Association of Nickel Exposure with the Occurrence of p53 and EGFR Mutations in Taiwanese Lung Cancer
博士 === 中山醫學大學 === 醫學研究所 === 103 === Occupational exposure to nickel compounds has been associated with lung cancer. The correlation of a high nickel levels with an increased risk of lung cancer has been reported in our previous case-control study. Thus, nickel exposure might participate in lung canc...
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ndltd-TW-103CSMU55340312016-09-25T04:05:11Z http://ndltd.ncl.edu.tw/handle/81583718326204595271 Association of Nickel Exposure with the Occurrence of p53 and EGFR Mutations in Taiwanese Lung Cancer 鎳暴露與台灣肺癌之p53與EGFR基因突變的相關性研究 Yu-Hu Chiou 邱育瑚 博士 中山醫學大學 醫學研究所 103 Occupational exposure to nickel compounds has been associated with lung cancer. The correlation of a high nickel levels with an increased risk of lung cancer has been reported in our previous case-control study. Thus, nickel exposure might participate in lung cancer development in Taiwan. Nickel-induced carcinogenesis has been reported to be mediated through increased benzo[a]pyrene 7,8-diol-epoxide (BPDE)-induced mutagenesis due to reduced DNA repair activity. We next examined whether nickel exposure could increase the occurrences of p53 and EGFR mutations. Lung tumors and adjacent normal lung tissues were surgically resected from 210 non-small cell lung cancer (NSCLC) patients. One hundred eighteen nine out of 210 lung tumors and adjacent normal lung tissues were enrolled to determine the nickel levels in adjacent normal lung tissues and p53 mutations in lung tumors using Graphite furnace atomic absorption spectrometry (AAS) and direct sequencing, respectively. Seventy six non-smoking patients among 210 patients were collected to evaluate the association between nickel level and EGFR mutations using inductively coupled plasma mass spectrometry (ICP-MS) and direct sequencing. The mean value of nickel levels in the study population was used as a cutoff point to divide patients into high- and low-nickel subgroup. The prevalence of p53 and EGFR mutations was significantly higher in the high-nickel subgroup than in the low-nickel subgroup, especially in female non-smokers. To determine whether nickel affected DNA repair capacity, we conducted the host cell reactivation assay in A549 and H1975 lung cancer cells and showed that the DNA repair activity was dose-dependently reduced by nickel chloride. This was associated with the elevated production of hydrogen peroxide-induced 8-oxo-deoxyguanosine (8-oxo-dG). These results suggest that nickel may increase p53 mutation occurrence risk via inhibiting DNA repair activity. SPRY2 and RECK expressions were decreased by nickel-induced miR-21 via activation of the EGFR/NF-κB signaling pathway, which promoted invasiveness in H1355 and H23 lung cancer cells, and particularly in the cells with EGFR L858R expression vector transfection. The patients’ nickel levels were associated with miR-21 expression levels. Kaplan-Meier analysis revealed poorer overall survival (OS) and shorter relapse free survival (RFS) in the high-nickel subgroup than in low-nickel subgroup. The high-nickel/high-miR-21 subgroup exhibited shorter OS and RFS periods when compared to the low-nickel/low-miR-21 subgroup. Our findings support previous epidemiological studies indicating that nickel exposure may not only contribute to cancer incidence but also promote tumor invasion in lung cancer. We therefore suggest that environmental nickel exposure in general population may contribute to tumor initiation and invasion in NSCLC. Ruey-Hong Wong Huei Lee 翁瑞宏 李 輝 2015 學位論文 ; thesis 107 zh-TW |
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博士 === 中山醫學大學 === 醫學研究所 === 103 === Occupational exposure to nickel compounds has been associated with lung cancer. The correlation of a high nickel levels with an increased risk of lung cancer has been reported in our previous case-control study. Thus, nickel exposure might participate in lung cancer development in Taiwan. Nickel-induced carcinogenesis has been reported to be mediated through increased benzo[a]pyrene 7,8-diol-epoxide (BPDE)-induced mutagenesis due to reduced DNA repair activity. We next examined whether nickel exposure could increase the occurrences of p53 and EGFR mutations. Lung tumors and adjacent normal lung tissues were surgically resected from 210 non-small cell lung cancer (NSCLC) patients. One hundred eighteen nine out of 210 lung tumors and adjacent normal lung tissues were enrolled to determine the nickel levels in adjacent normal lung tissues and p53 mutations in lung tumors using Graphite furnace atomic absorption spectrometry (AAS) and direct sequencing, respectively. Seventy six non-smoking patients among 210 patients were collected to evaluate the association between nickel level and EGFR mutations using inductively coupled plasma mass spectrometry (ICP-MS) and direct sequencing. The mean value of nickel levels in the study population was used as a cutoff point to divide patients into high- and low-nickel subgroup. The prevalence of p53 and EGFR mutations was significantly higher in the high-nickel subgroup than in the low-nickel subgroup, especially in female non-smokers. To determine whether nickel affected DNA repair capacity, we conducted the host cell reactivation assay in A549 and H1975 lung cancer cells and showed that the DNA repair activity was dose-dependently reduced by nickel chloride. This was associated with the elevated production of hydrogen peroxide-induced 8-oxo-deoxyguanosine (8-oxo-dG). These results suggest that nickel may increase p53 mutation occurrence risk via inhibiting DNA repair activity. SPRY2 and RECK expressions were decreased by nickel-induced miR-21 via activation of the EGFR/NF-κB signaling pathway, which promoted invasiveness in H1355 and H23 lung cancer cells, and particularly in the cells with EGFR L858R expression vector transfection. The patients’ nickel levels were associated with miR-21 expression levels. Kaplan-Meier analysis revealed poorer overall survival (OS) and shorter relapse free survival (RFS) in the high-nickel subgroup than in low-nickel subgroup. The high-nickel/high-miR-21 subgroup exhibited shorter OS and RFS periods when compared to the low-nickel/low-miR-21 subgroup. Our findings support previous epidemiological studies indicating that nickel exposure may not only contribute to cancer incidence but also promote tumor invasion in lung cancer. We therefore suggest that environmental nickel exposure in general population may contribute to tumor initiation and invasion in NSCLC.
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author2 |
Ruey-Hong Wong |
author_facet |
Ruey-Hong Wong Yu-Hu Chiou 邱育瑚 |
author |
Yu-Hu Chiou 邱育瑚 |
spellingShingle |
Yu-Hu Chiou 邱育瑚 Association of Nickel Exposure with the Occurrence of p53 and EGFR Mutations in Taiwanese Lung Cancer |
author_sort |
Yu-Hu Chiou |
title |
Association of Nickel Exposure with the Occurrence of p53 and EGFR Mutations in Taiwanese Lung Cancer |
title_short |
Association of Nickel Exposure with the Occurrence of p53 and EGFR Mutations in Taiwanese Lung Cancer |
title_full |
Association of Nickel Exposure with the Occurrence of p53 and EGFR Mutations in Taiwanese Lung Cancer |
title_fullStr |
Association of Nickel Exposure with the Occurrence of p53 and EGFR Mutations in Taiwanese Lung Cancer |
title_full_unstemmed |
Association of Nickel Exposure with the Occurrence of p53 and EGFR Mutations in Taiwanese Lung Cancer |
title_sort |
association of nickel exposure with the occurrence of p53 and egfr mutations in taiwanese lung cancer |
publishDate |
2015 |
url |
http://ndltd.ncl.edu.tw/handle/81583718326204595271 |
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