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Xiaorong Dong



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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-24 - MLPH Activates CDC42/PAK1 Signaling to Promote Epithelial–Mesenchymal Transition via TGF-β in Non-Small Cell Lung Cancer (ID 13838)

      16:45 - 18:00  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 Result

      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-β 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-β.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Together, our findings demonstrated that MLPH positively modulated the CDC42/PAK1 signaling pathway via TGF-β 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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