Ninjurin1 drives lung tumor formation and progression by potentiating Wnt/[beta]-Catenin signaling through Frizzled2-LRP6 assembly

Background Cancer stem-like cells (CSCs) play a pivotal role in lung tumor formation and progression. Nerve injury-induced protein 1 (Ninjurin1, Ninj1) has been implicated in lung cancer; however, the pathological role of Ninj1 in the context of lung tumorigenesis remains largely unknown. Methods Th...

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Published in:Journal of experimental & clinical cancer research 2022-04, Vol.41 (1)
Main Authors: Hyun, Seung Yeob, Min, Hye-Young, Lee, Ho Jin, Cho, Jaebeom, Boo, Hye-Jin, Noh, Myungkyung, Jang, Hyun-Ji, Lee, Hyo-Jong, Park, Choon-Sik, Park, Jong-Sook, Shin, Young Kee, Lee, Ho-Young
Format: Article
Language:English
Subjects:
Analysis
Cell death
Development and progression
Genetic engineering
Genetic transcription
Lung cancer, Non-small cell
Medical research
Medicine, Experimental
Stem cells
Tumors
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Summary:Background Cancer stem-like cells (CSCs) play a pivotal role in lung tumor formation and progression. Nerve injury-induced protein 1 (Ninjurin1, Ninj1) has been implicated in lung cancer; however, the pathological role of Ninj1 in the context of lung tumorigenesis remains largely unknown. Methods The role of Ninj1 in the survival of non-small cell lung cancer (NSCLC) CSCs within microenvironments exhibiting hazardous conditions was assessed by utilizing patient tissues and transgenic mouse models where Ninj1 repression and oncogenic Kras.sup.G12D/+ or carcinogen-induced genetic changes were induced in putative pulmonary stem cells (SCs). Additionally, NSCLC cell lines and primary cultures of patient-derived tumors, particularly Ninj1.sup.high and Ninj1.sup.low subpopulations and those with gain- or loss-of-Ninj1 expression, and also publicly available data were all used to assess the role of Ninj1 in lung tumorigenesis. Results Ninj1 expression is elevated in various human NSCLC cell lines and tumors, and elevated expression of this protein can serve as a biomarker for poor prognosis in patients with NSCLC. Elevated Ninj1 expression in pulmonary SCs with oncogenic changes promotes lung tumor growth in mice. Ninj1.sup.high subpopulations within NSCLC cell lines, patient-derived tumors, and NSCLC cells with gain-of-Ninj1 expression exhibited CSC-associated phenotypes and significantly enhanced survival capacities in vitro and in vivo in the presence of various cell death inducers. Mechanistically, Ninj1 forms an assembly with lipoprotein receptor-related protein 6 (LRP6) through its extracellular N-terminal domain and recruits Frizzled2 (FZD2) and various downstream signaling mediators, ultimately resulting in transcriptional upregulation of target genes of the LRP6/[beta]-catenin signaling pathway. Conclusions Ninj1 may act as a driver of lung tumor formation and progression by protecting NSCLC CSCs from hostile microenvironments through ligand-independent activation of LRP6/[beta]-catenin signaling. Keywords: Ninjurin1, cancer stem cell-like subpopulation, non-small cell lung cancer, Wnt signaling
ISSN:0392-9078
DOI:10.1186/s13046-022-02323-3