Author of

• 17629

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  P2.03b - Poster Session with Presenters Present (ID 465)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17653

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    P2.03b-024 - microRNA-330-3p Promotes Brain Metastasis of Non-Small Cell Lung Cancer (NSCLC) by Activating MAPK/MEK/ERK Signaling Pathway (ID 5684)

    14:30 - 14:30  |  Author(s): F. Tong
    • Abstract

    Background:
    Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). MicroRNAs (miRNAs) play an essential role in the development of NSCLC. We investigated miRNAs that serve as biomarkers to differentiate NSCLC patients with and without BM, and explored the underlying mechanism.
    
    Methods:
    The significant association for BM of NSCLC was analysed by univariate and multivariable logistic regression analysis of the clinical features of NSCLC patients with BM and without BM. The effects of miR-330-3p on NSCLC cells (A549 and HCC827) were investigated using assays of cell viability, migration, invasion, cell cycle, Western blot, and a tumor xenograft and brain metastatic xenografts models. The miR-330-3p targets were identified using microarray analysis and verified by luciferase reporter assay.
    
    Results:
    Female gender (OR = 3.15，P = .003), age under 60 (OR = 4.54, P < .001), adenocarcinoma (OR = 3.57, P = .01), EGFR19 exon mutation (OR = 3.76, P = .05), N2 (OR = 8.23, P = .01) or N3 (OR = 29.38, P < .001) were highly associated with BM in NSCLC patients. The miR-330-3p was expressed at a higher level in BM+ than in BM- NSCLC serum samples, and also higher in NSCLC cell lines than the normal human bronchial epithelial cell line. Cell proliferation, migration and invasiveness of 2 representative NSCLC cell lines (A549 and HCC827) were increased by over-expressing miR-330-3p using a lentivirus carrying a sequence of miR-330-3p, and decreased by knockdown of miR-330-3p. In nude mice receiving subcutaneous A549 and HCC827 cell inoculation, tumor growth were significantly faster in mice receiving A549 and HCC827 cell permanently expressing exogenous miR-330-3p, and slower in cells permanently expressing an anti- miR-330-3p sequence. The mice receiving cancer cells stably expressing exogenous miR-330-3p injection directly into the brain almostly developed multiple metastatic foci, while developed a smaller orthotopic tumor in mice receiving injection of cells expressing an anti- miR-330-3p sequence. GRIA3 was identified as a direct target of miR-330-3p using luciferase reporter assays. Real-time PCR and Western blot confirmed that miR-330-3p downregulated GRIA3 expression. MEK inhibition suggested that GRIA3 was regulated by miR-330-3p via MAPK/MEK/ERK signaling pathway.
    
    Conclusion:
    These results support the oncogenic role of miR-330-3p in NSCLC brain metastasis, providing a rationale for miRNA-targeted therapeutic strategies.