DDX56 modulates post-transcriptional Wnt signaling through miRNAs and is associated with early recurrence in squamous cell lung carcinoma

Early recurrence is a major obstacle to prolonged postoperative survival in squamous cell lung carcinoma (SqCLC). The molecular mechanisms underlying early SqCLC recurrence remain unclear, and effective prognostic biomarkers for predicting early recurrence are needed. We analyzed primary tumor sampl...

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Published in:	Molecular cancer 2021-08, Vol.20 (1), p.108-108, Article 108
Main Authors:	Wu, Qingqing, Luo, Xiaoyang, Terp, Mikkel G, Li, Qingrun, Li, Yuan, Shen, Lei, Chen, Ying, Jacobsen, Kirstine, Bivona, Trever G, Chen, Haiquan, Zeng, Rong, Ditzel, Henrik J
Format:	Article
Language:	eng
Subjects:	Analysis Animals Apoptosis Biomarkers Biomarkers, Tumor Breast cancer Cancer Carcinoma Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - mortality Carcinoma, Squamous Cell - pathology Cell adhesion & migration Cell culture Cell growth Cell Line, Tumor Cell migration Cell survival DDX56 DEAD-box RNA Helicases - metabolism Derepression Development and progression Disease Models, Animal Diseases DNA microarrays Female Gene expression Gene Expression Profiling Gene Expression Regulation Gene regulation Genes Genetic aspects Genetic transcription Humans Immunohistochemistry Lung cancer Lung carcinoma Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - mortality Lung Neoplasms - pathology Male Medical prognosis Metastasis Mice MicroRNA MicroRNAs - genetics miRNA Models, Biological Molecular modelling Online databases Patients Post-transcription Prognosis Proteins Proteomics Relapse RNA Processing, Post-Transcriptional Signal transduction Squamous cell carcinoma Squamous cell lung cancer Stains & staining Stem cells Surgery Tumors West Nile virus Wnt protein Wnt Signaling Pathway Wound healing Xenografts
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Summary:	Early recurrence is a major obstacle to prolonged postoperative survival in squamous cell lung carcinoma (SqCLC). The molecular mechanisms underlying early SqCLC recurrence remain unclear, and effective prognostic biomarkers for predicting early recurrence are needed. We analyzed primary tumor samples of 20 SqCLC patients using quantitative proteomics to identify differentially-expressed proteins in patients who experienced early versus late disease recurrence. The expression and prognostic significance of DDX56 was evaluated using a SqCLC tumor tissue microarray and further verified using different online databases. We performed in vitro and in vivo experiments to obtain detailed molecular insight into the functional role of DDX56 in SqCLC. We found that DDX56 exhibited increased expression in tumors of patients who experienced early versus late disease recurrence. Increased DDX56 expression in SqCLC tumors was subsequently confirmed as an independent prognostic factor of poor recurrence-free survival in independent SqCLC cohorts. Functionally, DDX56 promotes SqCLC cell growth and migration in vitro, and xenograft tumor progression in vivo. Mechanistically, DDX56 post-transcriptionally promotes expression of multiple Wnt signaling pathway-related genes, including CTNNB1, WNT2B, and represses a subset of miRNAs, including miR-378a-3p, a known suppressor of Wnt signaling. Detailed analysis revealed that DDX56 facilitated degradation of primary miR-378a, leading to down-regulation of mature miR-378a-3p and thus derepression of the target gene WNT2B. We identified DDX56 as a novel independent prognostic biomarker that exerts its oncogenic effects through miRNA-mediated post-transcriptional regulation of Wnt signaling genes to promote early SqCLC recurrence. DDX56 may assist in identifying SqCLC patients at increased risk of early recurrence and who could benefit from Wnt signaling-targeted therapies.
ISSN:	1476-4598 1476-4598