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John D Minna
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P1.03 - Biology (Not CME Accredited Session) (ID 935)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.03-13 - eIF2β, A Subunit of Translation-Initiation Factor EIF2, as a Potential Therapeutic Target for Non-Small Cell Lung Cancer (ID 11293)
16:45 - 18:00 | Author(s): John D Minna
- Abstract
Background
To identify potential therapeutic targets for non-small cell lung cancer (NSCLC), we recently performed a semi-genome wide shRNA screen in a NSCLC cell line H460 . Through this approach, we identified multiple potential targets for NSCLC (Kakumu et al. Cancer Sci, 2017). In the present study, to search for genes with more generalized potential as therapeutic targets, we did shRNA screen using the alternative NSCLC cell line H358 and combined its results with those of our previous screen.
a9ded1e5ce5d75814730bb4caaf49419 Method
19 NSCLC cell lines, two cdk4/hTERT-immortalized normal human bronchial epithelial (HBEC) cell lines and primary NHBE culture were used. A semi-genome wide shRNA screen was performed with the DECIPHER library in H358, and its results were integrated with those of our previous screen in H460. Gene silencing was done with RNA interference followed by growth and cell cycle analyses.
4c3880bb027f159e801041b1021e88e8 Result
24 genes overlapped between results of two shRNA screens in H460 and H358 and we identified these as more generalized targets. Gene-annotation enrichment analysis showed that the RNA transport pathway including three genes is one of the overrepresented pathways in the 24 genes. Among the three genes, we determined to focus on eIF2β, a subunit of translation-initiation factor EIF2 because other two genes included in the RNA transport pathway, XPO1 and RAN are well characterized therapeutic targets for human cancers including lung cancer. eIF2β protein was more abundantly expressed in all the 19 lung cancer cell lines analyzed than in NHBE used as a control. To determine the clinical relevance of eIF2β in lung cancer, we examined eIF2β mRNA expression in lung adenocarcinoma tissues using TCGA dataset. These analyses showed significantly higher expression of eIF2β mRNA in lung adenocarcinoma tissues than in normal adjacent tissues. Importantly, we found that expression of eIF2β mRNA correlated with worse prognosis in patients with lung adenocarcinoma in multiple independent datasets, suggesting its potential as a prognostic marker. Next, we examined the effects of eIF2β knockdown on the growth of the H460 and H1975. Colorimetric growth and colony formation assays showed that eIF2β knockdown in H460 and H1975 suppresses cell growth and colony formation.
8eea62084ca7e541d918e823422bd82e Conclusion
eIF2β is highly expressed in NSCLC cells, and its expression correlates with poor prognosis in patients with lung adenocarcinoma. Knockdown of eIF2β caused G1 arrest in lung cancer cell lines. These results suggest that eIF2β is a potential therapeutic target for NSCLC and that it is a prognostic marker for lung adenocarcinoma.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.03 - Biology (Not CME Accredited Session) (ID 969)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.03-14 - Downregulation of FOXM1 Inhibits Tumor Proliferation, Colony Formation and Spheroid Formation of Non-Small Cell Lung Cancer (ID 14079)
12:00 - 13:30 | Author(s): John D Minna
- Abstract
Background
Forkhead box protein M1 (FOXM1) is a member of the forkhead superfamily of transcription factors. It plays numerous critical roles in cancer development and progression, such as the regulation of G2/M transitions of cell cycle, anti-apoptosis, DNA damage repair, invasion, and drug resistance. In a pan-cancer meta-analysis of mRNA expression signatures from ~18,000 human tumors with overall survival outcomes across 39 malignancies, over expression of the FOXM1 was a major predictor of adverse outcomes and appeared anti-correlated with tumor immune cell populations (Nat Med. 2015;21(8):938-945). Thus, we examined the prognostic and biological role of FOXM1 in non-small cell lung cancer (NSCLC).
a9ded1e5ce5d75814730bb4caaf49419 Method
We examined the prognostic impact of FOXM1 expression in lung cancer patients using a genomic database (UTSW – “Lung Cancer Explorer” and KM-Plotter). We also assessed the expression of FOXM1 in NSCLC lines, and human bronchial epithelial cells (HBECs), and assessed the association between FOXM1 and cell cycle related genes in RNA-seq data. We examined the effect of the downregulation of FOXM1 on tumor proliferation and colony formation of lung adenocarcinoma cell lines by short hairpin RNA (Tet-pLKO-FOXM1-shRNA), and the effect of the downregulation of FOXM1 on tumor 3D spheroid formation in spheroid-forming cell lines using Nunclon Sphera.
4c3880bb027f159e801041b1021e88e8 Result
High FOXM1 expression correlated with poor prognosis in NSCLC patients who underwent surgical resection, especially adenocarcinoma. FOXM1 expression in lung cancer cell lines was also much higher than in HBECs. The expression level of FOXM1 was significantly correlated with cell cycle regulator genes such as CCNB1, CCNA2, and PLK1 in both tissue samples (Lung cancer explorer) and cell lines (our data). shRNA mediated reduction of FOXM1 expression significantly inhibited tumor cell proliferation and colony formation of NSCLC cells. Additionally, in the 3D spheroid formation assay, FOXM1 knockdown altered spheroid morphology.
8eea62084ca7e541d918e823422bd82e Conclusion
FOXM1 was over expressed in NSCLC compared to normal lung epithelial cells, and high tumor FOXM1 expression was prognostic of poor survival in patients with NSCLC who underwent surgical resection, especially in patients with adenocarcinoma. FOXM1 expression correlated with the expression of regulators of the G2/M transition, and functional knockdown studies demonstrate an important role in tumor proliferation, colony formation, and 3D spheroid formation. Overall, our results suggest that FOXM1 has important roles in NSCLC growth, while data from other groups using “CIBERSORT” analyses suggest a possible role for FOXM1 in tumor immune cells infiltration, collectively indicating that FOXM1 is a potential target for the treatment of lung cancer adenocarcinoma.
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