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FOXM1 is required for small cell lung cancer tumorigenesis and associated with poor clinical prognosis

Oncogene volumeĀ 40,Ā pages 4847ā€“4858 (2021)Cite this article

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A Correction to this article was published on 12 October 2021

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Abstract

Small cell lung cancer (SCLC) continues to cause poor clinical outcomes due to limited advances in sustained treatments for rapid cancer cell proliferation and progression. The transcriptional factor Forkhead Box M1 (FOXM1) regulates cell proliferation, tumor initiation, and progression in multiple cancer types. However, its biological function and clinical significance in SCLC remain unestablished. Analysis of the Cancer Cell Line Encyclopedia and SCLC datasets in the present study disclosed significant upregulation of FOXM1 mRNA in SCLC cell lines and tissues. Gene set enrichment analysis (GSEA) revealed that FOXM1 is positively correlated with pathways regulating cell proliferation and DNA damage repair, as evident from sensitization of FOXM1-depleted SCLC cells to chemotherapy. Furthermore, Foxm1 knockout inhibited SCLC formation in the Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) mouse model associated with increased levels of neuroendocrine markers, Ascl1 and Cgrp, and decrease in Yap1. Consistently, FOXM1 depletion in NCI-H1688 SCLC cells reduced migration and enhanced apoptosis and sensitivity to cisplatin and etoposide. SCLC with high FOXM1 expression (Nā€‰=ā€‰30, 57.7%) was significantly correlated with advanced clinical stage, extrathoracic metastases, and decrease in overall survival (OS), compared with the low-FOXM1 group (7.90 vs. 12.46 months). Moreover, the high-FOXM1 group showed shorter progression-free survival after standard chemotherapy, compared with the low-FOXM1 group (3.90 vs. 8.69 months). Our collective findings support the utility of FOXM1 as a prognostic biomarker and potential molecular target for SCLC.

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Fig. 1: Analysis of FOXM1 mRNA expression in SCLC cell lines and tissues.
Fig. 2: FOXM1 is correlated with SCLC markers and other biological processes in vivo.
Fig. 3: Deletion of Foxm1 prevents small cell lung cancer tumorigenesis in Rb1fl/fl Trp53fl/fl MycLSL/LSL (RPM) mice.
Fig. 4: Increased cell proliferation and neuroendocrine marker levels of SCLC tumors in RPM mice.
Fig. 5: Depletion of FOXM1 reduces SCLC cell survival in response to cisplatin-based chemotherapy agents, cell migration, and anchorage-independent growth in soft agar.
Fig. 6: SCLC specimen staining and quantitative scoring.
Fig. 7: Kaplanā€“Meier plot of overall survival (OS) and progression-free survival (PFS) curves of SCLC patients at NTUH-HC.

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Acknowledgements

We thank all study participants and staff at NTUH-HC for their contribution to this project, Feng-Yuan Tsai (NHRI), and NHRI Laboratory Animal Center (LA-109-PP-01), and I-BEN Service (TSSI-BN-31) for technical assistance, Stephen Elledge (Harvard Medical School) for kindly providing the pInducer10-mir-RUP-PheS plasmid, Pradip Raychaudhuri (UIC) and Vladimir Kalinichenko (CCHMC) for kindly providing the Foxm1fl/fl mice. This work was supported by the National Taiwan University Hospital Hsinchu Branch research grant NTUH-HC 108-s267 (S-K L), the Ministry of Science and Technology of Taiwan grant MOST105-2628ā€Bā€007ā€003ā€MY3 and MOST109-2314-B-007-005-MY3 (I-C W), National Tsing Hua University grant 108Q2502E1, 109Q2714E1, 110Q2501E1 (I-C W), and by the Brain Research Center under the Higher Education Sprout Project, co-funded by the Ministry of Education and the Ministry of Science and Technology in Taiwan.

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  1. These authors contributed equally: Sheng-Kai Liang and Chia-Chan Hsu.

Authors and Affiliations

  1. Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, 300, Taiwan

    Sheng-Kai LiangĀ &Ā Hui-Chen Yang

  2. Institute of Biotechnology, National Tsing Hua University, Hsinchu, 300, Taiwan

    Sheng-Kai Liang,Ā Chia-Chan Hsu,Ā Yu-Chi Huang,Ā Xiang Yao,Ā Chien-Cheng Li,Ā Yu-Ling Hung,Ā Sheng-Yang ChaoĀ &Ā I-Ching Wang

  3. Department of Pathology, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan

    Hsiang-Lin SongĀ &Ā Chun-Wei Kuo

  4. Brain Research Center, National Tsing Hua University, Hsinchu, 300, Taiwan

    Yu-Chi Huang,Ā Yu-Ling HungĀ &Ā I-Ching Wang

  5. Department of Engineering and System Science, National Tsing Hua University, Hsinchu, 300, Taiwan

    Shun-Chi WuĀ &Ā Feng-Ren Tsai

  6. Institute of Biomedical Engineering & Nanomedicine, National Health Research Institutes, Zhunan, Miaoli, 350, Taiwan

    Jen-Kun ChenĀ &Ā Wei-Neng Liao

  7. School of Life Sciences, Xiamen University, Xiamen, Fujian Province, 361102, China

    Shih-Chin Cheng

  8. National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, 350, Taiwan

    Tsui-Chun Tsou

  9. Department of Life Sciences, National Tsing Hua University, Hsinchu, 300, Taiwan

    I-Ching Wang

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Supplementary Figure Legends

Fig. S1_Acquisition of the ratio of soft tissue, nodules and tumors in the lung.

Fig. S2_A panel of chest microCT images of the individual mice

Fig. S3_A representative immunohistochemistry (IHC) for semi-quantification

Fig. S4_Cgrp expression in the developing lung tumors of RPM mice

Fig. S5_Increased expression of FOXM1 stimulates mouse Cgrp promoter activity

41388_2021_1895_MOESM8_ESM.pdf

Fig. S6_The clonogenic cell survival assay for the FOXM1-depleted NCI-H1688 cells after cisplatin-based chemotherapeutic reagents treatment

Fig. S7_FOXM1 inhibitors suppressed SCLC cell survival in response to cisplatin-based chemotherapy agents

Fig. S8_FOXM1 is critical to SCLC-associated biological processes in vitro

Fig. S9_Expression of MYC, MYCN and MYCL1 are mutually exclusive in SCLC patient dataset GSE60052

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Liang, SK., Hsu, CC., Song, HL. et al. FOXM1 is required for small cell lung cancer tumorigenesis and associated with poor clinical prognosis. Oncogene 40, 4847ā€“4858 (2021). https://doi.org/10.1038/s41388-021-01895-2

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