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Lucheng Zhu
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EP1.03 - Biology (ID 193)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.03-16 - Lysimachia Capillipes Capilliposide C Restores Radiation Sensitivity in Radiation Resistant Lung Cancer Cells by Enhancing ERRFI1 Expression (ID 810)
08:00 - 18:00 | Author(s): Lucheng Zhu
- Abstract
Background
Radiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance and local failure remain to be the major clinic problems for lung cancer patients. It is therefore crucial to find new therapeutic targets and/or drugs to enhance the effects of radiation without increasing the adverse effects. Lysimachia capillipes capilliposide C (LC-C) extracts from LC Hemsl. show anti-cancer effects both in vitro and in vivo. The purpose of this study is to investigate a potential therapeutic impact of LC-C as a radiation sensitizer in lung cancer cells.
Method
Non small cell lung cancer (NSCLC) cell line A549 was initially irradiated with a total dose of 60 Gy (3 Gy/Fx, 20 Fx, 2-3 Fx/week) to generate radiation-resistant cancer cell line A549-IR. RNA-seq analysis was used to examine the whole-transcriptome alteration in A549-IR cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of the target gene ErbB receptor feedback inhibitor 1 ( ERRFI1) on radiosensitivity of A549-IR cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blot was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of A549-IR cells in vivo.
Result
ERRFI1 was significantly up-regulated in A549-IR cells when cells were treated with LC-C (IC20=3.5 μM). With irradiation treatment, clonogenic formation decreased in the ERRFI1 overexpressed cells when comparing to the parental cells, with reduced survival fraction-2 value from 0.54±0.07 to 0.24±0.06 (p<0.01). The sensitizing enhancement ratio for LC-C was 1.667. Furthermore, ERRFI1 overexpression may enhance radiosensitivity of A549-IR cells in vitro by inducing G2/M phase arrest and inhibiting DNA damage repair. Overexpression of the ERRF11 decreased the activation of EGFR and STAT3 signaling pathways in A549-IR cells. Knocking down ERRFI1 expression in A549-IR cells attenuated the radiosensitization effect of LC-C. Moreover, in a A549-IR cells-derived xenograft model, combination treatment with LC-C (25 mg·kg−1·d−1, qod, ig) and irradiation (6Gy) dramatically enhanced tumor growth suppression comparing with LC-C or radiation alone.
Conclusion
LC-C can restore the cells' sensitivity to irradiation through regulation of ERRFI1 expression in lung cancer cells. Combination treatment of LC-C and irradiation may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a poteintal therapeutic target to improve radiosensitivity in NSCLCs.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-84 - Serumal SERPINE2 as a Potential Biomarker for Radioresistance in NSCLC (ID 349)
10:15 - 18:15 | Author(s): Lucheng Zhu
- Abstract
Background
Radioresistance is the main reason for the failure of clinical radiotherapy in lung cancer. Among the different tumors, SERPINE2 is a protein with anticoagulant properties which could promote or inhibit solid tumor growth. However, its role in the pathogenesis of lung cancer has not been determined.
Method
To get radioresistant cell lines A549R and PC9R, A549 and PC9 cells were treated with fractionated irradiation by high energy X-ray. Cell survival fractions were measured by colony formation assay. Furthermore, we performed RNA-SEQ and protein profiling to screen genes differentially expressed in the A549/A549R and PC9/PC9R cells. To elucidate the biological role of SERPINE2 in radioresistance of NSCLC, we conducted SERPINE2 gene overexpression/knockdown experiments using NSCLC cell lines. The aim of this study was to assess serum SERPINE2 concentrations in a group of 26 NSCLC patients with radiation therapy alone in one course of treatment. Blood samples were collected before treatment. Serum SERPINE2 concentration was measured using specific ELISA methods. We analyzed its prognostic significance regarding outcome analysis, as well as its potential biomarker for radiotherapy.
Result
Two radioresistant lung adenocarcinoma sublines A549R and PC9R were successfully established through dose fractionated irradiation after six months. Results of RNA-SEQ and protein profiling showed the SERPINE2 was higher in A549R and PC9R compared to that in parental cells A549/PC9. We also demonstrated that knockdown of SERPINE2 expression inhibit cell migration and invasion in A549/PC9 cell lines. And the overexpression of SERPINE2 promote cell migration and invasion in H1975/HCC827 cell lines. Knockdown of SERPINE2 expression in the A549R/PC9R by shRNA also reduced significantly cell radiation resistance.The radiobiology parameters, which including SF2, D0, Dq and α/β, were significant differences compared with non-silencing shRNA cells. According to response evaluation criteria in solid tumors, the concentrations of SERPINE2 were significantly higher in PD patients compared with SD and PR.
Conclusion
The preliminary study indicates the SERPINE2 play an important role in the radioresistance of NSCLC and implies the evaluation of SERPINE2 expression in serum may be considered as a potential biomarker in radiotherapy of NSCLC patients. Further research must be explored to clarify the function and mechanism of SERPINE2 in the radioresistance of lung cancer.
