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Fan Tong



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    MA27 - Novel Drugs and PDX Models (ID 931)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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      MA27.02 - Hypofractionated Radiotherapy Normalizes Tumor Vasculature in Non-Small Cell Lung Cancer Xenografts Through p-STAT3/HIF-1 Alpha Pathway (ID 14322)

      13:35 - 13:40  |  Author(s): Fan Tong

      • Abstract
      • Presentation
      • Slides

      Background

      Our study aimed to investigate specific biological effect of hypofractionated radiotherapy (HFRT) on tumor angiogenesis, when compared with conventional radiotherapy (CRT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Firstly, models of nude mice as well as dorsal skinfold window chamber (DSWC) bearing H460 and HCC827 (NSCLC cell lines) were established. Tumors suffered irradiation with doses of 0 Gy (control group), 22 Gy delivered into 11 fractions (CRT group) or 12 Gy delivered into 1 fraction (HFRT group). After irradiation, xenograft volumes were recorded every other day. At different time points after irradiation, the vasculature of DSMC was visualized by FITC-Dextran; α-SMA and CD34 immune-histochemical staining was employed to detect the micro-vessel density (MVD) and coverage rates of pericyte on tumor vessels; pimonidazole hydrochloride was used to detect hypoxia; western blotting and RT-PCR were used to detect the expression levels of p-STAT3, HIF-1α, SDF-1 and VEGFA. Then, S3I-201, the STAT3 inhibitor, was used to further verify the mechanism of the effect of HFRT on vascular normalization.

      4c3880bb027f159e801041b1021e88e8 Result

      Compared to CRT groups, the growth suppression effect of HFRT on tumor tissue was enhanced, accompanied by stronger effect on decrease in MVD, vascular normalization and improvement of tumor hypoxia. RT-PCR and western blotting exhibited that HFRT promoted the vascular normalization by activating STAT3/ HIF-1α signaling pathway.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Compared to CRT, the pathway of p-STAT3/HIF-1α and its downstream angiogenic factors (VEGFA and SDF-1) might play important roles in forming of a window-period of vascular normalization in NSCLC, which contributed to the specific biological effect of HFRT on tumor vasculature.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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: 2
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-126 - MicroRNA-330-3p Modulates Tumor Vascular Normalization After Hypofractionated Radiotherapy by Targeting p-STAT3/ HIF-1 Alpha Pathway (ID 14339)

      16:45 - 18:00  |  Author(s): Fan Tong

      • Abstract
      • Slides

      Background

      Our study aimed to explore the effect of microRNA-330-3p (miR-330-3p) on radiosensitivity of NSCLC on HFRT both in vivo and in vitro.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The miR-330-3p over-expressed H460 (H460-OE) and HCC827 (HCC827-OE) cell lines were established using lentivirus vector expressed miR-330-3p. Tumor-bearing nude mice and the dorsal skinfold window chamber (DSWC) models (divided into H460-OE, HCC827-OE, H460 and HCC827 groups) were established and received 0-Gy (control group) or 12-Gy (HFRT group) radiation respectively. At different time points after irradiation, the vasculature of DSMC was visualized by FITC-Dextran; co-immunofluorescence of α-SMA/CD34 staining was employed to detect the coverage rate of pericyte cells on tumor vessels; pimonidazole hydrochloride (PIM) was used to detect the hypoxia; Western blotting and RT-PCR were used to detect the expression levels of p-STAT3/HIF-1α/VEGFA signal pathway and downstream factors CXCL12/CXCR4. In vitro, after radiation, the colony formation assay was used to detect the radiosensitivity. The rate of apoptosis cells were detected by flow cytometry. Moreover, STAT3 inhibitor, S3I-201, was used to further verify the mechanism of miR-330-3p regulating HIF-1α and its downstream factor by Western blotting.

      4c3880bb027f159e801041b1021e88e8 Result

      The curve of relative volume-time displayed that the radiosensitivity of miR-330-3p over-expressed xenografts decreased as compared to H460 and HCC827 xenografts. HFRT-induced decrease of MVD and hypoxia, increase of pericyte coverage on tumor vasculars in H460 and HCC827 xenografs were inhibited in H460-OE and HCC827-OE xenografts (P <0.05). Colony formation assay showed that the radiosensitivities in miR-330-3p over-expressed groups decreased and the flow cytometry assay showed that after HFRT, apoptosis rate was higher in H460-OE than H460 cell lines. Western blotting and RT-PCR displayed that, both on the 7th and 14th day after HFRT, the levels of p-STAT3, HIF-1α, VEGFA and CXCL12/CXCR4 in miR-330-3p over-expressed xenografts were higher than that in HCC827 and H460 xenografts (P <0.05). The in vitro studies showed that 2-28 hours after HFRT, the expression levels of p-STAT3, HIF-1α and VEGFA in H460-OE cells was up-regulated as compared to H460 cells (P<0.05). After adding S3I-201, the levels of p-STAT3/HIF-1α could not be inhibited in H460-OE, but could be inhibited in the H460 group (P<0.05). Also compared to the HCC827 cells after HFRT, the levels of p-STAT3 in HCC827-OE group could not inhibited by S3I-201 (P<0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      miR-330-3p may decrease the HFRT-radiosensitivity of NSCLC via upregulating the p-STAT3/HIF-1α pathway and its downstream factors, VEGFA and CXCL12/CXCR4, therefore inhibiting vascular normalization effect of HFRT.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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  |  Author(s): Fan Tong

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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