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H. Lee



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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-014 - Interaction between environmental exposure and HPV infection on developing lung cancer among Taiwanese nonsmokers (ID 2533)

      09:30 - 09:30  |  Author(s): H. Lee

      • Abstract

      Background
      Majority of investigation is focused on lung tumorigenesis in smokers, little in nonsmokers. Previously, Benzo[a]pyrene (B[a]P)-DNA adducts levels in nonsmoking female patients were higher than in nonsmoking male patients. However, p53 mutation rate in female patients did not differ from male patients. Moreover, HPV16/18 infection rate in female patients was much higher than in male patients. We therefore hypothesized that HPV infection could synergistically increased chromosomal instability (CIN) induced by B[a]P-DNA adducts and might contribute to lung tumorigenesis.

      Methods
      Herein, three HPV-positive and five HPV-negative lung cancer cells were enrolled to test the hypothesis. FISH analysis was used to determine the micronuclei formation when these cells were treated with various concentrations of B[a]P for different time-intervals.

      Results
      The efficacy of micronuclei and DNA adduct formation induced by B[a]P in HPV-positive cells were significantly higher than HPV-negative cells. Mechanistically, the micronuclei and DNA adduct formation are dependent on HPV E6 oncoprotein expression. We next questioned whether B[a]P-induced CIN enhanced by E6 could be through altering DNA repair gene expressions. The promoter hypermethylation and mRNA expression of six DNA repair genes including hMLH1, hMSH2, BRCA1, and BRCA2, and XRCC3, and XRCC5 were evaluated by MSP and real-time RT-PCR, and data indicated that XRCC3 and XRCC5 expressions in E6-positive cells were markedly lower than in E6-negative cells and the reduction of both genes was caused by promoter hypermethylation.

      Conclusion
      Collectively, the promoter hypermethylation of XRCC3 and XRCC5 induced by E6 may increase B[a]P-induced CIN and contribute to lung tumorigenesis in nonsmokers.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-033 - Subcellular localization of Nrf2 promotes tumor aggressiveness, poor outcome, and unfavorable response to chemotherapy via increased IKKβ stability in NSCLC (ID 2514)

      09:30 - 09:30  |  Author(s): H. Lee

      • Abstract

      Background
      Dysfunction of Nrf2-Keap1 interaction by Keap1 or Nrf2 mutations may promote tumor growth, drug resistance, and poor outcomes in non-small cell lung cancer (NSCLC). However, both gene mutations are uncommon in Asian patients, suggesting that a different mechanism might be involved in lung tumor progression via altering Nrf2-Keap1 pathway.

      Methods
      Two strategies—treatment of NO scavenger and a nuclear location sequence (NLS)-mutated Nrf2 expression vector transfected into Nrf2-knockdown stable clones—were used to explore whether IKKβ could be elevated by cytoplasmic Nrf2 and promotes cell invasion. The prognostic values of cytoplasmic Nrf2 and IKKβ mRNA levels in tumors from NSCLC patients were estimated by Kaplan Meier and Cox regression model.

      Results
      We showed that mutated p53 upregulated Nrf2 transcription by de-repression of Sp1 binding to the Nrf2 promoter. Interestingly, cytoplasmic Nrf2 expression was markedly increased in p53-mutated cells compared with p53 wildtype cells due to a decrease in iNOS-mediated NO production. The stability of IKKβ protein was also increased by the interaction of cytoplasmic Nrf2 with Keap1, which blocked IKKβ degradation by the Keap1-mediated proteasomal pathway. An increase in IKKβ expression due to cytoplasmic Nrf2 was responsible for soft agar growth and invasion capability. Positive cytoplasmic Nrf2 immunostaining or high IKKβ mRNA expression in tumors from NSCLC patients may predict poorer overall survival and relapse free survival. Moreover, patients with cytoplasmic Nrf2 positive tumors had unfavorable responses to cisplatin-based chemotherapy.

      Conclusion
      Cytoplasmic Nrf2 may promote tumor aggressiveness, poor outcome, and unfavorable response to chemotherapy in NSCLC.