p = 0.07, I2 = 85%). CONCLUSIONS The ALDH2 polymorphism modifies the risk of gastric cancer. Moderate/heavy drinkers are more susceptible to gastric cancer than non-drinkers or light drinkers with inactive ALDH2.
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Affiliation(s)
- Seung Joo Kang
- From the, Department of Internal Medicine, (SJK), Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, (CMS, NK), Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea
| | - Joohon Sung
- School of Public Health and Institute of Health and Environment, (JS), Seoul National University, Seoul, Korea
| | - Nayoung Kim
- Department of Internal Medicine, (CMS, NK), Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea.,Department of Internal Medicine and Liver Research Institute, (NK), Seoul National University College of Medicine, Seoul, Korea
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19
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Zhang XN, Meng FG, Wang YR, Liu SX, Zeng T. Transformed ALDH2 -/- hepatocytes by ethanol could serve as a useful tool for studying alcoholic hepatocarcinogenesis. Med Hypotheses 2020; 146:110366. [PMID: 33208242 DOI: 10.1016/j.mehy.2020.110366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/16/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023]
Abstract
Alcohol is a well-recognized hepatic carcinogen. Alcohol is metabolized into genotoxic acetaldehyde in hepatocytes, which is catalyzed by aldehyde dehydrogenase 2 (ALDH2). The detailed underlying mechanisms of alcohol-related hepatocellular carcinoma (HCC) remains unclear, at least partially, due to the absence of appropriate experimental models. Current studies suggest that rodents are not good models of the most common liver diseases that trigger HCC including alcoholic liver injury. We hypothesize that ethanol could induce transformation of immortalized normal liver cells, which may serve as a versatile tool for studying alcoholic HCC. Besides, we believe that knockout of ALDH2 will help to shorten the time course of transformation, as ALDH2 deficiency will significantly increase the accumulation of acetaldehyde in hepatocytes. Using this model, the dynamic changes of carcinogenesis-related molecular events could be easily examined. Furthermore, the transformed cells isolated from soft agar could be inoculated to mice for studying invasion, metastasis, and also for screening prophylactics.
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Affiliation(s)
- Xiu-Ning Zhang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Fan-Ge Meng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yi-Ran Wang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Shi-Xuan Liu
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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20
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Hirohashi K, Ohashi S, Amanuma Y, Nakai Y, Ida T, Baba K, Mitani Y, Mizumoto A, Yamamoto Y, Kikuchi O, Matsubara J, Yamada A, Miyamoto S, Seno H, Matsuda T, Muto M. Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice. Carcinogenesis 2020; 41:194-202. [PMID: 31074772 PMCID: PMC7175241 DOI: 10.1093/carcin/bgz091] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 04/15/2019] [Accepted: 05/09/2019] [Indexed: 12/15/2022] Open
Abstract
Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2′-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.
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Affiliation(s)
- Kenshiro Hirohashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Shinya Ohashi
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Yusuke Amanuma
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Yukie Nakai
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Tomomi Ida
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Kiichiro Baba
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Yosuke Mitani
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Ayaka Mizumoto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Yoshihiro Yamamoto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Osamu Kikuchi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Junichi Matsubara
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Atsushi Yamada
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Shin’ichi Miyamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Tomonari Matsuda
- Research Center for Environmental Quality Management, Kyoto University, Yumihama, Otsu, Japan
| | - Manabu Muto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
- To whom correspondence should be addressed. Tel: +81 75 751 4592; Fax:+81 75 751 4594;
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21
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Moubadder L, McCullough LE, Flowers CR, Koff JL. Linking Environmental Exposures to Molecular Pathogenesis in Non-Hodgkin Lymphoma Subtypes. Cancer Epidemiol Biomarkers Prev 2020; 29:1844-1855. [PMID: 32727723 DOI: 10.1158/1055-9965.epi-20-0228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/27/2020] [Accepted: 07/20/2020] [Indexed: 12/24/2022] Open
Abstract
Non-Hodgkin lymphoma comprises a heterogeneous group of hematologic malignancies, with about 60 subtypes that arise via various pathogenetic mechanisms. Although establishing etiology for specific NHL subtypes has been historically difficult given their relative rarity, environmental exposures have been repeatedly implicated as risk factors across many subtypes. Large-scale epidemiologic investigations have pinpointed chemical exposures in particular, but causality has not been established, and the exact biologic mechanisms underpinning these associations are unclear. Here we review chemical exposures that have been associated with development of NHL subtypes and discuss their biologic plausibility based on current research.
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Affiliation(s)
- Leah Moubadder
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Lauren E McCullough
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Christopher R Flowers
- Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jean L Koff
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
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22
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Yokoyama A, Taniki N, Nakamoto N, Tomita K, Hara S, Mizukami T, Maruyama K, Yokoyama T. Associations among liver disease, serum lipid profile, body mass index, ketonuria, meal skipping, and the alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes in Japanese men with alcohol dependence. Hepatol Res 2020; 50:565-577. [PMID: 31845443 DOI: 10.1111/hepr.13475] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/19/2019] [Accepted: 12/14/2019] [Indexed: 02/08/2023]
Abstract
AIM To elucidate associations among liver disease, lipid profile, body mass index (BMI), ketonuria, and meal skipping under the influence of alcohol dehydrogenase-1B (ADH1B; rs1229984) and aldehyde dehydrogenase-2 (ALDH2; rs671) genotypes in men with alcohol dependence. METHODS We investigated the associations among these variables in 1768 Japanese men with alcohol dependence. Serum lipid levels were followed up after abstinence. RESULTS The slow-metabolizing ADH1B Arg/Arg genotype and inactive ALDH2 Glu/Lys genotype increased the age- and drinking-adjusted odds ratio or regression coefficient for fatty liver, ketonuria, and serum high-density-lipoprotein cholesterol levels (HDL-C), and decreased these for cirrhosis and serum triglyceride levels (TG). The ADH1B Arg/Arg genotype increased the adjusted regression coefficient for BMI and non-HDL-C. In addition to the positive interlinkage among fatty liver, BMI, and atherogenic dyslipidemia, positive associations were observed of fatty liver with ketonuria and meal skipping, of cirrhosis with the BMI, and of ketonuria with non-HDL-C. Negative associations were observed of cirrhosis with fatty liver, TG, non-HDL-C, and HDL-C, and of ketonuria with BMI and TG. Overall, after admission for 4 or 6 weeks, the TG and HDL-C decreased, and the serum low-density lipoprotein cholesterol levels increased. However, there was no change of the serum low-density lipoprotein in the patients with cirrhosis or of the serum TG in those with fatty liver. CONCLUSIONS These associations and the alterations in lipid profile after abstinence serve as useful information for a better understanding of the clinical features of men with alcohol dependence.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Kengo Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan
| | - Sachiko Hara
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Takeshi Mizukami
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Katsuya Maruyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Wako, Japan
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23
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Hernandez-Castillo C, Termini J, Shuck S. DNA Adducts as Biomarkers To Predict, Prevent, and Diagnose Disease-Application of Analytical Chemistry to Clinical Investigations. Chem Res Toxicol 2020; 33:286-307. [PMID: 31638384 DOI: 10.1021/acs.chemrestox.9b00295] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Characterization of the chemistry, structure, formation, and metabolism of DNA adducts has been one of the most significant contributions to the field of chemical toxicology. This work provides the foundation to develop analytical methods to measure DNA adducts, define their relationship to disease, and establish clinical tests. Monitoring exposure to environmental and endogenous toxicants can predict, diagnose, and track disease as well as guide therapeutic treatment. DNA adducts are one of the most promising biomarkers of toxicant exposure owing to their stability, appearance in numerous biological matrices, and characteristic analytical properties. In addition, DNA adducts can induce mutations to drive disease onset and progression and can serve as surrogate markers of chemical exposure. In this perspective, we highlight significant advances made within the past decade regarding DNA adduct quantitation using mass spectrometry. We hope to expose a broader audience to this field and encourage analytical chemistry laboratories to explore how specific adducts may be related to various pathologies. One of the limiting factors in developing clinical tests to measure DNA adducts is cohort size; ideally, the cohort would allow for model development and then testing of the model to the remaining cohort. The goals of this perspective article are to (1) provide a summary of analyte levels measured using state-of-the-art analytical methods, (2) foster collaboration, and (3) highlight areas in need of further investigation.
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Affiliation(s)
- Carlos Hernandez-Castillo
- Department of Molecular Medicine , Beckman Research Institute at City of Hope Duarte , California 91010 , United States
| | - John Termini
- Department of Molecular Medicine , Beckman Research Institute at City of Hope Duarte , California 91010 , United States
| | - Sarah Shuck
- Department of Molecular Medicine , Beckman Research Institute at City of Hope Duarte , California 91010 , United States
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24
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Yokoyama A, Omori T, Yokoyama T. Changing trends in cancer incidence of upper aerodigestive tract and stomach in Japanese alcohol-dependent men (1993-2018). Cancer Med 2020; 9:837-846. [PMID: 31957322 PMCID: PMC6970038 DOI: 10.1002/cam4.2737] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC), head and neck SCC (HNSCC), and gastric adenocarcinoma (GA) are frequently detected at an early stage using endoscopic screening in Japanese alcohol-dependent men. METHODS We performed endoscopic screening with esophageal iodine staining and oropharyngolaryngeal inspection in 7582 Japanese alcohol-dependent men (40-79 years) during 1993-2018, and retrospectively investigated their initial screening results. RESULTS The 2008-2018 screening showed lower detection rates for ESCC (2.6% vs 4.0%, P = .0009) and GA (0.5% vs 1.4%, P < .0001) for all age brackets, compared with the 1993-2007 screening. The HNSCC detection rate did not change (1.0% vs 1.1%). Multiple logistic regression analyses showed that the 2008-2018 screening had a reduced OR (95% CI) for ESCC (0.34 [0.25-0.47]) and GA (0.19 [0.10-0.35]), compared with the 1993-2007 screening. The reduction in H pylori infection is probably the main reason for the decrease in GA detection over time. Declining trends in pack-years and gastric atrophy and increasing trends in age and body mass index (BMI) were found over time. The presence of advanced gastric atrophy increased the risk for ESCC as well as GA. The inactive heterozygous aldehyde dehydrogenase-2*1/*2 genotype was a strong risk factor for ESCC, HNSCC, and GA. Fewer pack-years and a larger BMI decreased the ESCC risk. However, these confounders cannot fully explain why the incidence of ESCC has decreased markedly over the recent decade. CONCLUSIONS The detection rates of ESCC and GA have markedly decreased during the past decade in the alcohol-dependent population. The enigmatic declining trend of ESCC warrants research on this topic.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction CenterKanagawaJapan
| | - Tai Omori
- Endoscopy CenterKawasaki Municipal Ida HospitalKanagawaJapan
| | - Tetsuji Yokoyama
- Department of Health PromotionNational Institute of Public HealthSaitamaJapan
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25
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Serio RN, Gudas LJ. Modification of stem cell states by alcohol and acetaldehyde. Chem Biol Interact 2019; 316:108919. [PMID: 31846616 PMCID: PMC7036011 DOI: 10.1016/j.cbi.2019.108919] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 11/13/2019] [Accepted: 12/10/2019] [Indexed: 12/20/2022]
Abstract
Ethanol (EtOH) is a recreationally ingested compound that is both teratogenic and carcinogenic in humans. Because of its abundant consumption worldwide and the vital role of stem cells in the formation of birth defects and cancers, delineating the effects of EtOH on stem cell function is currently an active and urgent pursuit of scientific investigation to explicate some of the mechanisms contributing to EtOH toxicity. Stem cells represent a primordial, undifferentiated phase of development; thus encroachment on normal physiologic processes of differentiation into terminal lineages by EtOH can greatly alter the function of progenitors and terminally differentiated cells, leading to pathological consequences that manifest as fetal alcohol spectrum disorders and cancers. In this review we explore the disruptive role of EtOH in differentiation of stem cells. Our primary objective is to elucidate the mechanisms by which EtOH alters differentiation-related gene expression and lineage specifications, thus modifying stem cells to promote pathological outcomes. We additionally review the effects of a reactive metabolite of EtOH, acetaldehyde (AcH), in causing both differentiation defects in stem cells as well as genomic damage that incites cellular aging and carcinogenesis.
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Affiliation(s)
- Ryan N Serio
- Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences of Cornell University, USA.
| | - Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences of Cornell University, USA; Department of Pharmacology, Weill Cornell Medical College of Cornell University, USA.
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26
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Seo W, Gao Y, He Y, Sun J, Xu H, Feng D, Park SH, Cho YE, Guillot A, Ren T, Wu R, Wang J, Kim SJ, Hwang S, Liangpunsakul S, Yang Y, Niu J, Gao B. ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles. J Hepatol 2019; 71:1000-1011. [PMID: 31279903 PMCID: PMC6801025 DOI: 10.1016/j.jhep.2019.06.018] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 06/14/2019] [Accepted: 06/19/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Excessive alcohol consumption is one of the major causes of hepatocellular carcinoma (HCC). Approximately 30-40% of the Asian population are deficient for aldehyde dehydrogenase 2 (ALDH2), a key enzyme that detoxifies the ethanol metabolite acetaldehyde. However, how ALDH2 deficiency affects alcohol-related HCC remains unclear. METHODS ALDH2 polymorphisms were studied in 646 patients with viral hepatitis B (HBV) infection, who did or did not drink alcohol. A new model of HCC induced by chronic carbon tetrachloride (CCl4) and alcohol administration was developed and studied in 3 lines of Aldh2-deficient mice: including Aldh2 global knockout (KO) mice, Aldh2*1/*2 knock-in mutant mice, and liver-specific Aldh2 KO mice. RESULTS We demonstrated that ALDH2 deficiency was not associated with liver disease progression but was associated with an increased risk of HCC development in cirrhotic patients with HBV who consumed excessive alcohol. The mechanisms underlying HCC development associated with cirrhosis and alcohol consumption were studied in Aldh2-deficient mice. We found that all 3 lines of Aldh2-deficient mice were more susceptible to CCl4 plus alcohol-associated liver fibrosis and HCC development. Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl4 plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2, and TAZ), thereby promoting HCC. CONCLUSIONS ALDH2 deficiency is associated with an increased risk of alcohol-related HCC development from fibrosis in patients and in mice. Mechanistic studies reveal a novel mechanism that Aldh2-deficient hepatocytes promote alcohol-associated HCC by transferring harmful oxidized mitochondrial DNA-enriched extracellular vesicles into HCC and subsequently activating multiple oncogenic pathways in HCC. LAY SUMMARY Alcoholics with an ALDH2 polymorphism have an increased risk of digestive tract cancer development, however, the link between ALDH2 deficiency and hepatocellular carcinoma (HCC) development has not been well established. In this study, we show that ALDH2 deficiency exacerbates alcohol-associated HCC development both in patients and mouse models. Mechanistic studies revealed that after chronic alcohol exposure, Aldh2-deficient hepatocytes produce a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which can be delivered into neighboring HCC cells and subsequently activate multiple oncogenic pathways, promoting HCC.
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Affiliation(s)
- Wonhyo Seo
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Yanhang Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA;,Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jing Sun
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seol Hee Park
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Young-Eun Cho
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA;,Department of Food and Nutrition, Andong National University, Andong, South Korea
| | - Adrien Guillot
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tianyi Ren
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ruihong Wu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Jingyun Wang
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Seung-Jin Kim
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine;,Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA;,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
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Song BJ, Abdelmegeed MA, Cho YE, Akbar M, Rhim JS, Song MK, Hardwick JP. Contributing Roles of CYP2E1 and Other Cytochrome P450 Isoforms in Alcohol-Related Tissue Injury and Carcinogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1164:73-87. [PMID: 31576541 DOI: 10.1007/978-3-030-22254-3_6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The purpose of this review is to briefly summarize the roles of alcohol (ethanol) and related compounds in promoting cancer and inflammatory injury in many tissues. Long-term chronic heavy alcohol exposure is known to increase the chances of inflammation, oxidative DNA damage, and cancer development in many organs. The rates of alcohol-mediated organ damage and cancer risks are significantly elevated in the presence of co-morbidity factors such as poor nutrition, unhealthy diets, smoking, infection with bacteria or viruses, and exposure to pro-carcinogens. Chronic ingestion of alcohol and its metabolite acetaldehyde may initiate and/or promote the development of cancer in the liver, oral cavity, esophagus, stomach, gastrointestinal tract, pancreas, prostate, and female breast. In this chapter, we summarize the important roles of ethanol/acetaldehyde in promoting inflammatory injury and carcinogenesis in several tissues. We also review the updated roles of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and other cytochrome P450 isozymes in the metabolism of various potentially toxic substrates, and consequent toxicities, including carcinogenesis in different tissues. We also briefly describe the potential implications of endogenous ethanol produced by gut bacteria, as frequently observed in the experimental models and patients of nonalcoholic fatty liver disease, in promoting DNA mutation and cancer development in the liver and other tissues, including the gastrointestinal tract.
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Affiliation(s)
- Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
| | - Mohamed A Abdelmegeed
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
| | - Young-Eun Cho
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.,Department of Food Science and Nutrition, Andong National University, Andong, Republic of Korea
| | - Mohammed Akbar
- Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
| | - Johng S Rhim
- Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Min-Kyung Song
- Investigational Drug Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - James P Hardwick
- Biochemistry and Molecular Pathology in the Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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Association of ADH1B Arg47His polymorphism with the risk of cancer: a meta-analysis. Biosci Rep 2019; 39:BSR20181915. [PMID: 30872408 PMCID: PMC6443950 DOI: 10.1042/bsr20181915] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 03/03/2019] [Accepted: 03/08/2019] [Indexed: 01/04/2023] Open
Abstract
Alcohol consumption has been established to be a major factor in the development and progress of cancer. Genetic polymorphisms of alcohol-metabolism genes result in differences between individuals in exposure to acetaldehyde, leading to possible carcinogenic effects. Arg47His (rs1229984 G > A) in ADH1B have been frequently studied for its potential effect on carcinogenesis. However, the findings are as yet inconclusive. To gain a more precise estimate of this potential association, we conducted a meta-analysis including 66 studies from 64 articles with 31999 cases and 50964 controls. The pooled results indicated that ADH1B Arg47His polymorphism is significantly associated with the decreased risk of overall cancer (homozygous model, odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.49–0.77; heterozygous model, OR = 0.71, 95% CI = 0.60–0.84; recessive model, OR = 0.83, 95% CI = 0.76–0.91; dominant model, OR = 0.62, 95% CI = 0.53–0.72; and allele comparison, OR = 0.82, 95% CI = 0.75–0.89). Stratified analysis by cancer type and ethnicity showed that a decreased risk was associated with esophageal cancer and head and neck cancer amongst Asians. In conclusion, our meta-analysis suggested that ADH1B Arg47His polymorphism was significantly associated with decreased overall cancer risk. These findings need further validation in large multicenter investigations.
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Risk Factors Linking Esophageal Squamous Cell Carcinoma With Head and Neck Cancer or Gastric Cancer. J Clin Gastroenterol 2019; 53:e164-e170. [PMID: 29498952 DOI: 10.1097/mcg.0000000000001019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
GOALS To investigate retrospectively the risk factors for synchronous and metachronous cancers in the upper gastrointestinal tract in patients with superficial esophageal squamous cell carcinoma (ESCC). BACKGROUND In patients who have received endoscopic resection (ER) for ESCC, synchronous and metachronous cancers are frequently detected not only in the esophagus but also in the head and neck area and the stomach. STUDY A total of 285 patients who received ER for superficial ESCC were enrolled in this analysis. These patients were periodically followed-up endoscopically. Cumulative occurrence rates of the metachronous second primary cancers were determined by Kaplan-Meier method. Risk factors for synchronous and metachronous cancers in the head and neck area and the stomach were determined by logistic regression analyses. RESULTS During a mean follow-up period of 76 months, the 5-year cumulative occurrence of metachronous esophageal, head and neck, and stomach cancer was 14.0%, 2.8%, and 4.1%, respectively. Although the presence of multiple lugol-voiding lesions in the esophagus was a significant risk factor for synchronous and metachronous head and neck cancers (odds ratio, 3.8; 95% confidence interval, 1.7-9.0), older age (>65 y) was a significant risk factor for synchronous and metachronous gastric cancer (odds ratio, 3.1; 95% confidence interval, 1.2-9.3). CONCLUSIONS The risk factors for the cooccurrence of head and neck cancer and that of gastric cancer in patients with ESCC differ. This information will likely be useful for managing patients who have been treated with ER for ESCC and who possess carcinogenic potential throughout the upper gastrointestinal tract.
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Shiotani A, Ishikawa H, Mutoh M, Takeshita T, Nakamura T, Morimoto K, Sakai T, Wakabayashi K, Matsuura N. Impact of Diarrhea after Drinking on Colorectal Tumor Risk: A Case Control Study. Asian Pac J Cancer Prev 2019; 20:795-799. [PMID: 30909690 PMCID: PMC6825756 DOI: 10.31557/apjcp.2019.20.3.795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Background: Recently, the number of colorectal cancer (CRC) cases in Japan has been increasing, and is strongly influenced by alcohol consumption. On the other hand, there are several reports suggesting a relationship between bowel movement (constipation and diarrhea) and CRC development. Moreover, it is generally known that diarrhea may occur after drinking. However, the mechanism by which drinking alcohol increases CRC is not fully clarified yet. We hypothesized that diarrhea after drinking may play an important role in colorectal carcinogenesis. Methods: We examined the presence of diarrhea after drinking and further evaluated the correlation of diarrhea after drinking with the incidence of colorectal tumors. To obtain the status of the feces, a self-recorded questionnaire survey was administered using the dietary-recording method. Blood samples were obtained to analyze the ALDH2 Glu504Lys and ADH1B His48Arg polymorphisms. Results: The participants were 417 patients who had undergone a total colonoscopy. The control was selected from 186 patients who underwent a medical checkup at the same hospital during the same time period. The odds ratio for all subjects was 2.1 (95% CI: 1.18 - 3.80), and that for heavy drinkers was 4.2 (1.48 - 11. 90). Conclusions: The results demonstrated that those who have diarrhea after drinking possess a high risk of developing colon tumors.
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Affiliation(s)
- Akiko Shiotani
- Department of Molecular Pathology, Osaka University Graduate School of Medicine and Health Science, Osaka, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michihiro Mutoh
- Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.
| | - Tatsuya Takeshita
- Department of Public Health, Wakayama Medical University School of Medicine, Wakayama, Japan
| | | | - Kanehisa Morimoto
- Department of Hygiene and Preventive Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Toshiyuki Sakai
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keiji Wakabayashi
- Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan
| | - Nariaki Matsuura
- Department of Molecular Pathology, Osaka University Graduate School of Medicine and Health Science, Osaka, Japan
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Rodríguez-Zavala JS, Calleja LF, Moreno-Sánchez R, Yoval-Sánchez B. Role of Aldehyde Dehydrogenases in Physiopathological Processes. Chem Res Toxicol 2019; 32:405-420. [PMID: 30628442 DOI: 10.1021/acs.chemrestox.8b00256] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Many different diseases are associated with oxidative stress. One of the main consequences of oxidative stress at the cellular level is lipid peroxidation, from which toxic aldehydes may be generated. Below their toxicity thresholds, some aldehydes are involved in signaling processes, while others are intermediaries in the metabolism of lipids, amino acids, neurotransmitters, and carbohydrates. Some aldehydes ubiquitously distributed in the environment, such as acrolein or formaldehyde, are extremely toxic to the cell. On the other hand, aldehyde dehydrogenases (ALDHs) are able to detoxify a wide variety of aldehydes to their corresponding carboxylic acids, thus helping to protect from oxidative stress. ALDHs are located in different subcellular compartments such as cytosol, mitochondria, nucleus, and endoplasmic reticulum. The aim of this review is to analyze, and highlight, the role of different ALDH isoforms in the detoxification of aldehydes generated in processes that involve high levels of oxidative stress. The ALDH physiological relevance becomes evident by the observation that their expression and activity are enhanced in different pathologies that involve oxidative stress such as neurodegenerative disorders, cardiopathies, atherosclerosis, and cancer as well as inflammatory processes. Furthermore, ALDH mutations bring about several disorders in the cell. Thus, understanding the mechanisms by which these enzymes participate in diverse cellular processes may lead to better contend with the damage caused by toxic aldehydes in different pathologies by designing modulators and/or protocols to modify their activity or expression.
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Affiliation(s)
| | | | - Rafael Moreno-Sánchez
- Departamento de Bioquímica , Instituto Nacional de Cardiología , México 14080 , México
| | - Belem Yoval-Sánchez
- Departamento de Bioquímica , Instituto Nacional de Cardiología , México 14080 , México
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Yokoyama A, Yokoyama T, Omori T, Maesato H, Takimura T, Iwahara C, Kimura M, Matsui T, Mizukami T, Maruyama K. Endoscopic screening using esophageal iodine staining and genotypes of ADH1B and ALDH2 in Japanese alcohol-dependent women. PLoS One 2019; 14:e0210546. [PMID: 30629674 PMCID: PMC6328133 DOI: 10.1371/journal.pone.0210546] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 12/27/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The presence of large or multiple esophageal distinct iodine-unstained lesions (DIULs) is a strong predictor of field cancerization in the upper aerodigestive tract. Several risk factors for DIULs, including genetic polymorphisms of alcohol and aldehyde dehydrogenases (ADH1B, rs1229984; ALDH2, rs671), have been demonstrated in Japanese alcohol-dependent men. However, few evaluations of alcohol-dependent women have been conducted in this field. METHODS Using multiple logistic regression models, we investigated the results of screening using esophageal iodine staining and the identification of determinants for esophageal DIULs in 472 Japanese alcohol-dependent women. RESULTS DIULs ≥5 mm, multiple DILUs, and both characteristics were observed in 35 (7.4%), 31 (6.6%), and 16 (3.4%) patients, respectively. DIULs ≥5 mm were histologically diagnosed as low-grade intraepithelial neoplasia in 26 patients and superficial squamous cell carcinoma in 9 patients. Although the inactive heterozygous ALDH2*1/*2 genotype was more common (33.3% vs. 11.4%, p = 0.002) in the group with DIULs ≥5 mm than in the group without DIULs ≥5 mm, no significant differences in the results of a questionnaire asking about current and past facial flushing after a glass of beer were seen between the groups with and without DIULs ≥5 mm. When individuals with current or former flushing were assumed to have inactive ALDH2, the sensitivity and specificity of current or former flushing to identify the presence of inactive ALDH2 were 50.0% and 93.5%, respectively; these values were previously reported to be 88% and 92%, respectively, in a Japanese general female population. The low sensitivity in the present study suggests that a lack of alcohol flushing may play a crucial role in the development of alcohol dependence in women with inactive ALDH2. No significant differences in age, usual alcohol consumption, or smoking habits were observed according to ADH1B and ALDH2 genotypes. Multiple logistic regression analyses showed that the slow-metabolizing ADH1B*1/*1 genotype (odds ratio [95% confidence interval], 12.5 [4.82-32.4] and 9.89 [3.50-27.9]), the inactive heterozygous ALDH2*1/*2 genotype (2.94 [1.18-7.38] and 3.79 [1.40-10.3]), a lower body mass index per -1 kg/m2 (1.17 [1.02-1.35] and 1.38 [1.14-1.67]), and a mean corpuscular volume ≥106 fl (3.70 [1.56-8.81] and 3.27 [1.24-8.64]) increased the risk of DIULs ≥5 mm and multiple DIULs, respectively. The combination of ADH1B*1/*1 and ALDH2*1/*2 markedly increased the risk of esophageal DIULs ≥5 mm (39.3 [10.6-146]). CONCLUSIONS Japanese alcohol-dependent women shared several common risk factors for esophageal squamous cell neoplasia with alcohol-dependent men, but with considerably different magnitudes.
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Affiliation(s)
- Akira Yokoyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Tetsuji Yokoyama
- Department of Health Promotion, National Institute of Public Health, Wako, Saitama, Japan
| | - Tai Omori
- Endoscopy Center, Kawasaki Municipal Ida Hospital, Kawasaki, Kanagawa, Japan
| | - Hitoshi Maesato
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Tsuyoshi Takimura
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Chie Iwahara
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Mitsuru Kimura
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Toshifumi Matsui
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Takeshi Mizukami
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
| | - Katsuya Maruyama
- National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Kanagawa, Japan
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Juárez OE, Lafarga-De la Cruz F, Leyva-Valencia I, López-Landavery E, García-Esquivel Z, Díaz F, Re-Araujo D, Vadopalas B, Galindo-Sánchez CE. Transcriptomic and metabolic response to chronic and acute thermal exposure of juvenile geoduck clams Panopea globosa. Mar Genomics 2018; 42:1-13. [DOI: 10.1016/j.margen.2018.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 09/18/2018] [Accepted: 09/18/2018] [Indexed: 10/28/2022]
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Ishioka K, Masaoka H, Ito H, Oze I, Ito S, Tajika M, Shimizu Y, Niwa Y, Nakamura S, Matsuo K. Association between ALDH2 and ADH1B polymorphisms, alcohol drinking and gastric cancer: a replication and mediation analysis. Gastric Cancer 2018; 21:936-945. [PMID: 29616362 DOI: 10.1007/s10120-018-0823-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 03/29/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde accumulation after alcohol drinking. To date, however, evidence for a significant ALDH2-alcohol drinking interaction and a mediation effect of ALDH2/ADH1B through alcohol drinking on gastric cancer have remained unclear. We conducted two case-control studies to validate the interaction and to estimate the mediation effect on gastric cancer. METHODS We calculated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2/ADH1B genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways. RESULTS ALDH2 Lys alleles had a higher risk with increased alcohol consumption compared with ALDH2 Glu/Glu (OR for heavy drinking, 3.57; 95% CI 2.04-6.27; P for trend = 0.007), indicating a significant ALDH2-alcohol drinking interaction (Pinteraction = 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67; 95% CI 1.38-2.03) and a protective indirect effect (OR 0.84; 95% CI 0.76-0.92) of the ALDH2 Lys alleles with the ALDH2-alcohol drinking interaction. No significant association of ADH1B with gastric cancer was observed. CONCLUSION The observed ALDH2-alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.
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Affiliation(s)
- Kuka Ishioka
- Department of Pathology and Clinical Laboratories, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
| | - Hiroyuki Masaoka
- Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.,Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hidemi Ito
- Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.,Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Isao Oze
- Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Masahiro Tajika
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yasumasa Niwa
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Shigeo Nakamura
- Department of Pathology and Clinical Laboratories, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keitaro Matsuo
- Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. .,Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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35
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Watanabe M. Recent Topics and Perspectives on Esophageal Cancer in Japan. JMA J 2018; 1:30-39. [PMID: 33748520 PMCID: PMC7969908 DOI: 10.31662/jmaj.2018-0002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 05/31/2018] [Indexed: 12/18/2022] Open
Abstract
Despite recent advances in multidisciplinary treatment strategy, outcomes of esophageal cancer treatment still remain unsatisfactory. There are two histologic subtypes of esophageal cancer, namely, squamous cell carcinoma and adenocarcinoma, and these subtypes turned out to be genetically separate diseases. I focused on nine topics among the cancer's epidemiology, diagnosis, and treatment, and reviewed the literature. Although the number of patients with esophageal cancer has been continuously increasing, the cause of esophageal cancer is evident in a substantial proportion of patients, and public education may be able to decrease its incidence. Early detection and less invasive treatment will improve the outcome of patients. Minimally invasive esophagectomy decreased surgical invasiveness and improved short-term outcomes in the clinical trials. Centralization of patients to high-volume centers and introduction of multidisciplinary perioperative care bundle may further improve the outcome of patients undergoing esophagectomy. Although no targeting agent has shown efficacy in patients with esophageal cancer, immune checkpoint blockades are promising, and the results of phase III trials are awaited.
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Affiliation(s)
- Masayuki Watanabe
- Department of Gastroenterological Surgery, the Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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36
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Yamamoto K, Takano K, Kondo A, Kurose M, Obata K, Himi T. Clinical and Prognostic Analysis of Hypopharyngeal Squamous Cell Carcinoma with Synchronous and Metachronous Multiple Malignancies. ACTA ACUST UNITED AC 2018; 32:165-170. [PMID: 29275315 DOI: 10.21873/invivo.11220] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/09/2017] [Accepted: 11/10/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIM To analyze the clinical features and prevalence of synchronous and metachronous second primary malignancies (SPMs) in patients with hypopharyngeal squamous cell carcinoma (HSCC), their associated risk factors, and cause-specific mortality. PATIENTS AND METHODS We retrospectively reviewed 136 patients treated with curative intent at our hospital. Statistical analyses were performed to determine factors predictive of SPM and cause-specific mortality. RESULTS Sixty-three of 136 patients (46.3%) developed SPM; of these, 41 (30.1%) and 42 (30.9%) had synchronous and metachronous SPMs, respectively, with patient overlap. The most common site of synchronous and metachronous SPMs was the oesophagus (65.8% and 24.4%, respectively); the corresponding overall survival rates were 34.1% and 66.5%, respectively. Furthermore, heavy drinking was significantly correlated with synchronous SPM (p<0.001). CONCLUSION Oesophageal cancer surveillance is recommended for patients with HSCC, especially heavy drinkers. Our findings may help identify and properly manage HSCC patients at high risk of SPMs.
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Affiliation(s)
- Keisuke Yamamoto
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kenichi Takano
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Atsushi Kondo
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Makoto Kurose
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kazufumi Obata
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tetsuo Himi
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Wichmann G, Lehmann C, Herchenhahn C, Kolb M, Hofer M, Wiegand S, Dietz A. Development of a Human Leukocyte Antigen Score to Predict Progression-Free Survival in Head and Neck Squamous Cell Carcinoma Patients. Front Oncol 2018; 8:168. [PMID: 29868484 PMCID: PMC5966661 DOI: 10.3389/fonc.2018.00168] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 05/01/2018] [Indexed: 01/09/2023] Open
Abstract
Background In personalized medicine and treatment stratification of head and neck squamous cell carcinoma (HNSCC), the heterogeneous genetic background of patients is not considered. Human leukocyte antigen (HLA) alleles and HLA haplotypes (HLA traits) are linked to development of HNSCC and affect progression-free survival (PFS) of HNSCC patients but most head and neck oncologists are not familiar with HLA typing. Hence, we developed an HLA-score abstracting from complexity of HLA-typing results to facilitate potential use of HLA-associated hazard ratios (HR) for prognostic stratification. Methods The HR for PFS of 8 HLA traits shown to be independent predictors (Pi) of PFS in a test cohort (TC) of 90 HNSCC patients were used to build the HLA-score based on the natural logarithm (ln) of the Pi-associated HR. Crude ln-transformed HR of the eight Pi, alleles B*13 (2), B*35 (1), B*51 (2), DQB1*06 (1), homozygous Cw (1), homozygous DRB4 (2), and haplotypes A*01/B*08 (−6) and B*08/C*07 (4), were summed up to yield the individual patient’s HLA-score. Receiver operating characteristic (ROC) and Kaplan–Meier curves were used to proof the suitability of the HLA-score as prognostic marker for PFS. An independent validation cohort (iVC) of 32 patients treated in the larynx-organ preservation trial DeLOS-II was utilized for validation. Results The individual HLA-scores (range −2 to 6) in TC classified HNSCC patients regarding PFS. ROC analysis (area under the curve = 0.750, 95% CI 0.665–0.836; P = 0.0000034) demonstrated an optimum cutoff for the HLA-score at 0.5 (97.9% sensitivity, 34.7% specificity), and 70/90 patients in TC with HLA-score > 0 had significant reduced PFS (P = 0.001). Applying the same classifier (HLA-score > 0) confirmed these findings in the iVC revealing reduced PFS of 25/32 patients (P = 0.040). Conclusion HLA traits constitute critical Pi. Considering the HLA-score may potentially facilitate the use of genetic information from HLA typing for prognostic stratification, e.g., within clinical trials.
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Affiliation(s)
- Gunnar Wichmann
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Leipzig, Germany.,LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
| | - Claudia Lehmann
- Institute for Transfusion Medicine, University Hospital Leipzig, Leipzig, Germany
| | - Cindy Herchenhahn
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Leipzig, Germany.,Clinic for Anesthesiology and Intensive Care, University Hospital Leipzig, Leipzig, Germany
| | - Marlen Kolb
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Mathias Hofer
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Susanne Wiegand
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Andreas Dietz
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Leipzig, Germany.,LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
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Ye X, Wang X, Shang L, Zhu G, Su H, Han C, Qin W, Li G, Peng T. Genetic variants of ALDH2-rs671 and CYP2E1-rs2031920 contributed to risk of hepatocellular carcinoma susceptibility in a Chinese population. Cancer Manag Res 2018; 10:1037-1050. [PMID: 29765251 PMCID: PMC5942392 DOI: 10.2147/cmar.s162105] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective Acetaldehyde dehydrogenase 2 (ALDH2) and cytochrome P450 2E1 (CYP2E1) have been associated with hepatocellular carcinoma (HCC) susceptibility and prognosis. The polymorphisms ALDH2 rs671 and CYP2E1 rs2031920 are reportedly correlated with the prevalence of HCC in other countries. The aim of this study was to investigate associations between ALDH2 and CYP2E1, and HCC susceptibility in a population of Guangxi, southern China, an area with a high incidence of HCC. Patients and methods The study cohort included 300 HCC cases, 292 healthy controls for HCC susceptibility analysis, and another 20 HCC cases and 10 healthy controls for ascertainment. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. Results The study results demonstrated that mutant genotypes of ALDH2 (G/A and A/A) led to significant differences in HCC susceptibility, as compared with the wild genotype (G/G) with the same C1/C1 genotype in non-drinking individuals (adjusted P=0.010, OR=0.20, 95% CI=0.06–0.68). The mutant genotypes of CYP2E1 (C1/C2 and C2/C2) brought about significant differences in HCC susceptibility, as compared with the wild genotype (C1/C1) and the same G/G genotype (adjusted P=0.025, OR=0.42, 95% CI=0.20–0.90). Drinking plays a role in HCC susceptibility in the same G/G genotype individuals (adjusted P=0.004, OR=0.32, 95% CI=0.15–0.69), but had no impact when combined with CYP2E1 for analysis (all P>0.05). Conclusion These results suggest that the mutant genotypes of ALDH2 and CYP2E1 may be protective factors for HCC susceptibility in Guangxi province, China.
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Affiliation(s)
- Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Liming Shang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Guanghui Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
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Okuda M, Inoue J, Fujiwara N, Kawano T, Inazawa J. Subcloning and characterization of highly metastatic cells derived from human esophageal squamous cell carcinoma KYSE150 cells by in vivo selection. Oncotarget 2018; 8:34670-34677. [PMID: 28410227 PMCID: PMC5471001 DOI: 10.18632/oncotarget.16668] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 03/19/2017] [Indexed: 11/25/2022] Open
Abstract
Esophageal cancer is the eighth most common cancer and the sixth most common cause of cancer-related deaths worldwide. Despite the research progress in understanding the disease, the mechanism underlying the metastasis is still unclear. Here, we successfully generated a highly metastatic cell subline, designated as KYSE150-LuM, derived from an esophageal squamous cell carcinoma cell line (KYSE150) by in vivo selection. To elucidate the mechanisms driving metastasis, we characterized the gene expression differences between LuM cells and parent KYSE150 cells. IL-6, IL-1β, and LCN2, previously associated with tumor growth and metastasis, were up-regulated in LuM cells. Recent studies on cancer have increasingly focused on the tumor microenvironment, from which these cytokines are released. The fact that these three cytokines (IL-6, IL-1β, LCN2) were up-regulated in LuM cells indicates that these highly metastatic cells obtained through in vivo selection will be a useful resource for further studies on elucidating the mechanisms underlying the tumor microenvironment which is associated with cytokine-related tumor growth and metastasis. Moreover, LuM cells could disseminate to the lung in shorter period of time in vivo, indicating their utility for in vivo experiments of metastasis and new therapeutic targets in a shorter period of time than currently possible.
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Affiliation(s)
- Masafumi Okuda
- Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Inoue
- Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Bioresource Research Center, Research and Industry-University Alliance Organization, Tokyo Medical and Dental University, Tokyo, Japan
| | - Naoto Fujiwara
- Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatsuyuki Kawano
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Johji Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Bioresource Research Center, Research and Industry-University Alliance Organization, Tokyo Medical and Dental University, Tokyo, Japan
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Pastorino R, Iuliano L, Vecchioni A, Arzani D, Milic M, Annunziata F, Zerbinati C, Capoluongo E, Bonassi S, McKay JD, Boccia S. Effect of alcohol dehydrogenase-1B and -7 polymorphisms on blood ethanol and acetaldehyde concentrations in healthy subjects with a history of moderate alcohol consumption. Drug Test Anal 2018; 10:488-495. [PMID: 28731573 DOI: 10.1002/dta.2251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 07/18/2017] [Accepted: 07/18/2017] [Indexed: 03/25/2024]
Abstract
This study aims to evaluate the effect of ADH1B and ADH7 genotypes on blood acetaldehyde and ethanol levels after alcohol ingestion, and to measure the genotoxic effect of smoking and ethanol on the buccal cells, also controlling for ADH variants. We recruited healthy Italian subjects with at least a moderate history of alcohol consumption. All subjects were given an alcoholic drink of 0.4 g ethanol /kg of body weight. Blood venous samples were collected at baseline, and 30, 60, 90, and 120 minutes after ingestion. Buccal cells were collected before ethanol ingestion. Sixty subjects were enrolled in the study. Individuals with the ADH1B GG genotype had median ethanol levels of 5.0mM (IQR 3.4-7.2), and those with the ADH1B GT/TT genotype had 4.7mM (IQR 4.2-4.8). Corresponding acetaldehyde levels were 1.5μM (IQR 0.7-2.6) for ADH1B GG genotype and 1.6μM (IQR 1.5-1.7) for ADH1B CG/GG genotype. Individuals with the ADH7 CC genotype had median ethanol levels of 5.0mM (IQR 3.3-7.2), while 5.0mM (IQR 4.7-5.6) was in those with the ADH7 CG/GG genotype. Corresponding acetaldehyde levels were 1.5 μM (IQR 0.7-2.6) for ADH7 CC genotype and 1.5 μM (IQR 1.4-1.6) for ADH7 CG/GG genotypes. A non-significant increase in the frequency of karyolitic and pyknotic cells was found in the group of heavy drinkers and current smokers, when compared to the moderate drinkers and the non-smokers. Our study does not support the hypothesis that ADH1B and ADH7 genotypes affect blood ethanol and acetaldehyde concentration.
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Affiliation(s)
- Roberta Pastorino
- Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luigi Iuliano
- Department of Medico-Surgical Sciences and Biotechnologies, Laboratory of Vascular Biology and Mass Spectrometry, Sapienza University of Rome, Latina, Italy
| | - Alessia Vecchioni
- Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Dario Arzani
- Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Mirta Milic
- IRCCS San Raffaele Pisana, Clinical and Molecular Epidemiology, Rome, Italy
- Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Francesca Annunziata
- Laboratory of Clinical Molecular and Personalized Diagnostics, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara Zerbinati
- Department of Medico-Surgical Sciences and Biotechnologies, Laboratory of Vascular Biology and Mass Spectrometry, Sapienza University of Rome, Latina, Italy
| | - Ettore Capoluongo
- Laboratory of Clinical Molecular and Personalized Diagnostics, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Stefano Bonassi
- IRCCS San Raffaele Pisana, Clinical and Molecular Epidemiology, Rome, Italy
| | - James D McKay
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Stefania Boccia
- Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Fondazione Policlinico 'A. Gemelli' Rome, Italy
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Kim J, Yum S, Kang C, Kang SJ. Gene-gene interactions in gastrointestinal cancer susceptibility. Oncotarget 2018; 7:67612-67625. [PMID: 27588484 PMCID: PMC5341900 DOI: 10.18632/oncotarget.11701] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 08/24/2016] [Indexed: 01/02/2023] Open
Abstract
Cancer arises from complex, multi-layer interactions between diverse genetic and environmental factors. Genetic studies have identified multiple loci associated with tumor susceptibility. However, little is known about how germline polymorphisms interact with one another and with somatic mutations within a tumor to mediate acquisition of cancer traits. Here, we survey recent studies showing gene-gene interactions, also known as epistases, affecting genetic susceptibility in colorectal, gastric and esophageal cancers. We also catalog epistasis types and cancer hallmarks with respect to the interacting genes. A total of 22 gene variation pairs displayed all levels of statistical epistasis, including synergistic, redundant, suppressive and co-suppressive interactions. Five genes primarily involved in base excision repair formed a linear topology in the interaction network, MUTYH-OGG1-XRCC1-PARP1-MMP2, and three genes in mTOR cell-proliferation pathway formed another linear network, PRKAG2-RPS6KB1-PIK3CA. Discrete pairwise epistasis was also found in nucleotide excision repair, detoxification, proliferation, TP53, TGF-β and other pathways. We propose that three modes of biological interaction underlie the molecular mechanisms for statistical epistasis. The direct binding, linear pathway and convergence modes can exhibit any level of statistical epistasis in susceptibility to gastrointestinal cancers, and this is likely true for other complex diseases as well. This review highlights the link between cancer hallmarks and susceptibility genes.
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Affiliation(s)
- Jineun Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Seoyun Yum
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Changwon Kang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Suk-Jo Kang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
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Lu RB, Chang YH, Wang TY, Lee SY, Chen PS, Yang YK. The aldehyde dehydrogenase 2 polymorphisms on neuropsychological performance in bipolar II disorder with or without comorbid anxiety disorder. PLoS One 2018; 13:e0192229. [PMID: 29425204 PMCID: PMC5806854 DOI: 10.1371/journal.pone.0192229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 01/18/2018] [Indexed: 01/26/2023] Open
Abstract
Anxiety disorders (ADs), the most common comorbid illnesses with bipolar disorder (BP) has been reported to associate with dopamine system. Dopamine, metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase 2 (ALDH2), and the distribution of the ALDH2*1/*1, and ALDH2*1/*2+ALDH*2/*2 alleles in the Han Chinese general population is relatively equal. The association between dopamine metabolic enzymes and cognitive performance in patients with bipolar II disorder (BP-II) comorbid with AD is unclear. This study proposed to explore the role of ALDH2 polymorphisms on neuropsychological performance between BP-II comorbid with or without AD. One hundred ninety-seven BP-II patients with and without a comorbid AD were recruited and compared with 130 healthy controls (HCs). A polymerase chain reaction and a restriction fragment length polymorphism analysis were used to determine genotypes for ALDH2, and study participants underwent neuropsychological tests. An interaction between AD comorbidity and the ALDH2 polymorphisms was found in different domain of cognitive dysfunction in the BP-II patients. The ALDH2 polymorphisms might have different effects on the neuropsychological performance of BP-II patients with and without comorbid AD.
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Affiliation(s)
- Ru-Band Lu
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yun-Hsuan Chang
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- * E-mail: ,
| | - Tzu-Yun Wang
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
| | - Sheng-Yu Lee
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Psychiatry, Kaohsiung Veteran’s General Hospital, Kaohsiung, Taiwan
- Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Psychiatry, Faculty of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan
| | - Po See Chen
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
- Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen Kuang Yang
- Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
- Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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HPV, KRAS mutations, alcohol consumption and tobacco smoking effects on esophageal squamous-cell carcinoma carcinogenesis. Int J Biol Markers 2018; 27:1-12. [PMID: 22020370 DOI: 10.5301/jbm.2011.8737] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2011] [Indexed: 12/18/2022]
Abstract
Esophageal squamous-cell carcinoma (ESCC) is an invasive neoplastic disease generally associated with poor survival rates. The incidence of ESCC is characterized by marked geographic variation, with highest rates noted in developing Southeastern African, Central and Eastern Asian countries. In the developed Western European and North American regions where there is a low disease incidence, heavy alcohol and cigarette consumption constitute major risk factors. The toxic effects of both these risk factors cause chronic irritation and inflammation of the esophageal mucosa, while at the cellular level they further confer mutagenic effects by the activation of oncogenes (e.g., RAS mutations), inhibition of tumor-suppressor genes, and profound DNA damage. Viral infections, particularly with human papillomavirus, may activate specific antiapoptotic, proliferative and malignant cellular responses that may be intensified in combination with the effects of alcohol and tobacco. In countries with a high ESCC incidence, low socioeconomic status and an inadequate diet of poorly preserved food are combined with basic nutritional deficiencies and inadequate medical treatment. These conditions are favorable to the above-mentioned risk factors implicated in ESCC development, which may be present and/or habitually used in certain populations. New perspectives in epidemiological studies of ESCC development and its risk factors allow genome-wide research involving specific environments and habits. Such research should consist of adequately large and representative samples, should use newly designed informative genetic markers, and apply genomic variation analysis of the functional transcripts involved in malignant cell cycle regulation and neoplastic transformation in the multi-step process of ESCC carcinogenesis.
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Stornetta A, Guidolin V, Balbo S. Alcohol-Derived Acetaldehyde Exposure in the Oral Cavity. Cancers (Basel) 2018; 10:E20. [PMID: 29342885 PMCID: PMC5789370 DOI: 10.3390/cancers10010020] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/09/2018] [Accepted: 01/10/2018] [Indexed: 12/12/2022] Open
Abstract
Alcohol is classified by the International Agency for Research on Cancer (IARC) as a human carcinogen and its consumption has been associated to an increased risk of liver, breast, colorectum, and upper aerodigestive tract (UADT) cancers. Its mechanisms of carcinogenicity remain unclear and various hypotheses have been formulated depending on the target organ considered. In the case of UADT cancers, alcohol's major metabolite acetaldehyde seems to play a crucial role. Acetaldehyde reacts with DNA inducing modifications, which, if not repaired, can result in mutations and lead to cancer development. Despite alcohol being mainly metabolized in the liver, several studies performed in humans found higher levels of acetaldehyde in saliva compared to those found in blood immediately after alcohol consumption. These results suggest that alcohol-derived acetaldehyde exposure may occur in the oral cavity independently from liver metabolism. This hypothesis is supported by our recent results showing the presence of acetaldehyde-related DNA modifications in oral cells of monkeys and humans exposed to alcohol, overall suggesting that the alcohol metabolism in the oral cavity is an independent cancer risk factor. This review article will focus on illustrating the factors modulating alcohol-derived acetaldehyde exposure and effects in the oral cavity.
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Affiliation(s)
- Alessia Stornetta
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Valeria Guidolin
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Silvia Balbo
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN 55455, USA.
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Avinçsal MO, Shinomiya H, Teshima M, Kubo M, Otsuki N, Kyota N, Sasaki R, Zen Y, Nibu KI. Impact of alcohol dehydrogenase-aldehyde dehydrogenase polymorphism on clinical outcome in patients with hypopharyngeal cancer. Head Neck 2017; 40:770-777. [PMID: 29286190 DOI: 10.1002/hed.25050] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 09/04/2017] [Accepted: 11/16/2017] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The purpose of this research was to investigate the association between alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) polymorphisms and hypopharyngeal squamous cell carcinoma (SCC) survival. METHODS We genotyped ADH1B (rs1229984) and ALDH2 (rs671) single nucleotide polymorphisms (SNPs) in 85 Japanese male patients with hypopharyngeal SCC. The independent prognostic values of ADH1B-ALDH2 genotypes were analyzed by univariate and multivariate proportional hazard Cox regression, taking well-known clinical risk factors into account. RESULTS Heavy drinkers with ALDH2*2 allele resulted in significantly worse overall survival (OS; P = .028) and disease-free survival (DFS; P = .029) compared with other patients. Heavy drinkers with ALDH2*2 allele remained statistically significant in multivariate analysis for OS and DFS, indicating independent poor prognostic factor (hazard ratio [HR] 2.251; 95% confidence interval [CI] 1.018-4.975 and HR 2.261; 95% CI 1.021-5.006, respectively). CONCLUSION We conclude that heavy drinkers with the ALDH2*2 allele are associated with poor outcome in hypopharyngeal SCC.
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Affiliation(s)
- Mehmet Ozgur Avinçsal
- Department of Otolaryngology - Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.,Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hirotaka Shinomiya
- Department of Otolaryngology - Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masanori Teshima
- Department of Otolaryngology - Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mie Kubo
- Department of Otolaryngology - Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Naoki Otsuki
- Department of Otolaryngology - Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Naomi Kyota
- Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ryohei Sasaki
- Department of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoh Zen
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ken-Ichi Nibu
- Department of Otolaryngology - Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
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Yin J, Tang W, Long T, Pan H, Liu J, Lv L, Liu C, Shi Y, Zhu J, Sun Y, Shao A, Zhou Q, Ren Z, Ding G, Chen S, Liu Y, Yao J, Ding H, Yan Y, Gu H, Qian C, Wang L, Wang Q, Tan L. Association of ALDH3B2 gene polymorphism and risk factors with susceptibility of esophageal squamous cell carcinoma in a Chinese population: a case-control study involving 2,358 subjects. Oncotarget 2017; 8:110153-110165. [PMID: 29299137 PMCID: PMC5746372 DOI: 10.18632/oncotarget.22656] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 10/30/2017] [Indexed: 12/11/2022] Open
Abstract
Background Esophageal cancer (EC) is the sixth leading cause of cancer-associated death worldwide. The interaction of environmental risk factors and genetic factors might contribute to the carcinogenesis of EC synergistically. Results All seven single locus polymorphisms of ALDH3B2 were not associated with risk of ESCC as evaluated by allelic, dominant, co-dominant, recessive and Cochran-Armitage trend tests. Stratified analyses showed these SNPs were not correlated with the susceptibility of ESCC according to different age, gender, cigarette smoking and alcohol drinking status. None of the major haplotypes were related with ESCC susceptibility. Materials and Methods We conducted a hospital-based case-control study to evaluate the combined effects of environmental risk factors and the single nucleotide polymorphisms (SNPs) of ALDH3B2 gene on the development of esophageal squamous carcinoma (ESCC). A total of 1043 ESCC cases and 1315 controls were recruited for this study. Seven ALDH3B2 SNPs and four environmental factors were selected as independent variables. ALDH3B2 SNPs were determined by ligation detection reaction method. Conclusions Our study suggested that ALDH3B2 rs34589365, rs3741172, rs4646823, rs78402723, rs7947978, rs866907 and rs9787887 polymorphisms were not implicated with altered susceptibility of ESCC according to different age, gender, cigarette smoking and alcohol drinking status. Yet this conclusion needs to be verified in larger studies among different ethnic populations with validation design, the biological function of these SNPs in carcinogenesis are subject to further investigation.
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Affiliation(s)
- Jun Yin
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China.,Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
| | - Weifeng Tang
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Tao Long
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Huiwen Pan
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Jianchao Liu
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Lu Lv
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Chao Liu
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Yijun Shi
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Jingfeng Zhu
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Yangyong Sun
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Aizhong Shao
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Qiang Zhou
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Zhengbing Ren
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Guowen Ding
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Suocheng Chen
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Yan Liu
- Genesky Biotechnologies Inc., Shanghai, 201315, China
| | - Jun Yao
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Hao Ding
- Department of Respirology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Yulan Yan
- Department of Respirology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Haiyong Gu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, China
| | - Cheng Qian
- Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
| | - Liming Wang
- Cancer Institute, Department of Chemotherapy, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China
| | - Qun Wang
- Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
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Jiang Y, Zhang J, Wu Y, Wang J, Li L. Association between ALDH2 rs671 G>A polymorphism and gastric cancer susceptibility in Eastern Asia. Oncotarget 2017; 8:102401-102412. [PMID: 29254255 PMCID: PMC5731965 DOI: 10.18632/oncotarget.22060] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 09/20/2017] [Indexed: 12/20/2022] Open
Abstract
To date, the relationship between the aldehyde dehydrogenases-2 (ALDH2) rs671 G>A (Glu504Lys) polymorphism and gastric cancer (GC) risk has not been thoroughly elucidated. To derive a more precise estimation of the effect of the ALDH2 rs671 G>A polymorphism on GC, we conducted this meta-analysis. We searched for qualified studies in the Embase, PubMed, Wang Fan and China National Knowledge Infrastructure databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association. A total of 6,421 GC patients and 8,832 control subjects were included in the present study. The pooled results indicated no significant relationship between the ALDH2 rs671 G>A polymorphism and GC susceptibility in all genetic models. A stratified analysis by country showed that the ALDH2 rs671 G>A polymorphism might be a risk factor for GC in Japan (Allele model: Punadjusted = 0.034; Dominant model: Punadjusted = 0.040); however, the result was nonsignificant when the Bonferroni correction and false discovery rate (FDR) were applied. In subgroup analyses by drinking status in the dominant model, our study revealed that the ALDH2 rs671 G>A polymorphism significantly increased the risk of GC for drinkers (dominant model: P < 0.001). No relationship between the ALDH2 rs671 G>A polymorphism and GC risk was observed in any other subgroup. Our present study indicated no association between the ALDH2 rs671 G>A polymorphism and GC risk in Eastern Asian populations. However, the ALDH2 rs671 G>A polymorphism can significantly increase GC risk for drinkers.
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Affiliation(s)
- You Jiang
- Department of General Surgery, Hefei Second People's Hospital, Anhui Medical University, Hefei, Anhui, 230011, China
| | - Jun Zhang
- Department of General Surgery, Hefei Second People's Hospital, Anhui Medical University, Hefei, Anhui, 230011, China
| | - Yuee Wu
- Department of Electrocardiogram Diagnosis, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230060, China
| | - Jian Wang
- Department of Pathology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230022, China
| | - Liang Li
- Department of General Surgery, Hefei Second People's Hospital, Anhui Medical University, Hefei, Anhui, 230011, China
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48
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Matejcic M, Gunter MJ, Ferrari P. Alcohol metabolism and oesophageal cancer: a systematic review of the evidence. Carcinogenesis 2017. [PMID: 28645180 DOI: 10.1093/carcin/bgx067] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alcohol is a major risk factor for oesophageal squamous cell carcinoma (OSCC), the most prevalent histological subtype of oesophageal cancer (OC) worldwide. The metabolism of alcohol is regulated by specific enzymes whose activity and expression is influenced by genetic polymorphisms. We conducted a systematic review of current epidemiological evidence of the relationship between alcohol intake and OC risk, including the role of tobacco smoking and functional polymorphisms of alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). Potential biological mechanisms underlying oesophageal carcinogenesis are also discussed. Frequency and intensity of alcohol intake have been consistently associated with an increased risk of OSCC in regions with low and high incidence of the disease. The highest risk was reported among tobacco smokers, whereas the association between alcohol and OSCC risk was weak in the absence of tobacco use. The ADH1B, ADH1C and ALDH2 gene polymorphisms influence the risk of OSCC through modulation of acetaldehyde metabolism and propensity to alcohol intake. These functional variants may be suitable proxies of alcohol exposure for use in Mendelian randomization studies if complemented by reported alcohol intake data. Recent epidemiological and experimental studies investigating the role of alcohol consumption in OC development have implicated the microbiome as a new promising avenue for research, which entail novel potential mechanisms of alcohol-related oesophageal carcinogenesis. Microbial communities associated with alcohol consumption might be used as biomarkers to raise the potential of intervening among susceptible individuals.
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Affiliation(s)
- Marco Matejcic
- Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization, 150 cours Albert Thomas, 69372 Lyon CEDEX 08, France
| | - Marc J Gunter
- Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization, 150 cours Albert Thomas, 69372 Lyon CEDEX 08, France
| | - Pietro Ferrari
- Nutritional Epidemiology Group, International Agency for Research on Cancer, World Health Organization, 150 cours Albert Thomas, 69372 Lyon CEDEX 08, France
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49
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He Z, Zhao TT, Xu HM, Wang ZN, Xu YY, Song YX, Ni ZR, Xu H, Yin SC, Liu XY, Miao ZF. Association between alcohol consumption and the risk of gastric cancer: a meta-analysis of prospective cohort studies. Oncotarget 2017; 8:84459-84472. [PMID: 29137439 PMCID: PMC5663611 DOI: 10.18632/oncotarget.20880] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 08/26/2017] [Indexed: 12/16/2022] Open
Abstract
Alcohol consumption is inconsistently associated with the risk of gastric cancer morbidity and mortality. The aim of this study was to systematically evaluate the association between alcohol consumption on gastric cancer risk. The PubMed, Embase, and Cochrane Library databases were searched from inception through April 2017. Prospective cohort studies evaluating the association between alcohol consumption and risk of gastric cancer which report its effect estimates with 95% confidence intervals (CIs) were included. The results summary was performed using the random-effect model. Twenty-two cohort studies involving 22,545 cases of gastric cancer and 5,820,431 participants were identified and included in our data analysis. Overall, drinking had little or no effect on gastric cancer as compared with non-drinkers. Furthermore, light and moderate alcohol consumption had no significant effect on gastric cancer risk when compared with non-drinkers. However, heavy alcohol consumption was associated with a greater risk of gastric cancer when compared with non-drinkers. The findings of the subgroup analyses indicated that light alcohol consumption was associated with a lower risk of gastric cancer in women, while heavy alcohol consumption was associated with an increased risk of gastric cancer regardless of country, gender, whether the study reported gastric cancer incidence, or whether the study adjusted for body mass index, educational attainment, or physical activity. The findings of this study suggest that light alcohol consumption might play a protective effect on gastric cancer in women, while heavy alcohol consumption is associated with a significantly increased risk of gastric cancer in all subgroups.
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Affiliation(s)
- Zheng He
- Department of Radiation Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ting-Ting Zhao
- Department of Breast Surgery, First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Hui-Mian Xu
- Department of Surgical Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Zhen-Ning Wang
- Department of Surgical Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ying-Ying Xu
- Department of Breast Surgery, First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yong-Xi Song
- Department of Surgical Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Zhong-Ran Ni
- Department of Surgical Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China.,School of Life Science, Faculty of Science, University of Technology, Sydney, Australia
| | - Hao Xu
- Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Song-Cheng Yin
- Department of Surgical Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Xing-Yu Liu
- Department of Surgical Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Zhi-Feng Miao
- Department of Surgical Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China
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50
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Molecular Mechanisms of Acetaldehyde-Mediated Carcinogenesis in Squamous Epithelium. Int J Mol Sci 2017; 18:ijms18091943. [PMID: 28891965 PMCID: PMC5618592 DOI: 10.3390/ijms18091943] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 08/29/2017] [Accepted: 09/07/2017] [Indexed: 12/19/2022] Open
Abstract
Acetaldehyde is a highly reactive compound that causes various forms of damage to DNA, including DNA adducts, single- and/or double-strand breaks (DSBs), point mutations, sister chromatid exchanges (SCEs), and DNA-DNA cross-links. Among these, DNA adducts such as N²-ethylidene-2'-deoxyguanosine, N²-ethyl-2'-deoxyguanosine, N²-propano-2'-deoxyguanosine, and N²-etheno-2'-deoxyguanosine are central to acetaldehyde-mediated DNA damage because they are associated with the induction of DNA mutations, DNA-DNA cross-links, DSBs, and SCEs. Acetaldehyde is produced endogenously by alcohol metabolism and is catalyzed by aldehyde dehydrogenase 2 (ALDH2). Alcohol consumption increases blood and salivary acetaldehyde levels, especially in individuals with ALDH2 polymorphisms, which are highly associated with the risk of squamous cell carcinomas in the upper aerodigestive tract. Based on extensive epidemiological evidence, the International Agency for Research on Cancer defined acetaldehyde associated with the consumption of alcoholic beverages as a "group 1 carcinogen" (definite carcinogen) for the esophagus and/or head and neck. In this article, we review recent advances from studies of acetaldehyde-mediated carcinogenesis in the squamous epithelium, focusing especially on acetaldehyde-mediated DNA adducts. We also give attention to research on acetaldehyde-mediated DNA repair pathways such as the Fanconi anemia pathway and refer to our studies on the prevention of acetaldehyde-mediated DNA damage.
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