Heme Oxygenase-1 Promoter Polymorphism is Associated with Risk of Malignant Mesothelioma

Murakami, Aki; Fujimori, Yoshihiro; Yoshikawa, Yasuhiro; Yamada, Shusai; Tamura, Kazutoshi; Hirayama, Noriko; Terada, Takayuki; Kuribayashi, Kozo; Tabata, Chiharu; Fukuoka, Kazuya; Tamaoki, T; Nakano, Takashi

doi:10.1007/s00408-012-9371-2

Cited by 15 publications

(15 citation statements)

References 27 publications

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“…Several genetic studies have been carried out to assess the association between HO-1 gene polymorphism and the risk of cancer in humans [ 15 - 23 ]. It has been shown that subjects carrying the shorter (GT) repeats have lower risk in oral squamous cell carcinoma [ 15 ], lung adenocarcinoma [ 16 ], gastric adenocarcinoma [ 18 ], breast cancer [ 19 ], esophageal squamous cell carcinoma [ 21 ], and malignant mesothelioma [ 23 ]. However, some reported the higher risk for melanoma [ 17 ], gastric cancer [ 20 ], and pancreatic cancer [ 22 ] in subjects carrying the shorter repeats.…”

Section: Reviewmentioning

confidence: 99%

Heme oxygenase-1: emerging target of cancer therapy

2015

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Heme oxygenase-1 (HO-1) is a rate-limiting enzyme catalyzing oxidative degradation of cellular heme to liberate free iron, carbon monoxide (CO) and biliverdin in mammalian cells. In addition to its primary role in heme catabolism, HO-1 exhibits anti-oxidative and anti-inflammatory functions via the actions of biliverdin and CO, respectively. HO-1 is highly induced in various disease states, including cancer. Several lines of evidence have supported the implication of HO-1 in carcinogenesis and tumor progression. HO-1 deficiency in normal cells enhances DNA damage and carcinogenesis. Nevertheless, HO-1 overexpression in cancer cells promotes proliferation and survival. Moreover, HO-1 induces angiogenesis through modulating expression of angiogenic factors. Although HO-1 is an endoplasmic reticulum resident protein, HO-1 nuclear localization is evident in tumor cells of cancer tissues. It has been shown that HO-1 is susceptible to proteolytic cleavage and translocates to nucleus to facilitate tumor growth and invasion independent of its enzymatic activity. HO-1 also impacts cancer progression through modulating tumor microenvironment. This review summarizes the current understanding of the protumorigenic role of HO-1 and its potential as a molecular target for cancer therapy.

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Section: Reviewmentioning

confidence: 99%

Heme oxygenase-1: emerging target of cancer therapy

2015

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“…No association between the various single nucleotide polymorphisms of HO-1 and lung function decline could be found, nor was there any evidence that three promoter polymorphisms affected the regulation of HO-1 gene (101). In 44 asbestos-exposed subjects without mesothelioma and 78 asbestos-exposed subjects with mesothelioma, long GT repeats were significantly higher in the asbestos-exposed subjects with mesothelioma, suggesting that decreased induction of HO-1 is associated with a higher risk of malignant mesothelioma (68). In 749 French subjects aged 20-44, lung function was assessed and compared with the length of HO-1 promoter polymorphisms.…”

Section: Multiple Roles Of Ho-1 In Angiogenesis and Vascular Prolifermentioning

confidence: 99%

Heme Oxygenase in Neonatal Lung Injury and Repair

Dennery

2014

Antioxidants & Redox Signaling

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Significance: Premature and sick neonates are often exposed to high concentrations of oxygen, which results in lung injury and long-term adverse consequences. Nevertheless, neonates are more tolerant to hyperoxia than are adults. This may be, in part, explained by the high lung content of heme oxygenase-1 (HO-1), the rate-limiting enzyme in the degradation of heme and an important stress protein. The abundance of HO-1 dictates its cytoprotective and deleterious effects. Interestingly, in response to hyperoxia, lung HO-1 mRNA is not further up-regulated in neonates, suggesting that lung HO-1 gene expression is tightly regulated so as to optimize cytoprotection when faced with an oxidative stress such as hyperoxia. Recent Advances: In addition to the lack of induction of HO-1 mRNA, neonatal lung HO-1 protein is observed in the nucleus in neonatal mice exposed to hyperoxia but not in adults, which is further evidence for the developmental regulation of HO-1. Nuclear HO-1 had unique properties independent of its enzymatic activity. In addition, there has been increasing evidence that nuclear HO-1 contributes to cellular proliferation and malignant transformation in several human cancers. Critical Issues: Since HO-1 has dual effects in cytoprotection and cellular proliferation, the titration of HO-1 effects is critical to ensure beneficial actions against oxidative stress. Future Directions: Much more has to be understood about the specific roles of HO-1 so as to manipulate its abundance and/or nuclear migration to maximize the therapeutic benefit of this pleiotropic protein in the neonatal lung.

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“…Numerous studies have demonstrated that the LL genotype of the HO-1(GT)n locus may increase cancer susceptibility ( 12 , 13 , 16 , 18 , 19 , 21 ). However, the associations identified between the HO-1 polymorphisms and cancer susceptibility are inconsistent, and other studies have come to other conclusions ( 15 , 17 , 26 ).…”

Section: Discussionmentioning

confidence: 99%

“…In turn, ROS may modulate tumorigenesis by causing cell apoptosis/necrosis or an accumulation of DNA damage ( 11 ). Two loci of the HO-1 gene have been focused on when regarding its potential association with cancer, namely the (GT)n repeat length polymorphism [which according to repeat length is divided into two classes: S (short) and L (long)] and T(−413)A (rs2071746) ( 12 – 14 ); however, results so far are not conclusive. Both loci are localized on chromosome 22q12 and have been identified in the HO-1 gene promoter region ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Association between heme oxygenase-1 gene promoter polymorphisms and cancer susceptibility: A meta-analysis

et al. 2018

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Numerous studies have focused on the association between heme oxygenase-1 (HO-1) gene promoter polymorphisms and susceptibility to cancer; however, results remain ambiguous. The present systematic Human Genome Epidemiology review and meta-analysis aimed to clarify this association. A systematic search was used to assess the association of HO-1 gene polymorphisms with cancer susceptibility in the PubMed, Web of Science, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure databases, with all reviewed studies published before April 10, 2017. Review Manager 5.3 and Stata 12.0 software were used to perform the meta-analysis. A total of 14 studies were included in the analysis. Overall, no significant associations of the HO-1 (GT)n and T(−413)A polymorphisms with cancer susceptibility were identified. However, subgroup analyses by ethnicity and cancer type indicated that the LL and L-allele (LL+LS) genotypes of HO-1 (GT)n were associated with increased susceptibility to cancer compared with the SS+SL and SS genotypes in the following subgroups: East Asian [LL+LS vs. SS: odds ratio (OR)=1.51, 95% confidence interval (CI)=1.11–2.05, P=0.0003; LL vs. SS+SL: OR=1.44, 95% CI=1.04–2.01, P=0.03; LL vs. SS: OR=1.64, 95% CI=1.07–2.52, P=0.02]; squamous cell carcinoma (LL+LS vs. SS: OR=1.78, 95% CI=1.35–2.34, P<0.05; LL vs. SS+SL: OR=1.71, 95% CI=1.34–2.18, P<0.05; LL vs. SS: OR=2.26, 95% CI =1.62–3.14, P<0.05); and digestive tract cancer + East Asian (LL+LS vs. SS: OR=1.56, 95% CI=1.22–1.98, P<0.05; LL vs. SS: OR=1.80, 95% CI=1.06–3.05, P<0.05). These findings indicated that there was no association of the HO-1 (GT)n and T(−413)A polymorphisms with cancer susceptibility, while the L-allele genotypes (LL and LS) of HO-1 (GT)n may be susceptibility factors for cancer in East Asian, digestive tract cancer in East Asian and squamous cell carcinoma populations. Due to limitations of the reviewed studies, additional large-scale and refined studies are now required to confirm the present findings.

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Heme Oxygenase-1 Promoter Polymorphism is Associated with Risk of Malignant Mesothelioma

Abstract: The findings of this study suggest that long (GT)n repeats in the HO-1 gene promoter are associated with a higher risk of malignant mesothelioma in the Japanese population.

Cited by 15 publications

References 27 publications

Heme oxygenase-1: emerging target of cancer therapy

Heme oxygenase-1: emerging target of cancer therapy

Heme Oxygenase in Neonatal Lung Injury and Repair

Association between heme oxygenase-1 gene promoter polymorphisms and cancer susceptibility: A meta-analysis

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