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

Liang, Sheng-Kai; Hsu, Charles Ching–Hsiang; Song, Hsiang‐Lin; Huang, Yu-Chi; Kuo, Chang-Hung; Yao, Xiang; Li, Chien-Cheng; Yang, Hsuan-Chia; Hung, Yu-Ling; Chao, Sheng-Yang; Wu, Shun-Chi; Tsai, Feng-Ren; Chen, Jen‐Kun; Liao, Wei‐Neng; Cheng, Shih-Chin; Tsou, Tsui‐Chun; Wang, I‐Ching

doi:10.1038/s41388-021-01895-2

Cited by 32 publications

(24 citation statements)

References 57 publications

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“…Here, our integrative analyses identify prominent enrichment of FOXM1 binding sequences in demethylated regions coupled with the upregulation of this TF, directly caused by TP53/CDKN2A inactivation. FOXM1 is overexpressed in multiple solid tumors (60)(61)(62), and signaling downstream of this TF contributes to cancer development and progression via cross-talk with multiple cell signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Zhao

Cheng

Kalra

et al. 2022

Preprint

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Inactivation of the tumor suppressor genes TP53 and CDKN2A occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, due to a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have been incompletely characterized. Here we report the development of the first wild-type primary human GEJ organoid model, as well as a CRISPR-edited transformed GEJ organoid model. CRISPR/Cas9 engineering to inactivate TP53 and CDKN2A (TP53/CDKN2AKO) in GEJ organoids induced morphologic dysplasia as well as pro-neoplastic features in vitro and tumor formation in vivo. Notably, lipidomic profiling identified several Platelet-Activating Factors (PTAFs) among the most upregulated lipids in CRISPR-edited organoids; and importantly, PTAF/PTAFR abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) significantly blocked proliferation and other pro-neoplastic features of TP53/CDKN2AKO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts derived from Eso26, an established esophageal adenocarcinoma (EAC) cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly Forkhead Box M1 (FOXM1). Importantly, FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. In summary, we established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and discovered a potential cancer-therapeutic strategy, while providing insights into pro-neoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia.One Sentence SummaryNovel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model.Graphic Abstract

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Section: Discussionmentioning

confidence: 99%

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Zhao

Cheng

Kalra

et al. 2022

Preprint

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“…Currently, there are few studies on the biological function and clinical significance of FOXM1 in SCLC. Notably, Liang et al [ 59 ] found that FOXM1 knockout inhibited SCLC formation in mouse models through increased levels of neuroendocrine markers Ascl1 and Cgrp and decreased levels of Yap1. In addition, this study also confirmed that SCLC with high FOXM1 expression was significantly associated with reduced clinical stage, extracthoracic metastasis, and OS with shorter progression-free survival.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Biomarkers and Pathways in Small-Cell Lung Cancer Using Biological Analysis

Liu

et al. 2021

BioMed Research International

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Background. Small-cell lung cancer (SCLC) is a major cause of carcinoma-related deaths worldwide. The aim of this study was to identify the key biomarkers and pathways in SCLC using biological analysis. Methods. Key genes involved in the development of SCLC were identified by downloading three datasets from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using the GEO2R online analyzer; for the functional annotation and pathway enrichment analysis of genes, Funrich software was used. Construction of protein-to-protein interaction (PPI) networks was accomplished using the Search Tool for the Retrieval of Interacting Genes (STRING), and network visualization and module identification were performed using Cytoscape. Results. A total of 268 DEGs were ultimately obtained. The enriched functions and pathways of the upregulated DEGs included cell cycle, mitotic, and DNA replication, and the downregulated DEGs were enriched in epithelial-to-mesenchymal transition, serotonin degradation, and noradrenaline. Analysis of significant modules demonstrated that the upregulated genes are primarily concentrated in functions related to cell cycle and DNA replication. Kaplan-Meier analysis of hub genes revealed that they may promote the carcinogenesis and progression of SCLC. The result of ONCOMINE demonstrated that these 10 hub genes were significantly overexpressed in SCLC compared with normal samples. Conclusion. Identification of the molecular functions and signaling pathways of participating DEGs can deepen the current understanding of the molecular mechanisms of SCLC. The knowledge gained from this work may contribute to the development of treatment options and improve the prognosis of SCLC in the future.

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“…Inhibition of Notch signal can induce up to 10% of lung progenitor cells derived from human embryonic stem cells (hESCs) to produce PNEC and form early tumors similar to SCLC [ 141 ]. The expression of CGRP increased significantly during the carcinogenesis of PNECs [ 147 , 148 ]. Therefore, it is of great significance to explore the mechanism of high CGRP expression promoting the malignant transformation of PNECs, and it also lays a foundation for the research of tumor therapy.…”

Section: Cgrp and Tumor Stem Cellsmentioning

confidence: 99%

CGRP: A New Endogenous Cell Stemness Maintenance Molecule

Chen

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Stem cells have the ability of self-replication and multidirectional differentiation, but the mechanism of how stem cells “maintain” this ability and how to “decide” to give up this state and differentiate into cells with specific functions is still unknown. The Nobel Prize in physiology and medicine in 2021 was awarded to “temperature and tactile receptor,” which made the pain receptor TRPV1-calcitonin gene-related peptide (CGRP) pathway active again. The activation and blocking technology of CGRP has been applied to many clinical diseases. CGRP gene has complex structure and transcription process, with multiple methylation and other modification sites. It has been considered as a research hotspot and difficulty since its discovery. Drug manipulation of TRPV1 and inhibition of CGRP might improve metabolism and prolong longevity. However, whether the TRPV1-neuropeptide-CGRP pathway is directly or indirectly involved in stem cell self-replication and multidirectional differentiation is unclear. Recent studies have found that CGRP is closely related to the migration and differentiation of tumor stem cells, which may be realized by turning off or turning on the CGRP gene expression in stem cells and activating a variety of ways to regulate stem cell niches. In this study, we reviewed the advances in researches concentrated on the biological effects of CGRP as a new endogenous switching of cell stemness.

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

Cited by 32 publications

References 57 publications

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Identification of Key Biomarkers and Pathways in Small-Cell Lung Cancer Using Biological Analysis

CGRP: A New Endogenous Cell Stemness Maintenance Molecule

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