A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis

Schnepp, Robert W.; Khurana, Priya; Attiyeh, Edward F.; Raman, Pichai; Chodosh, Sara; Oldridge, Derek A.; Gagliardi, Maria; Conkrite, Karina L.; Asgharzadeh, Shahab; Seeger, Robert C.; Madison, Blair B.; Rustgi, Anil K.; Maris, John M.; Diskin, Sharon J.

doi:10.1016/j.ccell.2015.09.012

Cited by 100 publications

(95 citation statements)

References 66 publications

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“…Recently, LIN28B was identified as an oncogenic driver in high‐risk neuroblastoma 30. LIN28B–RAN–AURKA signaling was further revealed to drive neuroblastoma oncogenesis 19. We were interested in determining whether LIN28, RAN, and AURKA act as oncogenes in hepatoblastoma.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Zhang

Zhao

et al. 2018

Hepatology Communications

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Hepatoblastoma (HB) is the most common liver tumor in children. Despite recent improvements in treatment strategies, the survival of children with hepatoblastoma remains poor. In this study, we identified a novel role of microRNA‐26a‐5p (miR‐26a‐5p), lin‐28 homolog B (LIN28B), Ras‐related nuclear protein (RAN), and aurora kinase A (AURKA) in HB. The expression of LIN28B, RAN, and AURKA was significantly up‐regulated in human HB livers and cell lines. Knockdown of LIN28B and RAN by small interfering RNAs inhibited HB tumor cell proliferation and foci formation. We also elucidated miR‐26a‐5p‐mediated translational inhibition of LIN28B and AURKA in HB. Overexpression of miR‐26a‐5p markedly decreased LIN28B and AURKA 3′‐untranslated region activities and protein expression and repressed HB cell proliferation and colony formation. In contrast, re‐expression of LIN28B and AURKA rescued miR‐26a‐5p‐mediated suppression of HB cell growth and clonality. Importantly, a decreased miR‐26a‐5p expression correlated with the poor outcome of patients with HB. Conclusion: miR‐26a‐5p is a newly identified repressor of HB growth through its inhibition of the oncogenic LIN28B–RAN–AURKA pathway. (Hepatology Communications 2018;2:481‐491)

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Section: Resultsmentioning

confidence: 99%

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Zhang

Zhao

et al. 2018

Hepatology Communications

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“…Furthermore, LIN28A plays a functional role in the maintenance of the ALDH1-positive CSC population in tumors35. LIN28B also influences multiple oncogenic signaling networks in diverse cellular contexts, and is being recognized as oncogenic stem-cell factor2736. Indeed, CD166-positive tumor-initiating cells obtained from primary NSCLC tumor expressed high levels of LIN28B27.…”

Section: Discussionmentioning

confidence: 99%

Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features

Sato

Shien

Tomida

et al. 2017

Sci Rep

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MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.

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“…In p53-deficient and p53-mutant cells, these regulatory mechanisms are disrupted, and Aurora-A expression and stability are elevated. Functional genomic studies in N-Myc-amplified neuroblastoma have revealed that LIN28B RNA-binding protein promotes RAN level by directly binding to RAN mRNA and via RANBP2 by inhibiting let-7 expression, consequently facilitating Aurora-A activation and stabilization which in turn promote N-Myc stabilization (44). It was recently been reported that Aurora-A acts as a transactivating factor for hnRNPK, a known transcriptional cofactor of p53, to promote c-Myc expression and reciprocal c-Myc-mediated transactivation of Aurora-A gene in breast cancer stem-like cells (46).…”

Section: Mechanism Of Downregulation Of Aurora Kinases By P53mentioning

confidence: 99%

Functional Significance of Aurora Kinases–p53 Protein Family Interactions in Cancer

et al. 2016

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Aurora kinases play critical roles in regulating spindle assembly, chromosome segregation, and cytokinesis to ensure faithful segregation of chromosomes during mitotic cell division cycle. Molecular and cell biological studies have revealed that Aurora kinases, at physiological levels, orchestrate complex sequential cellular processes at distinct subcellular locations through functional interactions with its various substrates. Aberrant expression of Aurora kinases, on the other hand, cause defects in mitotic spindle assembly, checkpoint response activation, and chromosome segregation leading to chromosomal instability. Elevated expression of Aurora kinases correlating with chromosomal instability is frequently detected in human cancers. Recent genomic profiling of about 3000 human cancer tissue specimens to identify various oncogenic signatures in The Cancer Genome Atlas project has reported that recurrent amplification and overexpression of Aurora kinase-A characterize distinct subsets of human tumors across multiple cancer types. Besides the well-characterized canonical pathway interactions of Aurora kinases in regulating assembly of the mitotic apparatus and chromosome segregation, growing evidence also supports the notion that deregulated expression of Aurora kinases in non-canonical pathways drive transformation and genomic instability by antagonizing tumor suppressor and exacerbating oncogenic signaling through direct interactions with critical proteins. Aberrant expression of the Aurora kinases–p53 protein family signaling axes appears to be critical in the abrogation of p53 protein family mediated tumor suppressor pathways frequently deregulated during oncogenic transformation process. Recent findings reveal the existence of feedback regulatory loops in mRNA expression and protein stability of these protein families and their consequences on downstream effectors involved in diverse physiological functions, such as mitotic progression, checkpoint response pathways, as well as self-renewal and pluripotency in embryonic stem cells. While these investigations have focused on the functional consequences of Aurora kinase protein family interactions with wild-type p53 family proteins, those involving Aurora kinases and mutant p53 remain to be elucidated. This article presents a comprehensive review of studies on Aurora kinases–p53 protein family interactions along with a prospective view on the possible functional consequences of Aurora kinase–mutant p53 signaling pathways in tumor cells. Additionally, we also discuss therapeutic implications of these findings in Aurora kinases overexpressing subsets of human tumors.

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A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis

Cited by 100 publications

References 66 publications

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features

Functional Significance of Aurora Kinases–p53 Protein Family Interactions in Cancer

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