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X. Dong



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    Poster Session (ID 8)

    • Event: ACLC 2018
    • Type: Poster Session
    • Track:
    • Presentations: 3
    • Moderators:
    • Coordinates: 11/07/2018, 00:00 - 00:00, Poster Hall
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      P095 - MicroRNA-330-3p Promotes Brain Metastasis of Non-Small Cell Lung Cancer by Activating MAPK/MEK/ERK Signaling Through GRIA3 (ID 172)

      00:00 - 00:00  |  Author(s): X. Dong

      • Abstract

      Background:
      Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with NSCLC. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. 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.


      Method:
      Logistic regression was conducted in 122 NSCLC patients (60 without BM, 62 with BM) to examine the association between miRNAs and BM. Stable over-expression and knock-down of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR). The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330-3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay.


      Results:
      High serum miR-330-3p was an independent risk for BM. Tissue miR-330-3p was also higher in subjects with BM (P=0.003). Migration and invasiveness were increased by over-expressing miR-330-3p using a lentivirus, and decreased by miR-330-3p knockdown in both cell lines. In nude mice receiving NSCLC cells, either subcutaneously or into the brain, tumor growth was faster in mice receiving cells permanently expressing exogenous miR-330-3p, and slower in cells expressing the anti-miR-330-3p sequence. Bioinformatics analysis, followed by microarray analysis of A549 cells over-expressing miR-330-3p and luciferase reporter assay suggested the glutamate receptor GRIA3 as a target of miR-330-3p. Experiments using selective kinase inhibitors suggested that GRIA3 is regulated by miR-330-3p via MAPK/MEK/ERK signaling pathway.


      Conclusion:
      miR-330-3p promotes NSCLC brain metastasis possibly in part via the MAPK/MEK/ERK pathway and GRIA3, and might be a potential target for the further research of NSCLC brain metastasis.

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      P096 - MLPH Activates CDC42/PAK1 Signaling to Promote Epithelial (ID 173)

      00:00 - 00:00  |  Author(s): X. Dong

      • Abstract

      Background:
      Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). Therefore, a better understanding of molecularmechanisms underlying NSCLC development and progression could provide helpful insights for NSCLC prevention and effective treatment. Melanophilin (MLPH) is a protein coding gene encoding a member of the exophilin subfamily of Rab effector proteins. Recently, MLPH was reported to be associated with cancers, however, to date, the role of MLPH in lung cancer has never been studied.


      Method:
      RNA-Sequencing was performed to identify differentially expressed genes- MLPH in lung tissues of NSCLC patients with and without BM, then the expression of MLPH was further examined in the serum of BM+ and BM- patients. To study the role of MLPH in the initiation and progression of NSCLC, we examined MLPH levels in NSCLC cells and tissues and analyzed the relationship between MLPH levels and patient survival. Then we knocked down MLPH in NSCLC cells. We used cell counting kit-8 assay, wound healing assay, transwell assay, flow cytometry analysis, Phalloidin staining, xenografted tumor model and brain metastasis model to determine the effects of MLPH on the proliferation, migration, invasion, EMT, tumorigenesis and brain metastasis of NSCLC. Western blot analysis was used to explore the underlying mechanism.


      Results:
      In this study, we found that MLPH was up-regulated in NSCLC tissues and cells. Patients with high levels of MLPH expression had significantly shorter survival than those with low MLPH expression. In NSCLC cell lines, shRNA-mediated depletion of MLPH inhibited the proliferation, lead to apoptosis, induced G0/G1 arrest and suppressed cell migration, invasion, EMT, tumorigenesis and brain metastasis. Mechanistically, we identified TGF-? as a key downstream effector of MLPH. More importantly, MLPH silencing attenuated CDC42/PAK1 signaling activation at least in part through the downregulation of TGF-?.


      Conclusion:
      Together, our findings demonstrated that MLPH positively modulated the CDC42/PAK1 signaling pathway via TGF-? to promote EMT and metastasis, suggesting MLPH as a potential oncogenic biomarker and a promising therapeutic target in the treatment of NSCLC and brain metastasis.

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      P097 - ctDNA Changes and TCR Diversity Associated with Clinical Outcomes Following Brain Therapy in NSCLC (ID 174)

      00:00 - 00:00  |  Author(s): X. Dong

      • Abstract

      Background:
      Radiotherapy (RT) is a highly effective anti-cancer treatment forming the standard strategies for brain metastasis in non-small cell lung cancer (NSCLC) patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity and T cell receptor (TCR) repertoire diversity. however, the genomic evolution and mechanisms of RT induced immune responses are unknown.


      Method:
      Here, we perform targeted deep sequencing of circulating tumor DNA (ctDNA) on peripheral blood samples and cerebrospinal fluid (CSF) samples collected prior to and during brain radiotherapy from 13 NSCLC patients with brain metastasis. We used a panel to identify cancer-associated gene mutations and analyze tumor mutation burden. We applied next-generation sequencing (NGS) to investigate the T-cell receptor (TCR) repertoire.


      Results:
      In this study, we showed that patients with high blood TMB (high >10 mutations/Mb) tended to benefit from brain radiotherapy both in the terms of clinical outcomes of brain lesions and lung lesions. High TMB of CSF was correlated with a favorable clinical efficacy of brain. Response to therapy indicated according to the changes of ctDNA level between baseline and 28 days post-treatment was consistent with clinical outcomes of lung lesions measured by thoracic CT. Moreover, we showed that the low overlap of TCR repertoire in paired blood samples (base to T0) was detected in patients with partial relief (PR), and high overlap of TCR repertoire was in patients with disease stable (SD). Within 24h post-therapy, a high degree of TCR overlap in peripheral blood and CSF was observed from patients with PR in lung lesions, and a low degree of TCR overlap was from patients with SD in lung lesions.


      Conclusion:
      These data demonstrated the potential of ctDNA analysis to be a sensitive tool for predicting treatment responsivity, and the level of TCR repertoire overlap correlated with clinical outcomes.