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Domenico Trombetta



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    Lunch & Poster Display session (ID 58)

    • Event: ELCC 2019
    • Type: Poster Display session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1
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      17P - REDOXI-miRNA of Keap1/Nrf2 axis in lung tumors (ID 505)

      12:30 - 13:00  |  Author(s): Domenico Trombetta

      • Abstract

      Background

      Oxidative and electrophilic changes in cellular redox balance are mainly coordinated by the Keap1/Nrf2 axis and is strongly related to tumor progression, chemo- and radio-therapy resistance of cancer cells. In lung tumors this system is constitutively activated mainly by the loss of Keap1 or gain of Nrf2 functions due to point mutations in the key interacting domains of these two proteins. Beside of genetic lesions, Keap1/Nrf2 epigenetic abnormalities, as aberrant Keap1 promoter methylation and regulation by microRNAs were reported as emerging mechanisms of deregulation. Here we investigated the contribution of miRNA machinery on the modulations of Keap1/Nrf2 activity in lung tumors by analyzing panels of NSCLC and SCLC cell lines.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We searched for candidate miRNAs interacting with Nrf2 and Keap1 by using a combination of published data and in silico analyses performed by multiple bioinformatics tools (miRTarBase for known miRNAmRNA interactions; TargetScan, MiRanda, microRNA.org, miRBase also for predicted interactions). After this preliminary analysis we selected a list of 11 miRNAs that are experimentally validated in other tumors and/or predicted to be associated to NRF2 or KEAP1 and profiled their expression levels by real-time PCR in lung cancer cell lines and tissues.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      miR-27 family (miR-27a and miR-27b) was found to be significantly downregulated in NSCLC and SCLC cell lines. Conversely, miR-200 family (miR-200a and miR-141) was found to be significantly upregulated. Afterward, the expression data for miR-27 family and miR-200a was validated on an available training set of 29 tumor/normal paired tissues from NSCLC patients. As expected, miR- 200a was significantly up-regulated (p < 0,01, t-test), whereas miR27a and miR-27b significantly downregulated (p < 0,001, t-test) in tumors compared to normal tissues.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Since the obtained results refer to currently un-investigated miRNAs related to Keap1/Nrf2 axis in lung cancer, we plan to extend our analysis and confirm their role and impact on KEAP1/NRF2 modulation by in vitro studies. Our preliminary results suggest that redoxi-miRNA in lung cancer should add a new order of complexity to the regulation of the Nrf2/ARE pathway and will need to be more deeply explored in the future.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      AIRC.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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